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PREFACE ..................................................................................................................IV ANTIMICROBIAL COST AWARENESS ....................................................................VI PROCEDURES TO FOLLOW AFTER NOTIFICATION OF A POSITIVE BLOOD CULTURE....................................................................................................................... 1 Interpretation of Laboratory Reports........................................................................ 1 Management Of Patients With Positive Blood Cultures .......................................... 3 Management Of Confirmed S. Aureus Bacteraemia ............................................... 5 EVALUATION AND MANAGEMENT OF THE FEBRILE PATIENT ............................. 7 Procalcitonin Testing ............................................................................................... 7 Septicaemia............................................................................................................. 8 Neutropenic Fever In Adult Patients...................................................................... 11 Neutropenic Fever In Paediatric Patients .............................................................. 13 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN ADULT PATIENTS .. 15 CARDIOVASCULAR SYSTEM INFECTIONS .......................................................... 15 Bacterial Endocarditis............................................................................................ 15 CENTRAL NERVOUS SYSTEM INFECTIONS ...................................................... 19 Community-Acquired Meningitis In Adults............................................................. 19 Herpes Simplex Encephalitis................................................................................. 21 EAR, NOSE AND THROAT INFECTIONS ............................................................... 22 Acute Otitis Media ................................................................................................. 22 Acute Sinusitis ....................................................................................................... 23 Chronic Sinusitis.................................................................................................... 24 Pharyngitis............................................................................................................. 25 RESPIRATORY TRACT INFECTIONS..................................................................... 26 Exacerbations Of COPD And Chronic Bronchitis .................................................. 26 Pneumonia ............................................................................................................ 27 Tuberculosis .......................................................................................................... 30 Influenza ................................................................................................................ 31 GASTROINTESTINAL TRACT AND INTRA-ABDOMINAL INFECTIONS............... 32 Dental And Gingival Infections .............................................................................. 32 Acute Peritonitis..................................................................................................... 33 Cholecystitis / Cholangitis...................................................................................... 34 Acute Pancreatitis/Severe Necrotising Pancreatitis .............................................. 35 Infectious Diarrhoea .............................................................................................. 36 Antibiotic-Associated Diarrhoea ............................................................................ 37 Typhoid / Paratyphoid Fever ................................................................................. 38 Helicobacter Pylori Infection .................................................................................. 39 URINARY TRACT INFECTIONS .............................................................................. 40 Uncomplicated Acute Urinary Tract Infections ...................................................... 40 Acute Pyelonephritis Or Complicated UTI ............................................................. 41 GENITAL TRACT INFECTIONS ............................................................................... 42 Pelvic Inflammatory Disease ................................................................................. 43 Bacterial Vaginosis ................................................................................................ 44 Candidosis / Vulvo-Vaginitis .................................................................................. 45 Chlamydial Cervicitis / Urethritis............................................................................ 46 Genital Herpes Simplex......................................................................................... 47 Gonorrhoea ........................................................................................................... 48 Non-Gonococcal Urethritis .................................................................................... 49 Trichomoniasis ...................................................................................................... 50 Syphilis .................................................................................................................. 50 SKIN, MUSCLE AND BONE INFECTIONS .............................................................. 51 Osteomyelitis - Acute............................................................................................. 51
Septic Arthritis - Non Prosthetic Joint .................................................................... 52 Septic Arthritis - Prosthetic Joint............................................................................ 52 Bites And Clenched Fist Injuries............................................................................ 53 Cellulitis - Simple ................................................................................................... 54 Cellulitis - Complicating Ulcer................................................................................ 56 Necrotising Fasciitis Or Synergistic Gangrene ...................................................... 57 Mastitis / Breast Abscess ...................................................................................... 58 Wound Infections................................................................................................... 59 EYE INFECTIONS .................................................................................................... 60 Blepharitis.............................................................................................................. 60 Conjunctivitis ......................................................................................................... 61 TRAVELLERS INFECTIONS ................................................................................... 62 Malaria................................................................................................................... 62 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN PAEDIATRIC PATIENTS .................................................................................................................... 64 Cellulitis ................................................................................................................. 64 Conjunctivitis Neonatorum..................................................................................... 65 Epiglottitis .............................................................................................................. 65 Meningitis .............................................................................................................. 66 Osteomyelitis - Acute............................................................................................. 68 Otitis Media Acute .............................................................................................. 69 Periorbital / Orbital Cellulitis .................................................................................. 70 Pharyngitis............................................................................................................. 71 Pneumonia ............................................................................................................ 72 Pyelonephritis ........................................................................................................ 73 Urinary Tract Infections ......................................................................................... 74 Aminoglycoside Dosing In Children....................................................................... 75 GUIDELINES FOR EFFECTIVE USE OF ANTIMICROBIAL DRUGS ........................ 78 INFORMATION ON SELECTED ANTIMICROBIAL DRUGS.................................... 78 Antibacterial Drugs ................................................................................................ 79 Antiviral Drugs ....................................................................................................... 88 Antifungal Agents .................................................................................................. 88 DOSING, PHARMACOKINETICS AND PHARMOCODYNAMICS ........................... 91 IMPORTANT PHARMACODYNAMIC PRINCIPLES............................................. 91 AMINOGLYCOSIDES: PRINCIPLES OF USAGE AND DOSING......................... 93 Vancomycin Dosing............................................................................................... 98 Metronidazole Dosing............................................................................................ 99 Beta-Lactam Dosing ............................................................................................ 100 IMPAIRED RENAL FUNCTION .............................................................................. 101 HEPATIC INSUFFICIENCY .................................................................................... 105 OBESE PATIENTS ................................................................................................. 106 PREGNANCY AND LACTATION............................................................................ 107 Drugs In Pregnancy............................................................................................. 107 Drugs In Lactation ............................................................................................... 108 ORAL ANTIMICROBIAL THERAPY ....................................................................... 111 Switch Therapy.................................................................................................... 111 Selecting An Appropriate Oral Antimicrobial Drug............................................... 112 PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS ............................................. 114 SURGICAL PROPHYLAXIS ................................................................................... 114 ENDOCARDITIS PROPHYLAXIS........................................................................... 119 Antibiotic Regimens............................................................................................. 120 SPLENECTOMY ..................................................................................................... 121 Prevention of Severe Infections........................................................................... 121 Treatment Of Post-Splenectomy Sepsis ............................................................. 121 APPENDICES ............................................................................................................ 122 Outpatient Intravenous Therapy.............................................................................. 122 ii
Long Term IV Antibiotics ..................................................................................... 122 Short Term IV Therapy ........................................................................................ 122 Chronic/Speciality Patients Requiring IV Therapy............................................... 122 Emergency Department Cellulitis Protocol .......................................................... 122 LOCAL RESISTANCE PATTERNS TO ANTIMICROBIAL DRUGS ....................... 123 Susceptibility of Common Organisms in Blood Culture ....................................... 123 CUMULATIVE SENSITIVITY STATISTICS WAIKATO HOSPITAL 1 JAN - 31 DEC 2006 ........................................................................................................................ 125 ANTIMICROBIAL RESISTANCE IN ORGANISMS OF SPECIAL INTEREST........ 128 MRSA MANAGEMENT ........................................................................................... 131 BLOOD AND BODY FLUID EXPOSURES ............................................................. 133 NOTIFIABLE DISEASES IN NEW ZEALAND......................................................... 135 How To Notify A Notifiable Disease..................................................................... 136
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PREFACE
Role of This Guide
This booklet is intended as a guide for the initial treatment of common conditions. Always remember that an alternative therapy is available if needed and is only a phonecall or a good textbook away. In most cases, antimicrobial treatment is initiated before the causative organism is known. A major role of microbiological laboratory testing is to enable the spectrum of the antibiotic used to be narrowed with confidence. Remember that restraint in the use of all antimicrobials is the best way to ensure their continuing efficacy. This document has been developed by Waikato District Health Board (Waikato DHB) specifically for its own use. Use of this document and any reliance on the information contained therein by any third party is at their own risk. Recommendations are based on current (July 2008) international clinical practice and may sometimes differ from product registration information. This handbook has been developed in association with the Waikato Hospital clinical services and is approved for use within Waikato District Health Board.
Intranet Version
The Antimicrobial Handbook is also available from the Waikato DHB Intranet under Clinical Guidelines.
Acknowledgements
The following documents have been helpful in the production of this handbook and are gratefully acknowledged: New Zealand Pharmaceutical Schedule, Pharmac, April 2008. Principles and Practice of Infectious Diseases, Mandell, Douglas, Bennett, 6th Edition, 2004. Guide to Pathogens and Antibiotic Treatment 7th Edition, Selwyn Lang, 2004. The Sandford Guide to Antimicrobial Therapy; 37th Edition, 2007. Antibiotic Guidelines, Victorian Medical Postgraduate Foundation Inc, 13th Edition, 2006. Antimicrobial Therapy and Vaccines; Yu, Merigan, Barriere, 1st Edition, 1999. A Practical Approach to Infectious Diseases, Reese & Betts, 4th Edition, 1996.
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Tolerability:
Economically Sound:
Ecological Impact:
The choices that have been made in this handbook reflect these concepts. The aim is to provide effective first-line therapy realising that the majority of our patients will improve without needing second-line therapy.
Drug
Route
ANTIBACTERIALS Cephalosporins Cephalexin 500mg Cefaclor 250mg Cephazolin 500mg Cefotaxime 1g Cefoxitin 1g Cefuroxime axetil 500mg Cefuroxime 750mg Ceftriaxone 1g Ceftazidime 1g Cefepime 1g Penicillins Amoxycillin 500mg Amoxycillin 1g Amoxycillin/ 500mg clavulanate Amoxycillin/ 1.2g clavulanate Penicillin V 500mg Benzylpenicillin 600mg Flucloxacillin 500mg Flucloxacillin 1g Piperacillin/ 4.5g tazobactam Ticarcillin/ clavulanate Carbapenems Meropenem 3.1g
250mg q6h 250mg q8h 1g q6h 1g q8h 1g q6h 500mg q12h 750mg q8h 1g q24h 1g q8h 1g q12h
0.54 0.29 1.69 5.99 9.25 0.71 3.06 9.00 17.10 23.00
1.08 0.87 13.52 17.97 37.00 2.84 9.18 9.00 51.30 46.00
500mg q8h 1g q8h 500mg q8h 1.2g q8h 500mg q6h 600mg q6h 500mg q6h 1g q6h 4.5g q8h 3.1g q6h
0.06 2.20 0.32 2.39 0.16 0.70 0.14 1.51 37.50 18.00
0.18 6.60 0.96 7.17 0.64 2.80 0.56 6.04 112.50 72.00
1g
IV/IM
1g q8h
59.50
178.50
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Drug
Route
ANTIBACTERIALS Aminoglycosides Gentamicin 80mg Tobramycin 80mg Amikacin 500mg Glycopeptides Vancomycin 500mg Teicoplanin 400mg Macrolides Erythromycin ethylsuccinate Erythromycin lactobionate Roxithromycin Clarithromycin Azithromycin 400mg 1g 300mg 250mg 500mg
400mg q24h 400mg q24h 1g q24h 1g q12h 400mg q24h 400mg q6h 1g q6h 300mg q24h 500mg q12h 1g stat 400mg q12h 500mg q12h 200mg q12h 400mg q24h 400mg q24h 500mg q12h 500mg q12h 400mg q12h 100mg q24h 300mg q6h 600mg q8h 960mg q12h 960mg q12h 500mg q8h 500mg q8h 600mg q24h 50mg q8h 300mg q24h
0.46 4.95 15.00 6.40 107.99 0.15 6.50 0.60 0.77 7.77 0.92 0.30 9.75 2.52 13.00 3.99 2.23 0.18 0.03 0.71 19.45 0.03 6.70 2.88 16.95 110.00 0.17 0.16
2.30 19.80 30.00 25.60 107.99 0.60 26.00 0.60 3.08 15.54 1.84 0.60 19.50 2.52 13.00 7.98 4.46 0.36 0.03 5.68 58.35 0.12 26.80 17.28 50.85 110.00 0.51 0.16
Fluoroquinolones Norfloxacin 400mg Ciprofloxacin 500mg Ciprofloxacin 200mg Gatifloxacin 400mg Moxifloxacin 400mg Nitroimidazoles Metronidazole 500mg Metronidazole 500mg Metronidazole 400mg Tetracyclines Doxycycline Miscellaneous Clindamycin Clindamycin Cotrimoxazole Cotrimoxazole Fusidic acid Fusidic acid Linezolid Nitrofurantoin Trimethoprim 100mg 150mg 600mg 480mg 480mg 250mg 500mg 600mg 50mg 300mg
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Drug
Route
ANTIBACTERIALS Antituberculins Isoniazid 100mg Pyrazinamide 500mg Rifampicin 600mg ANTIFUNGALS Amphotericin Amphotericin liposomal Caspofungin Fluconazole Fluconazole Itraconazole Ketoconazole Terbinafine Voriconazole Voriconazole ANTIVIRALS Acyclovir Acyclovir Acyclovir Acyclovir Valganciclovir Ganciclovir Foscarnet 50mg 50mg 50mg 200mg 100mg 100mg 200mg 250mg 200mg 200mg
PO PO PO IV IV IV PO IV PO PO PO PO IV
300mg q24h 2000mg q24h 600mg q24h 50mg q24h 200mg q24h 50mg q24h 200mg q24h 200mg q24h 100mg q24h 200mg q24h 250mg q24h 200mg q12h 200mg q12h
0.21 0.59 3.81 27.41 345.00 577.27 22.41 31.37 2.47 1.21 1.79 51.78 207.00
0.63 2.36 3.81 27.41 1380.00 577.27 22.41 62.74 2.47 1.21 1.79 103.56 414.00
PO PO PO IV PO IV IV
200mg 5 times daily 400mg 5 times daily 800mg 5 times daily Indication dependent Indication dependent Indication dependent Indication dependent
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Most Serious Most Likely Cause Possible of Infection Cause of Infection Staph. aureus Coagulase-negative Staph (usually contaminant) Strep. pneumoniae Viridans strep group
- Clusters
Micrococcus Aerococcus Anaerobic gram- positive Coccus Group C or G Strep Strep milleri or Strep anginosus Anaerobic gram-positive coccus Erysipelothrix Bacillus sp (Aerobic spore-forming grampositive bacillus) Clostridium (Anaerobic spore-forming grampositive bacillus) Commensal Neisseria Strep pneumoniae Anaerobic gram-negative cocci Gram-negative coccobacilli e.g. Kingella, Acinetobacter sp Neisseria gonorrhoeae Pseudomonas-like organisms Stenotrophomonas maltophilia Anaerobic gramnegative bacilli e.g. Bacteroides sp Aeromonas Haemophilus Other Candida sp e.g. C. krusei, C. glabrata
GRAM-POSITIVE BACILLI
Diphtheroids (Corynebacteria or Propionibacterium acnes - both are usually contaminants). Neisseria meningitidis
GRAM-NEGATIVE COCCI
Neisseria meningitidis
- Pairs (diplococci)
GRAM-NEGATIVE BACILLI
Neisseria meningitidis E. coli-like organisms (Coliform) e.g. Klebsiella, Enterobacter, Proteus, Serratia, Yersinia Campylobacter fetus Candida albicans
Neisseria meningitidis Coliform e.g. E. coli Klebsiella, Enterobacter, Proteus, Serratia, Yersinia
- Curved
YEAST
5. Suspected Endocarditis Or Subacute PUO Associated With Any Murmur Or Embolic Symptom
(Streptococci or Staph. aureus, for patient with any abnormal valve). Visit patient within 4 hours. Check the following tests have been done: 3 sets of blood cultures, preferably from different sites. Perform a clinical review for changing murmur, decompensated heart failure, sepsis syndrome and emboli, particularly cerebral. Discuss with General Medicine of Cardiology before giving further antibiotics or arranging TTE or TOE.
6. Apparent Contaminant
(Coagulase Negative Staph or Gram-Positive Bacilli from patient who is well) Check history to rule out possible Staph. aureus disease or Listeria. Arrange repeat blood cultures to confirm.
Approach to Management
There are no local or national guidelines but there are U.S. guidelines from the Duke Medical Centre and published Australian experience of using these U.S. guidelines. There has been agreement within the Medical Unit on local guidelines for: Categorisation into treatment groups. Use of repeated blood cultures. Use of echocardiography: TTE and TOE. Antibiotic treatment and duration. A system of notification for positive SAB cultures.
Investigation
Investigation needs to be individualised. Cultures are to be repeated after 2-4 days treatment. Trans-thoracic echocardiogram (TTE) to be performed if: - Unresponsive fever. - No apparent focus of infection. - IV device and abnormal heart examination. Trans-oesophageal echocardiogram (TOE) to be performed if: - High index suspicion of endocarditis. - Abnormal TTE with findings such that endocarditis cannot be excluded. - Continuing lack of response with a normal TTE.
Categorisation
Cases are categorised into 4 groups based on: Clinical features. Response after 72 hours treatment. Results of repeated cultures at 2-4 days. Echocardiographic findings. The presence of a removable focus or prosthesis.
(2) Bacteraemia with risk factors for complications (but without any evidence of endocarditis or deep tissue infection)
One or more of: - A superficial non-removable focus of infection. - A removable IV cannula associated focus of infection with persistent signs of infection after 72 hours or positive blood cultures after 2-4 days of antibiotic treatment. - Valve abnormalities but no vegetations on echocardiography. - An indwelling prosthetic device. If one or more of these condition apply, associated infection must be excluded. If there is no apparent focus of infection, the patient should have an echocardiography and a bone scan to exclude endocarditis and osteomyelitis. Treatment duration: If associated infections have been excluded 2 weeks of IV therapy for complicated bacteraemia is acceptable.
(3) Endocarditis
Diagnosis to be based on the Duke criteria. Treatment should be 4-8 weeks for endocarditis. Mono-therapy with Flucloxacillin IV is usually acceptable if MRSA has been excluded.
Treatment
Rembember that treatment always needs to be individualised. Single agent therapy with Flucloxacillin is acceptable if a sensitive organism (MSSA) is identified. MRSA infection requires specialist input
Microbiology Input
The requesting doctor will be notified as soon as the blood culture becomes positive and the patients consultant is to be notified after confirmation of SAB with a standard letter.
Septicaemia
Principles of Therapy
Therapy must be initiated urgently as soon as blood and site cultures are taken and before septic shock and/or toxic effects become irreversible. Initial therapy should be based on the predicted source of infection and the usual susceptibility of the common pathogens until results of microbiological specimens are known. Procalcitonin testing has been introduced into Waikato Hospital to assist in the evaluation of possible sepsis.
Meningococcus has to be covered in the setting of septicaemia without obvious cause for those under the age of 40 years. Treatment Duration: Dependent on specific aetiology
DOSE 1g iv 4 hourly
There is no need to combine flucloxacillin and benzylpenicillin in this setting, as flucloxacillin has excellent activity against Group A Streptococci. 2 For patients hypersensitive to penicillin, use cephazolin 1g 8 hourly, or clindamycin 600mg 8 hourly.
If patient has significant renal impairment, i.e. creatinine clearance <0.33ml/sec, or mild penicillin allergy, use ceftriaxone 1g iv 24 hourly (instead of gentamicin and amoxycillin) together with metronidazole 500mg iv inf 12 hourly. 2 Adjust gentamicin dosing interval for renal function.
If gentamicin is contraindicated, use ceftriaxone 1 g iv 24 hourly and metronidazole 500mg iv inf 12 hourly. 2 Adjust gentamicin dosing interval for renal function. 3 If patient has mild penicillin allergy, substitute amoxycillin with cephazolin 1g iv 8 hourly. 9
If patient has significant renal impairment or mild penicillin allergy, use ceftriaxone 1g iv 24 hourly (instead of gentamicin and flucloxacillin) together with metronidazole 500mg iv 12 hourly. 2 Adjust gentamicin dosing interval for renal function.
Note: Once the infected catheter is removed, sepsis may readily resolve if caused by organisms of relatively low virulence and may not always require antimicrobial therapy, e.g. coagulase-negative Staphylococci. Patients with bacteraemia or fungaemia caused by more virulent organisms, e.g. Staphylococcus aureus or Candida sp. must be subjected to more prolonged therapy because of the possibility of subsequent development of deep-seated infections, such as endocarditis, osteomyelitis and endophthalmitis (see specific Staphylococcus aureus guidelines).
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Principles Of Therapy
All patients who become febrile whilst severely neutropenic must be assessed by medical staff within 20 minutes of the fever (as defined above) developing. Treatment is empiric. Antibiotic therapy is commenced without an isolated organism or even possible site of infection. Antibiotic choice must be broad spectrum, particularly covering gram-negative organisms, which carry a high morbidity and mortality. Currently, all antibiotics are given intravenously with a high degree of urgency. The first dose of intravenous antibiotics should be given within 30 minutes. Patients on Ward 25 at Waikato Hospital will be routinely reviewed by their consultant each day. For patients in other locations (especially at T Hospitals), the relevant haematologist or oncologist should be contacted within 24 hours of admission or commencing treatment for neutropenic fever to discuss ongoing management. After hours, or at weekends, this should be discussed with the on-call consultant.
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Tobramycin In adults this should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance as per the modified Cockcroft and Gault formula, based on an extended interval regimen (see section on aminoglycoside dosing). Beware of continuing aminoglycosides for prolonged periods of time given the complication of renal toxicity and ototoxicity which are more likely to occur with treatment durations of more than seven days.
2. Patients with Penicillin Allergy but without Anaphylaxis (Cefepime and Tobramycin)
Cefepime is a fourth generation cephalosporin with slightly broader spectrum activity than ceftazidime. The usual dose is 2 g 12 hourly IV. Cross allergy with penicillins is estimated to be less than five percent. Usually, the benefits of highly potent gram-positive cover will outweigh the possible risk of allergic reactions. Tobramycin should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance as per the Cockcroft formula, based on an extended interval regimen (see guidelines on Aminoglycoside dosing).
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Definitions
Fever: Temperature > 38.0C on two consecutive occasions within 2 hours, or >38.5C on one occasion. Neutropenia: A neutrophil count of <0.5 x 109/L
Evaluation Of Patient
Examine patient. Obtain CBC. Culture blood from all lumens for bacteria and fungi and indicate which culture bottle contains blood from which lumen. Peripheral culture should be taken if possible. Culture other sites as clinically indicated. Order CXR/urine specimens, as clinically indicated.
Risk Groups
RISK FACTORS Absolute neutrophil count Duration of neutropenia Comorbidity LOW RISK 0.1 0.5 x 109/L <7 days Nil HIGH RISK <0.1 x 109/L >7-10 days Toxic/clinical focus/ High-dose Ara-C
Treatment i)
Low Risk
First line therapy is cefepime 50 mg/kg/dose 8-12 hourly (max 4g/day) Evaluate after 48 hours. - If afebrile with negative cultures and still neutropenic, discharge home on once daily IV ceftriaxone 80 mg/kg/day (max 2g/day). This can be given by District Nurse until neutrophil and platelet counts start to increase or until absolute neutrophil count >0.5 x 109/L. - If still febrile with negative cultures, reassess and re-culture. Add tobramycin 5mg/kg/dose 24 hourly. Note: Tobramycin/Ceftriaxone is inadequate for Pseudomonas. If still febrile at 96 hours, consider consulting ID team (Auckland Starship Hospital) for reassessment and individualised therapy.
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Monitoring Levels
Vancomycin Tobramycin (8 hourly dosing) Tobramycin (daily dosing) Troughs only prior to the 4th dose. Peak after 3rd dose and trough prior to the 4th dose. Trough prior to 2nd dose refer to Aminoglycoside nomogram
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DRUG Empiric1 (a) Native Valve Benzylpenicillin and Gentamicin and Flucloxacillin
DOSE
Consult Cardiology Specialist, Infectious Disease or Microbiology regarding treatment. Once the organism in known, move to specific therapy recommendation. 2 Extended interval dosing of aminoglycosides is usually recommended in endocarditis. The exceptions are proven enterococcal infection. 3 Adjust dosing interval according to renal function. Patients should be clinically monitored for vestibular and auditory ototoxicity particularly when aminoglycoside usage extends beyond 14 days. Vestibular toxicity may be irreversible; it can occur even when drug levels are within the normal therapeutic range. Pateints should be informed and regularly asked about ataxia, dysequibibrium and loss of balance or loss of visual acuity during head movement. 4 Staphylococcus aureus is likely if aggressive disease or patient is a drug addict. 5 Modify regimens as soon as the organism and its susceptibility pattern are known. Treatment Duration: Native Valve: 4 6 weeks Short course , i.e. 2 weeks appropriate in some cases Prosthetic Valve: 4 - 6 weeks Note: Prophylactic treatment is recommended for patients with pre-existing valvular abnormalities when procedures may cause bacteraemia (See section on Surgical Prophylaxis).
Native Valve Endocarditis P2G2 or P4 P4G2 or P4 if aminoglycosides are contraindicated. P4-6, G4-6
Prosthetic Valve Endocarditis P6G2 P6G4 P6G6 Monitor blood culture and inflammatory markers during treatment.
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V4-6, G4-6
Reference: Elliot, T.S.J. et al. Guidelines for the antibiotic treatment of endocarditis in 16
adults: report of the working party of the British Society for Antimicrobial Chemotherapy JAC 2004, 54:971-981. Contact the Clinical Microbiologist or Infectious Diseases Physician for specific advice.
2. Fever
Temperature >38oC
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3. Vascular phenomena
Major arterial emboli Septic pulmonary infarcts Mycotic aneurysm Intracranial haemorrhage Conjunctival haemorrhages Janeway's lesions.
4. Immunologic phenomena
Glomerulonephritis Oslers nodes Roths spots Rheumatoid Factor
5. Microbiological evidence
Positive blood culture but does not meet a major criterion as noted above, or Serological evidence of active infection with organism consistent with IE.
3. Rejected Diagnosis
Firm alternate diagnosis explaining evidence of infective endocarditis syndrome or Resolution of infective endocarditis syndrome with antibiotic therapy for 4 days; or No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for 4 days; or Does not meet criteria for possible infective endocarditis, as above.
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Pathogens: Common: Viruses, Streptococcus pneumoniae, Neisseria meningitidis. Other: Haemophilus influenzae, Staphylococcus aureus, Listeria monocytogenes. Drug Treatment: DRUG Empiric 1 Ceftriaxone DOSE 2g iv 12 hourly for first 24 hours, then reduce to 1g iv 12 hourly (unless penicillin resistance identified) 2g iv 4 hourly
Amoxycillin 2 Pathogens Known Streptococcus pneumoniae5 Ceftriaxone or Benzylpenicillin Neisseria meningitidis Ceftriaxone
For clearance of nasopharyngeal Neisseria meningitidis 3 Rifampicin or Ceftriaxone Listeria monocytogenes Amoxycillin and Gentamicin 2g iv 4 hourly 5 mg / kg iv 4 19 250mg im single dose 600mg po 12 hourly for 2 days
Hospital acquired meningitis is commonly due to Escherichia coli or Staphylococcus aureus. An Infectious Disease consultation is recommended. 2 Add amoxycillin if at risk for infection with Listeria, which occurs mainly in pregnancy, immunosuppression, cirrhosis and those older than 60. Third generation cephalosporins are inactive in meningitis caused by L. monocytogenes and the addition of amoxycillin is required for empiric therapy. 3 Rifampicin is not required for nasal clearance if the patient has already received ceftriaxone. 4 Adjust gentamicin dosing interval according to renal function 5 Due to increasing resistance, Health Waikato policy determines that a positive CSF gram-stain suggestive of Streptococcus pneumoniae now requires treatment with both ceftriaxone and vancomycin, until sensitivity results become available. Use both agents until sensitivity results, available then reduce to benzylpenicillin or ceftriaxone alone. 6 Recent evidence suggests that early treatment with dexamethasone (starting before or with the first dose of antibiotic) may improve outcomes in some adults and children with acute bacterial meningitis. Recommendations on the initiation of steroids have yet to be developed within Waikato DHB (Aug 2008). Uncertainty still exists as to the role of dexamethasone in meningococcal meningitis.
Treatment Duration: Meningococcal disease Streptococcus pneumoniae Staphylococcus or Listeria Minimum of 3 days. 10 days. 14 days.
Prophylaxis for Hospital Staff It would be extremely unlikely that hospital staff will require prophylaxis as contacts of meningococcal disease. The Red Book states that Prophylaxis is not recommended routinely for medical personal except those who have had intimate exposure such as occurs with unprotected mouth to mouth resuscitation, intubation or suctioning before antibiotic therapy was begun.
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21
Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Streptococcus pyogenes, Moraxella catarrhalis, Staphylococcus aureus. Drug Treatment: DRUG Empiric
1
Amoxycillin
960mg po 12 hourly
500/125mg po 8 hourly
Cefaclor is no longer recommended due to the lack of efficacy for penicillin-resistant pneumococcus. Amoxycillin achieves levels in the middle ear fluid adequate to treat most infections due to S. pneumoniae with reduced susceptibility to penicillin. 2 Avoid cotrimoxazole in pregnancy. Beware with use of cotrimoxazole in the elderly. Treatment Duration: 5 days.
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Acute Sinusitis
Sinus congestion often occurs with viral infection or allergy, which require no antibacterial treatment. Antibiotic therapy should be considered when at least 3 of the following features are present: - persistent (greater than a week) mucopurulent nasal discharge - facial pain - poor response to decongestants - tenderness over the sinuses, especially unilateral maxillary tenderness - tenderness on percussion of maxillary molar and premolar teeth.
Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Moraxella catarrhalis, Staphylococcus aureus, Gram-negative bacilli, anaerobes.
Pathogens Known Beta-lactamase producing organisms or anaerobes Amoxycillin/clavulanate 500/125mg po 8 hourly Staphylococcus aureus Flucloxacillin4
1
500/125mg po 8 hourly
Cefaclor is no longer indicated due to its lack of effectiveness in penicillin-resistant pneumococcus. 2 Avoid doxycycline in both pregnancy and children. 3 Avoid cotrimoxazole in pregnancy and the elderly. 4 For treatment of patients with penicillin allergy - see Empiric treatment. Treatment Duration: At least 10 days.
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Chronic Sinusitis
Pathogens: Common: Anaerobes, Streptococci, Staphylococcus aureus. Other: Gram-negative bacilli, Pseudomonas aeruginosa. Drug Treatment: DRUG Empiric Amoxycillin/clavulanate Patients with penicillin allergy Doxycycline1, or Cotrimoxazole
2
500mg po 12 hourly
500mg po 8 hourly
Avoid doxycycline and ciprofloxacin in both pregnancy and children. Avoid cotrimoxazole in pregnancy and the elderly. 3 For treatment of patients with penicillin allergy - see Empiric treatment. Treatment Duration: At least 14 days. Note: Consider referral to the ENT Service as structural abnormalities may be present.
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Pharyngitis
Most cases of pharyngitis are caused by viral infection and therefore do not require antibiotic therapy. A bacterial cause of acute sore throat is more common in children aged 3 to 13 years (30-40%), than in children aged less then 3 years (5-10%) or adults (5-15%). The four diagnostic features suggestive of Streptococcus pyogenes infection are: - fever >38 C - tender cervical lymphadenopathy - tonsillar exudate - no cough
Pathogens: Common: Viral, Streptococcus pyogenes. Other: Corynebacterium diphtheriae, Chlamydia pneumoniae, Neisseria gonorrhoea, Mycoplasma pneumoniae. Drug Treatment: DRUG Empiric Phenoxymethylpenicillin Patients with penicillin allergy Roxithromycin Pathogens Known Streptococcus pyogenes Phenoxymethylpenicillin Other organisms, or penicillin allergy Roxithromycin Treatment Duration: 10 days. Note: Diphtheria infections require urgent referral to a Specialist. 300mg po daily 500mg po 12 hourly 500mg po 12 hourly DOSE
300mg po daily
25
DOSE
Smokers Amoxycillin/clavulanate Non Smokers Amoxycillin Patients with penicillin allergy Doxycycline2 Pathogens Known Streptococcus pneumoniae Amoxycillin 500mg po 8 hourly 100mg po 24 hourly 500mg po 8 hourly 500/125mg po 8 hourly
Empiric treatment is often used in moderate to severe exacerbations. Avoid doxycycline in pregnancy and children.
Treatment Duration: Variable depending on clinical response. Notes: Antibiotics have only been shown to be effective when all 3 cardinal symptoms of acute bacterial exacerbations are present: increased dyspnoea, increased sputum volume and sputum purulence. There is no indication for IV therapy in the treatment of chronic bronchitis. If pneumonia is diagnosed, refer to pneumonia protocol.
26
Pneumonia
Pathogens: Common: Streptococcus pneumoniae. Other: Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, Staphylococcus aureus, Moraxella catarrhalis, Klebsiella pneumoniae, Chlamydia pneumoniae.
DOSE
300mg po daily
IV therapy is usually only necessary when concerns are held regarding absorption of oral antibiotics. Treatment with atypical agents is not usually recommended in mild/moderate pneumonia
Treatment Duration: Usually 5 - 7 days depending on severity. Aspiration pneumonia 10 days Atypical pneumonia 14 days
27
Treatment Duration: 7-10 days, although most patients will change to oral therapy within 24 hours. Notes: Most patients admitted to hospital will not have severe disease by the above definition. Most patients will be able to change to oral therapy within 24 hours. If no pathogen is identified and the patient is improving, change iv amoxycillin/ clavulanate to oral amoxycillin 1g 8hrly and change IV erythromycin to oral macrolide e.g. roxithromicin 300 mg daily. CXR changes will persist despite appropriate therapy for up to eight weeks (dependent on age of patient and underlying lung condition). With increasing pneumococcal resistance, cefuroxime is no longer recommended for community acquired pneumonia. Its use may still be appropriate in patients with penicillin allergy. The new fluoroquinolone agents are not recommended for pneumonia at Waikato Hospital.
28
Aspiration Pneumonia
Drug Treatment: DRUG Amoxycillin/Clavulanate or Clindamycin Treatment Duration: 10 days. 600mg iv inf 8 hourly DOSE 1g/200mg iv 8 hourly
750mg iv 8 hourly
If methicillin-resistant, or patient has severe penicillin allergy Adjust vancomycin dosing for renal function.
Treatment Duration: Variable dependent on patient characteristics. Notes: Streptococcus pneumoniae still remains the most common cause of pneumonia and must be adequately covered by any regime chosen. If Legionella pneumophila is suspected, use high dose macrolide therapy. The addition of either ciprofloxacin or rifampicin may be used. Please seek Infectious Diseases advice. Legionella PCR can be undertaken on serum, sputum or BAL at Waikato Hospital. Although pneumococcal resistance is increasing, clinical trials suggest that amoxycillin still remains adequate treatment for pneumonia, as drug levels still exceed the MIC levels of the resistant organism (less than 5% of pneumococci show high level resistance August 2008).
29
Tuberculosis
Tuberculosis is a notifiable disease- notify to Medical Officer of Health ext 2065 Treatment of tuberculosis is a specialised area and should involve respiratory physician and public health input to ensure adequate treatment and contact tracing occurs. Liver function, serum creatinine, electrolytes, are essential blood tests that should be checked before treatment. Liver function should be monitored routinely.
Pathogen: Mycobacterium tuberculosis. Drug Treatment: Multiple antitubercular drug therapy is initiated primarily to guard against the existence and/or emergence of resistant organisms. The current recommendations are for a short course, i.e six months of therapy in pulmonary tuberculosis. Extra-pulmonary Tb often requires longer courses. This consists of an initial two months of therapy using 3 or 4 drugs, the aim of which is to obtain a rapid decrease in the number of viable organisms, followed by a further four months of therapy with 2 drugs, rifampicin and isoniazid, to eradicate any remaining organisms. The initial regimen must contain pyrazinamide for the short course to be effective. DOSE Wt <50kg, 450mg po mane for 6 months Wt 50kg, 600mg po mane for 6 months 300mg po mane for 6 months Wt <50kg, 1.5g po mane for 2 months Wt 50kg, 2g po mane for 2 months 15mg/kg po mane for 2 months, or until sensitivity results return
Four drugs are given daily in those with previous TB therapy, those from high incidence countries and those with extensive disease. i.e. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol. 2 Combination tablets of Isoniazid and Rifampicin exist in NZ Rifinah 150 (Rifampicin 150mg/Isoniazid 100mg) and Rifinah 300 (Rifampicin 300mg/Isoniazid 150mg) 3 Pyridoxine 25mg po is usually given daily while on isoniazid to prevent neurotoxicity. 4 Ethambutol (the 4th drug) can be omitted from NZ born patients without prior treatment. 5 Ethambutol is not recommended for children under 6 years. 6 Visual acuity with a Snellen chart and red-green vision should be checked prior to commencement of ethambutol and regularly throughout treatment Treatment Duration: At least 6 months Notes: Intermittent supervised therapy is often given in twice or three times week regimens and is preferred for infectious pulmonary tuberculosis. Always check dosages (Refer to Guidelines for Tuberculosis Control in NZ 1996). 30
Influenza
The typical clinical syndrome caused by Influenza virus infection is an abrupt onset of fever, myalgia and cough. Many cases are less typical, however. Most cases of Influenza like illness are caused by other agents. Influenza may mimic meningococcal disease be wary when making a clinical diagnosis Influenza usually circulates as a distinct epidemic for 4 to 6 weeks each winter. Superinfection with bacteria such as Haemophilus influenzae and Staphylococcus aureus can cause severe pneumonia and these should be covered in empiric treatment. Neuraminidase inhibitors such as oseltamivir, if administered early, reduce severity and duration of illness and reduce viral shedding and may be considered in specific circumstances. They are not currently Pharmac funded. Outbreaks can occur on hospital wards and in long-term care facilities. Nasopharyngeal swab for direct immunoflourescence is available within Waikato Hospital. This is available 6 days a week during influenza season. Sensitivity is 60-80%. Acute and convalescent serology is also available to make a retrospective diagnosis of influenza.
31
Pathogens: Common: Mixed aerobic and anaerobic oral flora. Drug Treatment: DRUG Empiric Amoxycillin/Clavulanate or Clindamycin1
1
32
Acute Peritonitis
Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. Other: Streptococcus milleri (especially in abscesses). Drug Treatment: DRUG Empiric Amoxycillin and Gentamicin and Metronidazole 500mg iv inf 12 hourly 5mg / kg iv1 1g iv 6 hourly DOSE
Patients with mild penicillin allergy or significant renal dysfunction Ceftriaxone 1g iv 24 hourly and Metronidazole
1
Treatment Duration: 5 - 10 days Notes: Consult Specialist to discuss management of patients with severe penicillin allergy. Various treatment strategies are suggested in the literature using single, dual and triple combinations. All strategies appear equally effective with the proviso that the drug regimen used has activity against Enterobacteriaceae and Bacteroides fragilis. Ceftriaxone covers the majority of Enterobacteriaceae involved in acute peritonitis. Abscesses may require longer therapy and/or drainage.
33
Cholecystitis / Cholangitis
Pathogens: Common: Enterobacteriaceae, Enterococcus. Drug Treatment: DRUG Empiric Amoxycillin and Gentamicin and Metronidazole2 500mg iv inf 12 hourly 5mg / kg iv1 1g iv 6 hourly DOSE
Patients with mild penicillin allergy or significant renal dysfunction Ceftriaxone 1g iv 24 hourly and Metronidazole
1 2
Adjust gentamicin dosing interval for renal function. Patients with simple cholecystitis may not need metronidazole unless obstruction is present.
Treatment Duration: 5 - 10 days Note: Consult Specialist to discuss management of patients with severe penicillin allergy.
34
Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. Drug Treatment: DRUG Empiric Meropenem or Ceftriaxone and Metronidazole Treatment Duration: 7 days Note: Empiric antibiotic regimens for severe necrotising pancreatitis should be administered for 7 days, following which a clinical assessment of their risks versus benefit should be undertaken. 500mg iv inf 12 hourly 1g iv 24 hourly 1g iv 8hourly DOSE
35
Infectious Diarrhoea
The first priority in management is to ensure adequate fluid and electrolyte replacement. A microbiological diagnosis was only established in 14.6% of 25,539 stools submitted to an Auckland Lab in 1999 (NZMJ 113; 224, 2000) Empiric treatment with antibiotics is not generally recommended even if a pathogen is identified. The principal aim of treatment is to achieve and maintain adequate hydration
Pathogens: Common: Campylobacter jejuni (73%). Salmonella sp (non typhi) (7%), Shigella sp (1%). Other: (<1%) Yersinia enterocolitica, Vibrio parahaemolyticus, Plesiomonas shigelloides. Drug Treatment: DRUG Pathogens Known Campylobacter jejuni 1 Usually self-limiting If antibiotic required - Erythromycin2 or Norfloxacin Salmonella species3 Usually self-limiting If antibiotic required - Ciprofloxacin4,5 Shigella species6,7 Norfloxacin8 Giardia9 Metronidazole
1
DOSE
800mg po 8 hourly 400mg po 12 hourly 500mg po 12 hourly 400mg po 12 hourly 2g po daily for 3 days
Does not require treatment as usually self-limiting. Consider therapy if high fever or bloody diarrhoea. 2 If illness is of duration >1 week, or very severe. 3 Most do not need treatment. In fact, treatment leads to an increased risk of clinical relapse. 4 If immuno-compromised, very severe illness or bacteraemia. 5 Avoid ciprofloxacin in pregnancy and childhood. 6 Of all enteric pathogens, Shigella is the one with most evidence for the effectiveness of therapy. However, mild disease may be self-limiting. 7 Amoxycillin is not recommended in treatment of Shigella infections. 8 For moderate or severe infections. 9 Giardia is a common cause of acute and sometimes persistent diarrhoea, both locally and in travellers. If treatment fails, a longer course of metronidazole is sometimes required. Treatment Duration: Variable.
36
Antibiotic-Associated Diarrhoea
Most mild cases are drug-induced and not associated with Clostridium difficile. The first step is to cease treatment with any antibiotic likely to be causing the symptoms. Most mild cases will improve upon discontinuation of antibiotics. Treat only if diarrhoea persists or antibiotic therapy must continue.
Pathogens: Common: Clostridium difficile. Other: Clostridium perfringens. Drug Treatment: DRUG Empiric Metronidazole or Vancomycin1
1
If metronidazole is inappropriate, or treatment failure occurs. In severe cases IV metronidazole can be used. IV Vancomycin is ineffective in this condition. Oral vancomycin is administered by dissolving 500mg vancomycin powder in water and measuring the appropriate amount. Flavouring syrups may be added before administration to improve palatability.
Notes: The recent emergence of resistance in enterococci makes it essential to reserve vancomycin for severe cases unresponsive to metronidazole. Relapse rate is 20% with either treatment and does not represent resistance. Spores persist in the GI tract, therefore re-treat with same agent. Treatment of asymptomatic colonisation of C. difficile is not warranted. Children under the age of 2 years are unlikely to have C. difficile-associated disease. Hospitalisation is a major risk-factor for C. difficile. This organism is highly transmissible to other patients. Fluoroquinolones are increasingly being recognised as a major risk factor for the development of C. difficile.
37
Treatment Duration: 5 - 10 days. Notes: Salmonella typhi resistance to ciprofloxacin is increasing (particularly from the Indian subcontinent and Vietnam). Susceptibility testing should be undertaken. If patient is still febrile at 5 days suspect resistance. Azithromycin and ceftriazone are alternatives.
38
39
Pathogens: Uncomplicated: Escherichia coli, Staphylococcus saprophyticus. Community Acquired: Proteus mirabilis. Drug Treatment: DRUG Empiric Trimethoprim1 If resistant to trimethoprim3 Nitrofurantoin4 or Norfloxacin1 Pathogens Known Alternatives used according to sensitivities. Enterococci Amoxycillin
1
500mg po 8 hourly
Avoid trimethoprim and norfloxacin during pregnancy. In pregnancy amoxycillin/clavulanate 500/125mg 12 hourly for 10 days, or cephalexin 500mg 12 hourly for 10 days are suitable. 2 Single dose therapies recommended for women only. 3 Trimethoprim resistance is present in less than 20% of E.coli with 50% of the women with resistant isolates responding to treatment. 4 Nitrofurantoin 50 mg 8 hourly for 10 days can be used in first or second trimester only. Treatment Duration: Single dose or 3 days (Therapies are comparable).
40
Pathogens: Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis, Gram-negative aerobes, Pseudomonas aeruginosa. Drug Treatment: DRUG Empiric Gentamicin (often single stat dose) 1 followed by Ciprofloxacin 3 or Trimethoprim 3 Pathogens Known Enterococci Amoxycillin Pseudomonas aeruginosa Tobramycin followed by Ciprofloxacin 3
1
DOSE 5mg / kg iv 2
5mg / kg iv2
Tobramycin is preferred for Pseudomonas aeruginosa infections but if patient is responding to gentamicin, there is no need to change. 2 Adjust dosing intervals of gentamicin and tobramycin for renal function. 3 Avoid trimethoprim and ciprofloxacin in pregnancy. Treatment Duration: 5 days total therapy. Use IV therapy until satisfactory clinical response, followed by oral therapy, if tolerated.
41
42
DOSE 2g iv tds 100mg po bd 100mg po bd 400mg po bd 900mg iv tds 2mg/kg loading dose iv followed by 1.5 mg/kg 8 hourly or 7mg/kg iv daily5 450mg po qds 100 mg po bd 400mg po bd
Outpatient Regimen Ceftriaxone, or 500 mg im stat Ciprofloxacin6 500 mg po stat followed by Doxycycline3 100 mg po bd and Metronidazole4 400mg po bd 1 All antibiotic regimens are evidence-based and are of similar efficacy. 2 Patients known to be allergic to one of the suggested regimens should be treated with an alternative. 3 Avoid doxycycline in pregnancy and children. 4 Metronidazole is included to improve coverage for anaerobic bacteria. Anaerobes are of relatively greater importance in patients with severe PID and metronidazole may be discontinued in those patients with mild or moderate PID who are unable to tolerate it. 5 Adjust dosing interval of gentamicin for renal function. 6 Avoid ciprofloxacin in pregnancy and children. Treatment Duration: 14 days total therapy. Intravenous therapy should be continued until 24 hours after clinical improvement and then switched to oral. 43
Bacterial Vaginosis
Pathogen: Gardnerella vaginalis. Other: Mixed anaerobes, e.g. Mobiluncus, Bacteroides, Mixed aerobes, e.g. Staphylococcus and Streptococci. Drug Treatment: DRUG Empiric Metronidazole 2g po stat or 400mg po 12 hourly for 7 days1
1
DOSE
Treatment Duration: See dosage above. Notes: G.vaginalis isolation per se should not be treated. Treatment is indicated only with Gram-stain confirmation of bacterial vaginosis symptoms e.g. malodorous vaginal discharge. Screen for all other sexually transmitted diseases. Empirical partner treatment for Gardnerella has no effect on reducing recurrence rate in women, but it may be advisable to exclude other infections e.g. non-specific urethritis in sexual partners.
44
Candidosis / Vulvo-Vaginitis
Pathogen: Candida albicans. Drug Treatment: DRUG Empiric Clotrimazole 500mg pv stat, or 100mg pv nocte for 6 nights DOSE
Recurrent infections Consider monthly therapy with: Itraconazole or Fluconazole Treatment Duration: See dosage above. Notes: Make sure diagnosis is correct. Treating the male partner does not reduce the frequency of recurrences in women; men should therefore only receive treatment if symptomatic. Exclude predisposing factors, e.g. urine dip stick for glycosuria. If frequent recurrences (>4 per year), refer to Sexual Health Clinic or combined Gynae/Skin Clinic for review. 200mg po 12 hourly for one day 150mg po stat
45
Stat treatment is possible due to the long half-life of azithromycin. Avoid doxycycline in pregnancy and children.
Treatment Duration: See dosage above. Note: Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for Chlamydia without delay i.e. without waiting for their test results, to avoid further transmission of infection.
46
960mg po 12 hourly
Treatment Duration: 5 days. Notes: Simple recurrences (secondary attacks) do not always require acyclovir tablets. Severe HSV infection (e.g. in immunocompromised patients, insulin-dependent diabetics) may require IV acyclovir. Suppressive therapy is indicated when confirmed recurrences are frequent (>6-8 per year), severe or associated with significant psychological morbidity usual dosage is 400mg po bd. Consider referral for specialist advice or counselling.
47
Gonorrhoea
Pathogen: Neisseria gonorrhoea.
Drug Treatment: DRUG Empiric Ceftriaxone and either: Doxycycline 1,2 or Azithromycin 2,3
1 2
Avoid doxycycline in pregnancy and children. The doxycycline or azithromycin is given to cover Chlamydia, which co-exists with gonorrhoea in 40-50% cases. This should be given, even if the Chlamydia test is negative, as false-negative Chlamydia tests have been reported in this situation.
Treatment Duration: See dosage above. Notes: The incidence of penicillin- resistant Neisseria gonorrhoea means that penicillin or amoxycillin should be reserved for known penicillin-sensitive strains. Ceftriaxone (500mg stat IM) is now used due to high rates of ciprofloxacin resistance. If sensitivity results are known at time of treatment Ciprofloxacin 500mg stat is an oral alternative. Pharyngeal and uncomplicated rectal gonorrhoea can be treated successfully with a single stat dose of ceftriaxone or ciprofloxacin (if the organism is sensitive). Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for gonorrhoea without delay, i.e. without waiting for their test results, to avoid further transmission of infection.
48
Non-Gonococcal Urethritis
(Non-Specific Urethritis, NSU) Pathogens: Common: Chlamydia trachomatis, Ureaplasma urealyticum. Other: Trichomonas vaginalis, Herpes simplex (less than 5% of cases of NSU) Various skin bacteria. Drug Treatment: DRUG Empiric Doxycycline1 or Azithromycin Pathogens Known Trichomonas vaginalis Metronidazole Herpes simplex Acyclovir
1
2g po stat
Treatment Duration: See dosage above. Note: Screen and treat partners as for Chlamydia infection.
49
Trichomoniasis
Trichomonas vaginalis causes vaginitis and occasionally urethritis in males.
Pathogen: Trichomonas vaginalis. Drug Treatment: DRUG Empiric Metronidazole 2g po stat for females or 400mg po bd for 7 days for male contacts DOSE
Syphilis
Pathogen: Treponema pallidum. Drug Treatment: See note below. Treatment Duration: Depending on stage of disease. Note: The management of syphilis usually requires specialist knowledge. Therefore regimens have not been included. Referral to Sexual Health Service, Health Waikato (07) 8398732 is recommended for people with reactive syphilis serology. Dr Jane Morgan, Health Waikato Specialist Sexual Health Physician is available for consultation.
50
Osteomyelitis - Acute
Pathogens: Common: Staphylococcus aureus (> 80%), Streptococci species. Other: Enterobacteriaceae, Pseudomonas aeruginosa. Drug Treatment: DRUG Empiric Flucloxacillin Patients with mild penicillin allergy Cephazolin followed by Cephalexin 2g iv 6 hourly, then 1g po 6 hourly DOSE
1g iv 6 hourly 1g po 6 hourly
Patients with severe penicillin allergy Clindamycin 450mg iv inf 8 hourly, then 450mg po 8 hourly Treatment Duration: Minimum duration of total treatment is 4 weeks in children and 6 weeks in adults. IV therapy should be given for at least 14 days in adults. Children with acute osteomyelitis can be treated with very brief IV courses (suggested by some authorities as a minimum of 3 days). Oral therapy may then be started if patient has been afebrile and clinically stable for several days. Notes: Chronic osteomyelitis diagnosis and treatment - refer Specialist. MRSA osteomyelitis - seek Infectious Diseases advice.
51
52
Pathogens: Usually multiple, including anaerobes, Staphylococcus aureus, Streptococci species, Pasteurella multocida (cats and dogs) and Eikenella corrodens (humans). Drug Treatment: DRUG Empiric Amoxycillin/clavulanate Patients with severe infection Amoxycillin/clavulanate Patients with penicillin allergy Cotrimoxazole1 and Metronidazole or Clindamycin alone 450mg iv inf 8 hourly or 450mg po 8 hourly 960mg po 12 hourly 400mg po 12 hourly 1g/200mg iv 8 hourly 500/125mg po 8 hourly DOSE
Treatment Duration: At least 5 days. Note: Severe infection or poor response to above regimens may also require surgery.
53
Compound Fractures
The patient with a compound frature should have their immune status to tetanus assessed. Prophylaxis or early treatment should be given. Pathogens: Common: Staphylococcus aureus Drug Treatment: DRUG Empiric Flucloxacillin
1
Patients with mild penicillin allergy Cephazolin followed by Cephalexin Patients with severe penicillin allergy Clindamycin 450mg iv inf 8 hourly, then 450mg po 8 hourly 500mg po 8 hourly 1g iv 8 hourly
The duration of antibiotic treatment in compound fractures should be for 1 to 3 days. If presentation is delayed (>8 hours), presumptive early treatment should be given for 5 to 7 days, but continued for longer if bone infection is established. If wound soiling or tissue damage is severe and/or devitalised tissue is present, use amoxicillin/clavulanate 1.2 gm IV 8 hourly instead of flucloxacillin..
54
Cellulitis - Simple
Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes. Drug Treatment: DRUG Empiric Flucloxacillin
1
Patients with mild penicillin allergy Cephazolin followed by Cephalexin Patients with severe penicillin allergy Clindamycin 450mg iv inf 8 hourly, then 450mg po 8 hourly 500mg po 8 hourly 1g iv 8 hourly
Pathogens Known Streptococcus pyogenes Benzylpenicillin followed by Penicillin V Staphylococcus aureus Flucloxacillin alone
1
As the distinction between Streptococcal and Staphylococcal cellulitis is often difficult on clinical grounds, empiric therapy is directed against both organisms.
Treatment Duration: Usual total duration of treatment at least 5 days, depending on response. Use IV therapy initially for severe infections. Note: There is no role for the combined usage of flucloxacillin and penicillin in any circumstance. The belief that flucloxacillin is able to cover Staphylococcus aureus and not Streptococcus pyogenes is incorrect. The MIC90 of flucloxacillin for Streptococcus pyogenes is 0.4g/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered. 55
Pathogens Common: Streptococcus pyogenes, Staphylococcus aureus, Enterobacteriaceae, Anaerobes. Drug Treatment: DRUG Empiric Amoxycillin/clavulanate alone 1g/200mg iv 8 hourly, then 500mg po 8 hourly Patients with mild penicillin allergy Cefuroxime and Metronidazole followed by Cephalexin and Metronidazole 400mg po 12 hourly 500mg po 8 hourly 500mg iv inf 8 hourly 750mg iv 8 hourly DOSE
Patients with severe penicillin allergy Gentamicin 5 mg/kg iv1 and Clindamycin
1
Treatment Duration: Minimum duration of total treatment is 10 days (longer treatment is often required). Use IV therapy initially for severe infections.
56
Pathogens: Common: Mixed aerobes and anaerobes, including Escherichia coli, Bacteroides fragilis, Streptococcus pyogenes and Staphylococcus aureus.
Drug Treatment: DRUG Empiric Benzylpenicillin and Metronidazole and Gentamicin 1,2
1
Gentamicin can be discontinued if Streptococcus pyogenes is proven to be causative agent. 2 Gentamicin can be substituted by cefuroxime if significant renal impairment exists. 3 Adjust dosing interval of gentamicin for renal function. Note: Meropenem monotherapy, or ciprofloxacin plus clindamycin, are also effective. Treatment Duration: Minimum of 10 days. Use IV therapy initially for severe infections.
57
500/125mg po 8 hourly
450mg po 8 hourly
58
Wound Infections
POST-OPERATIVE
Local measures such as surgical drainage and irrigation with sodium chloride 0.9% will usually suffice. Topical antibiotics may cause skin hypersensitivity and the emergence of resistant organisms, and are not recommended.
For more severe infections particularly where systemic symptoms are present, use:
Flucloxacillin 2g IV 6 hourly or Cephazolin 1g IV 8 hourly. If Gram-negative organisms are suspected or known to be involved, add Gentamicin 5mg/kg IV daily (adjust dose for renal function).
Episiotomy Infections
Infection of the episiotomy site is an uncommon occurrence. Overall, only 0.1% of episiotomies become infected, although this rate increases to 1% to 2% for episiotomies complicated by third- or fourth- degree extensions. Management is as per postoperative wound infections where gram-negative organisms may be involved i.e. Amoxycillin + clavulanate 500/125mg 8 hourly. Very rarely necrotising fasciitis may occur which requires surgery and management as per the necrotising fasciitis protocol.
59
EYE INFECTIONS
Blepharitis
Blepharitis is an inflammation of the lid margins. Lid hygiene is an important adjunct to antimicrobial therapy. Remove crusts with warm compresses prior to administration of eye drops or eye ointment. If in doubt about the need for antibiotics seek advice from Ophthalmology.
Pathogens: Common: Staphylococcus aureus. Drug Treatment: DRUG Empiric Chloramphenicol Eye drops 0.5% 1-2 drops in affected eyes(s) or Eye ointment 1% Applied to the affected eye(s) Patients with lid abscesses Add to empiric treatment: Flucloxacillin Treatment Duration: At least 7 days 250mg po 6 hourly 6 hourly 2-3 hourly initially DOSE
60
Conjunctivitis
Pathogens: May be mixed, including Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Group A Streptococci, Neisseria gonorrhoea, Chlamydia trachomatis, viruses. Drug Treatment: DRUG Empiric: Chloramphenicol Eye drops 0.5% 1-2 drops in both eyes or Eye ointment 1% applied to both eyes Pathogens Known Neisseria gonorrhoea 1 Ceftriaxone Chlamydia trachomatis 1 Doxycycline 2 or Azithromycin
1 2
DOSE
6 hourly
100mg po 1 gm po
Treat sexual partners for N. gonorrhoea and C. trachomatis infections. Avoid doxycycline in pregnancy and children.
61
TRAVELLERS INFECTIONS
Malaria
Malaria must be considered in any patient who has visited a malarious area and presents with a febrile illness. Thick and thin blood films together with a blood sample collected into an EDTA tube should be sent to the laboratory for examination. A single negative blood film does not exclude the diagnosis of malaria, particularly if antimalarials or antibiotics have been taken recently. The Waikato Hospital laboratory also uses a antigen card test which is extremely sensitive for Plasmodium falciparum. Therapy depends on the species of Plasmodium and on the clinical severity. All patients with Plasmodium falciparum should be admitted for the first 24 hours of treatment due to the rapid deterioration that may occur. Patients with Plasmodium vivax do not need to be admitted but follow-up is necessary.
Pathogens: Common: Plasmodium falciparum, Plasmodium vivax. Other: Plasmodium ovale, Plasmodium malariae. Drug Treatment: DRUG Empiric
1
DOSE
Pathogens Known Plasmodium falciparum - severe 2,9 Quinine dihydrochloride 20mg/kg iv over 4 hours as loading dose in 300ml 5% dextrose 3,4 , then 10mg/kg infusion over 2-4 hours every 8 hours. (Maximum 1800mg/day or 600mg/day in renal failure. When clinically improved, complete treatment with an oral regimen (see below).
Plasmodium falciparum uncomplicated5 Quinine sulphate and Doxycycline 4 Plasmodium vivax Chloroquine sulphate6 or Hydroxychloroquine and Primaquine 7,8 600mg (450mg for adults <50kg) po 8 hourly for 7 days 100mg po 12 hourly for 7 days
800mg stat po, followed by 400mg po 6 hours later, then 400mg po on days 2 and 3. 15mg po, daily with food for 2 weeks 62
1 2
Usually not required as species usually apparent from blood film. Severe: i.e. altered consciousness, jaundice, oliguria, severe anaemia, >2% of RBC parasitized, vomiting or acidotic. 3 No loading dose is given if the patient has received quinine, quinidine or mefloquine in the previous 48 hours. 4 Avoid doxycycline in pregnancy and children. 5 Malarone [Atovaquone/proguanil (250mg/100mg)] 4 tablets daily for 3 days in adults can be used in patients who are mildly unwell (low fever and low parasitaemia) if they did not take this medication as prophylaxis. 6 Chloroquine sulphate 200mg and hydroxychloroquine sulphate 200mg are equivalent to 150mg of chloroquine base. 7 For Plasmodium vivax infection from South-East Asia or the Pacific Islands, increase the dose to primaquine 30mg orally daily. 8 Severe haemolysis may occur with G6PD-deficient patients. 9 Artesunate 2.4 mg/kg IV on admission and repeated at 12 hours and 24 hours, then once daily until oral therapy is possible, is increasingly being used internationally in the setting of severe plasmodium falciparum infection. This drug is unregistered and is not available on-site at Waikato Hospital. It is available within Auckland hospital pharmacy department and rapid access by courier is possible. Treatment Duration: Dependent on Plasmodium species (see above).
63
Doses in this section are given in mg/kg/dose. Please note that dosage for children should never exceed the usual adult dosage.
Cellulitis
Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes. Drug Treatment: DRUG Empiric Flucloxacillin Pathogens Known Streptococcus pyogenes Benzylpenicillin followed by Penicillin V 7. 5 - 15 mg/kg/dose po 4 times daily 30 mg/kg/dose iv 6 hourly 25 mg/kg/dose iv 6 hourly DOSE
Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
64
Conjunctivitis Neonatorum
Pathogens: Common: Neisseria gonorrhoea, Chlamydia trachomatis. Other: Staphylococcus aureus, Pseudomonas aeruginosa. Drug Treatment: DRUG Empiric Ceftriaxone Pathogens Known Chlamydia trachomatis Erythromycin succinate 20 mg/kg/dose po 4 times daily for 2 weeks 30 mg/kg/dose iv 24 hourly DOSE
Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
Epiglottitis
Pathogens: Common: Haemophilus influenzae type b. Drug Treatment: DRUG Empiric Cefotaxime or Ceftriaxone 50 mg/kg/dose iv 8 hourly (max 2g per dose) 100 mg/kg/dose iv stat, then 50 mg/kg daily (max 2g daily) DOSE
Treatment Duration: 7 10 days. Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 65
Meningitis
Consider dexamexethasone 0.15mg/kg/dose 6 hourly for 16 doses, commencing one hour prior to antibiotics, if Streptococcus pneumoniae or Haemophilus influenzae suspected. Pathogens: Common: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae. Neonatal: Group B Streptococci, Escherichia coli, Listeria. Other: Staphylococcus aureus. Neonatal: Streptococci, coagulase-negative and positive Staphylococci, Klebsiella, Enterobacter, Pseudomonas. Drug Treatment: DRUG Empiric 0 - 3 Months Amoxycillin
DOSE
50-100 mg/kg/dose iv Age 1 week Age 2-4 weeks Age >4 weeks Age 1 week Age 2-4 weeks Age >4 weeks 12 hourly 8 hourly 6 hourly 12 hourly 8 hourly 6 hourly
and Cefotaxime
50 mg/kg/dose iv
Empiric: >3 Months1 Ceftriaxone 100 mg/kg/dose iv stat, then once daily (max 4g/day, 2g/dose)
50 mg/kg/dose iv
12 hourly 8 hourly
Streptococcus pneumoniae 2 Ceftriaxone 100 mg/kg/dose iv stat, then once daily (max 4g/day, 2g/dose) and Vancomycin 15mg/kg/dose iv 6 hourly (max 3g/day) Benzylpenicillin 3 Neisseria meningitidis Benzylpenicillin Haemophilus influenzae Ceftriaxone 60 mg/kg/dose iv 60 mg/kg/dose iv 4 hourly 4 hourly
66
1 2
If organisms are seen on the gram-stain, then therapy may be directed accordingly. Due to increasing resistance, Health Waikato policy determines that a positive gramstain suggestive of Streptococcus pneumoniae now requires treatment with both ceftriaxone and vancomycin, until sensitivity results become available. Use both agents until sensitivity results available, then reduce to ceftriaxone or benzylpenicillin alone. 3 For penicillin-sensitive organisms. Treatment Duration: Neonatal: Group B Streptococci Meningococcal Pneumococcal Haemophilus Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
days, or 14 days after CSF sterilisation, whichever is longer 14 - 21 days 4 days 7 - 10 days 7 - 14 days
21
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Osteomyelitis - Acute
Pathogens: Common: 0 -2 months: 2 months-2 years: >2 years:
Group B Streptococci, Staphylococcus aureus, E. coli. Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae B, Group B Streptococci. Staphylococcus aureus, Streptococci, E coli.
Other: Salmonella, anaerobes, fungi. Drug Treatment: DRUG Empiric: 0-2 months Flucloxacillin DOSE 25-50 mg/kg/dose iv Age 1 week 12 hourly Age 2-4 weeks 8 hourly Age >4 weeks 4-6 hourly 8 hourly
and Cefotaxime Empiric: >2 months Flucloxacillin and Cefotaxime Pathogens Known Staphylococcus aureus Flucloxacillin E. coli Cefotaxime H. influenzae Cefotaxime or Ceftriaxone Treatment Duration: 4-6 weeks
50 mg/kg/dose iv
25-50 mg/kg/dose iv
4-6 hourly
50 mg/kg/dose iv
8 hourly
8 hourly 24 hourly
Oral antibiotics may be commenced after 7-14 days of iv treatment, depending on clinical course. Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
68
Notes: With increasing pneumococcal resistance, cefaclor is no longer recommended, as it is active only against fully sensitive strains. Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
69
Treatment Duration: IV therapy for a minimum of 48 hrs, then continue with oral therapy. Total duration of therapy at least 7 days. Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
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Pharyngitis
Most cases of pharyngitis in preschool children are due to viral infection and do not require antibiotic treatment. Before commencing antibiotics obtain a bacterial pharyngeal throat swab. Review bacterial culture 3-4 days before deciding whether to continue antibiotics for a full 10-day course. The four diagnostic features suggestive of Streptococcus pyogenes infection are: Fever >38oC Tender cervical lymphadenopathy Tonsillar exudate No cough Pathogens: Common: Viruses, Streptococcus pyogenes. Other: Mycoplasma pneumoniae, Haemophilus influenza B, Corynebacterium diphtheriae. Drug Treatment: DRUG Empiric Penicillin V or Erythromycin Treatment Duration: 10 days. Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 10 mg/kg/dose po 6-8 hourly 15 mg/kg/dose po 3 times daily DOSE
71
Pneumonia
Most Lower Respiratory Tract infections in children are viral. Pathogens: Common: 0-3 months: 3 months:
Group B Streptococci, Staphylococcus aureus, Listeria, Chlamydia, Gram-negative bacilli. Viruses, Streptococcus pneumoniae.
Other: Streptococci, Staphylococcus aureus, Haemophilus influenzae, Mycoplasma pneumoniae, Klebsiella, Pseudomonas aeruginosa, Mycobacterium tuberculosis. Drug Treatment: DRUG Empiric: 0-3 months Amoxycillin DOSE 50 mg/kg/dose iv Age 1 week 12 hourly Age 2-4 weeks 6 hourly Age >4 weeks 3 hourly 8 hourly
2-2.5 mg/kg/dose iv
Treatment Duration: 7 days. Notes: If suspicious of Staphylococcal infections, use flucloxacillin 25 mg/kg/dose iv 6 hourly. Use erythromicin only if likely penicillin allergy, or mycoplasma pneumoniae infection suspected. If severely unwell, use broad-spectrum antibiotic cover e.g. cefuroxime 50mg/kg iv 8 hourly. Legionella pneumophila is extremely rare in immunocompetent children. Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
72
Pyelonephritis
Pathogens: Common: E. coli, Proteus sp., Klebsiella. Other: Staphylococcus aureus, Pseudomonas, Serratia. Drug Treatment: DRUG Empiric: Amoxycillin and Gentamicin 50 mg/kg/dose iv 6 hourly DOSE
Appropriate for children under one year of age. (See section on Aminoglycoside dosing in children).
Treatment Duration: 10 days. Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
73
Notes: Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage.
74
75
10-20 mg/kg 6 hourly 10-15 mg/kg 8 hourly 6-12.5 mg/kg 6 hourly Inappropriate 10-15 mg/kg 8 hourly Inappropriate Inappropriate Inappropriate Inappropriate Inappropriate
40 mg/kg 4 hourly 25 mg/kg 6 hourly Inappropriate 25 mg/kg 4-6 hourly Inappropriate 50 mg/kg 6-8 hourly 50 mg/kg 6 hourly 50-100 mg/kg 12-24 hourly, (max 2g/dose or 4 g/day) 50 mg/kg 8 hourly (max 4 g/day) 40-50 mg/kg 8 hourly (max 6 g/day)
76
Drug Carbapenems Meropenem Macrolides Erythromycin lactobionate Erythromycin base Erythromycin ethyl succinate Erythromycin stearate Erythromycin estolate Lincosamides Clindamycin
Route IV
IV PO PO PO PO
Inappropriate 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly
IV/IM PO
IV
Inappropriate
IV/IM IV/IM
Inappropriate Inappropriate
IV PO PR PR
5-10 mg/kg 8 hourly 5-10 mg/kg 8 hourly 1-5 years: 250 mg/kg 8 hourly 6-12 years: 500 mg/kg 8 hourly
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Antibacterial Drugs
Beta-Lactams
Penicillins, cephalosporins including cephamycins, monobactams and the carbapenems, are structurally related and share bactericidal activity primarily directed at the bacterial cell wall. Most beta-lactams are relatively safe, except in those patients hypersensitive to them.
Antistaphylococcal Penicillins
Flucloxacillin is stable to beta-lactamase produced by staphylococci. Anaerobic activity is minimal to none, while these agents do not cover enterococci. Flucloxacillin is reliably absorbed by the oral route, although preferably taken on an empty stomach. It is generally well tolerated but has recently been found to be associated with cholestatic jaundice in some patients. This can manifest up to 6 weeks after treatment and may last for months. It is more commonly seen in elderly patients. This propensity should not prevent use of this excellent anti-staphylococcal drug in patients with serious infections. Dicloxacillin is now available in New Zealand. Dicloxacillin may be less hepatotoxic and therefore may be preferable to flucloxacillin particularly in elderly patients requiring prolonged therapy. It is not fully funded (as at August 2008), on the Pharmaceutical Schedule. Methicillin-resistant Staphylococcus aureus (MRSA) should be regarded as clinically resistant to all beta-lactams, irrespective of laboratory reports of susceptibility. Conversely, the treatment of choice for methicillin-sensitive Staphylococcus aureus (MSSA) is a beta-lactam antibiotic, not a glycopeptide. In New Zealand, many MRSA are not multi-resistant and therapy with macrolides, cotrimoxazole or tetracyclines may be efficacious (see separate section on MRSA management page 152). The practice of combining flucloxacillin with penicillin frequently occurs. There is hardly ever an instance when this is necessary. The belief that you are able to cover Staphylococcus aureus with flucloxacillin and not Streptococcus pyogenes is incorrect. Although it is true that the MIC90 of Streptococcus pyogenes to penicillin is 0.015g/ml, the MIC90 of Streptococcus pyogenes to flucloxacillin is still excellent at 0.4g/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered.
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Broad-Spectrum Aminopenicillins
Amoxycillin has greater activity than benzylpenicillin against some Gram-negative organisms, e.g. Escherichia coli, Haemophilus influenzae but are destroyed by betalactamase producing strains. It is the agent of choice against enterococci.
Antipseudomonal Penicillins
Piperacillin and Ticarcillin (no longer marketed in NZ) are the only penicillins available that have activity against Pseudomonas aeruginosa. They are more expensive than most other penicillins.
Beta-Lactamase Inhibitors
Clavulanic acid, sulbactam and tazobactam inhibit the -lactamase enzymes produced by Staphylococcus aureus and Bacteroides fragilis; and also the ubiquitous TEM enzyme, found in Escherichia coli, Neisseria gonorrhoea and Haemophilus influenzae. They possess little inherent antibacterial activity, but in combination with penicillins such as amoxycillin, ticarcillin and piperacillin, they significantly extend their spectrum of activity. These combinations should be reserved for the treatment of organisms in which resistance to the beta-lactam antibiotic component is due to enzymes that these agents can inhibit. It should be noted that for Pseudomonas aeruginosa, the addition of a beta-lactamase inhibitor offers no increased activity. The combinations are often more expensive than the beta-lactam antibiotics alone. Amoxycillin/clavulanic acid can cause diarrhoea and cholestasis, which occur more frequently than with amoxycillin alone.
Carbapenems
Imipenem/cilastatin, meropenem and ertapenem are now available in New Zealand. Due to inactivation by a renal dipeptidase, imipenem is formulated in combination with the dipeptidase inhibitor, cilastatin. This preparation has wide activity against enteric Gram-negative rods and Pseudomonas aeruginosa, comparable to that of aminoglycosides, and, in addition, has excellent activity against anaerobes including Bacteroides fragilis, and many Gram-positive organisms. However, it is not active against MRSA or some strains of Pseudomonas species. This drug is expensive and should not be regarded as a first-line agent. Meropenem is resistant to renal dipeptidase and can therefore be given alone. It also attains better levels in CSF than imipenem and the risk of seizures is said to be less than with imipenem. At Waikato Hospital, carbapenems are restricted to the Haematology/Oncology ward and Intensive Care. Meropenem is currently the major carbapenem used at Waikato Hospital. Ertapenem has a narrower spectrum of activity; Pseudomonas and Acinetobacter spp. are resistant. Its advantage is that it has a long half-life allowing for once a day administration. Ertapenem is currently on the Waikato Hospital formulary for use with ESBL infections.
Monobactams
Aztreonam is a member of this family of beta-lactams. This compound is inactive against Gram-positive organisms and anaerobes but is highly active against the majority of aerobic Gram-negative bacteria, including beta-lactamase producing Haemophilus influenzae, enteric Gram-negative rods and Pseudomonas species, including those resistant to aminoglycosides. It can be given to people with severe penicillin hypersensitivity, as there is little cross sensitisation. It is expensive and has so far found little place in treatment of infections within WDHB. 80
Cephamycins
Cefoxitin and cefotetan (no longer marketed in NZ) are cephalosporin-like, but in fact, make up a separate class known as cephamycins. They are resistant to the extended spectrum beta-lactamases of gram-negative organisms. Cefoxitin and cefotetan are less active against gram-positive organisms, particularly against Staphylococcus aureus compared to the second-generation cephalosporins. They however, have greater activity against Bacteroides fragilis (60% to 70% of strains have been reported to be susceptible) than second generation cephalosporins. These drugs have a limited role in therapy and have traditionally been used for prophylaxis, although metronidazole provides superior cover for anaerobes than either cefoxitin or cefotetan.
useful concentrations, third generation drugs have been effective in meningitis because of better penetration and higher intrinsic activity. Some organisms, e.g. Serratia, Citrobacter and Enterobacter species, have inducible beta-lactamases and resistance can develop during treatment. Combination therapy with an aminoglycoside has been suggested for serious infections with these organisms. Ceftazidime, cefepime and cefpirome have valuable activity against Pseudomonas aeruginosa, with cefepime and cefpirome having improved gram-positive activity compared with ceftazidime. All third and fourth generation cephalosporins are more expensive than gentamicin. Their use should be reserved for meningitis, resistant hospital pathogens and occasions where gentamicin or the other aminoglycoside antibiotics are contraindicated.
Desensitisation
It is possible to desensitise individuals. Desensitisation is appropriate for patients who require penicillin treatment who have a history of penicillin allergy with a positive skin prick test or a history of penicillin allergy when skin prick testing is not available. 82
If there has been a history of a life-threatening drug hypersensitivity, desensitisation should be carried out in a hospital setting, with an intravenous line in situ in the patient and resuscitation equipment available, including oxygen and adrenaline. Heart rate and blood pressure should be monitored every 15 minutes with continuous observation of the patient. Intensive Care should be made aware prior to commencing the protocol. Where non-life threatening features (e.g. rash) have occurred, desensitisation may occur on an outpatient basis with regular observation and telephone contact available, and with an action plan for hypersensitivity reactions in place. Protocols are available from the Pharmacy Department who will be involved in making up the solutions. The process involves administration of incremental doses of penicillin oral followed by IV given every 15 - 30 minutes. The whole process takes 5 to 6 hours. This process of acute desensitisation is effective and relatively safe. The first therapeutic dose should be given within 4 hours of the end of the desensitisation procedure. The state of desensitisation induced does not last longer than the penicillin course that is administered immediately after the desensitisation process.
Aminoglycosides
Gentamicin, tobramycin and amikacin are active against aerobic Gram-negative bacilli including Pseudomonas and are amongst the most rapidly bactericidal drugs available for treatment of aerobic Gram-negative sepsis. Anaerobes are resistant. Alone they are inactive against enterococci, but in combination with penicillin (or amoxycillin) are synergistic. Gentamicin plus penicillin (or amoxycillin) is bactericidal for most enterococci. Although aminoglycosides are active against most staphylococci and may be life-saving in unsuspected staphylococcal sepsis, they should not be used alone to treat staphylococcal infections, because resistance commonly develops. Gentamicin is the aminoglycoside of choice for most cases of hospital-acquired aerobic Gram-negative sepsis. Tobramycin produces greater in vitro activity than gentamicin against Pseudomonas aeruginosa, but not other aerobic Gram-negative bacteria and is nine times more expensive. All aminoglycosides are potentially ototoxic and nephrotoxic, with clinically significant adverse effects more likely with advancing age or pre-existing renal impairment. Yet, despite these limitations, aminoglycosides remain a very valuable group of antibiotics for the treatment of infections within hospitals. During the 1990s there was a significant change in the way aminoglycosides were prescribed, based on increased understanding of concentration-dependent killing and the post-antibiotic effect.
Pharmacodynamic Properties
The aminoglycosides demonstrate a property known as concentration-dependent killing. Clinical studies have demonstrated that achievement of high peak serum concentrations of the aminoglycoside relative to the minimum inhibitory concentration of the micro-organism being treated, is the major determinant of the clinical response to the aminoglycosides. This optimisation of the Peak : MIC ratio, can best be obtained by the extended interval" administration of aminoglycosides, which result in high peak concentrations of the drug (peak target ~ 20 g/ml). In addition to this property of the aminoglycosides, these drugs also demonstrate a property known as the post-antibiotic effect, which may be defined as a period of time after complete removal of the antibiotic during which there is no growth of the target organism. Although "extended interval" dosing of aminoglycosides may result in a period of up to 12 hours during which there are no detectable serum concentrations of the drug, this property of the aminoglycosides allows for extended interval dosing without compromising therapeutic efficacy. This has now been confirmed by a large 83
number of studies.
Drug Toxicity
The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within both the renal cortex and the perilymph of the inner ear, respectively. Uptake and accumulation of aminoglycosides into renal cortical tissue demonstrates saturable kinetics. The saturable feature of these kinetics makes peak aminoglycoside concentrations irrelevant when considering tissue accumulation of the drug. Less frequent dosing of aminoglycosides allows for trough levels of the drug to fall well below the threshold for binding to their tissue receptors. This also allows for the back-diffusion of aminoglycosides from the renal cortex and inner ear that may theoretically limit drug toxicity. In animal models, rats receiving a single daily dose of aminoglycosides have demonstrated less nephrotoxicity and less renal accumulation of the drug than those rats receiving the same total dose by a multiple daily dosing schedule. For recommendations on dosing and monitoring of aminoglycosides, refer to Dosing, Pharmacokinetics and Pharmacodynamics Section (page 92).
Tetracyclines
Tetracyclines all have a broad spectrum of activity, which includes Gram-positive and Gram-negative bacteria, Chlamydia, Rickettsia, Mycoplasma, Spirochaetes, some Mycobacteria and some Protozoa. Their main use is in the treatment of pelvic inflammatory disease, acne, periodontal disease, exacerbations of chronic obstructive pulmonary disease, brucellosis, plague, cholera and Lyme disease. Tetracyclines are contraindicated in pregnancy and lactation and in children <8-12 years of age. Minocycline and doxycycline each have a longer half-life and absorption is not significantly affected by the presence of food.
Fluoroquinolones
This class of antibiotic has a broad spectrum of antimicrobial activity, good bioavailability, excellent penetration into tissues, long serum half-lives, and are generally well tolerated. Their major downfall is the alarming development of resistance with the use of these agents. Norfloxacin is used in the treatment of urinary tract and gastrointestinal infection. Ciprofloxacin has a wider range of therapeutic activity against Gram-negative bacilli including Haemophilus influenzae, enteric Gram-negative rods, Pseudomonas aeruginosa, some Gram-positive cocci, Gram-negative cocci, and various species of 84
Mycobacteria. They generally have poor activity against streptococci and in general should not be considered as the preferred therapy of gram-positive infections. Fluoroquinolone therapy is not advocated as first-line therapy for S. aureus osteomyelitis. These drugs are expensive and adverse effects are relatively common but most are not serious. They should be reserved for treatment of infections resistant to cheaper agents or where an oral agent with this particular antibacterial spectrum is required. Resistance to these fluoroquinolones has commonly occurred, especially where they have been widely used, principally in infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, enteric Gram-negative rods, Campylobacter species and Neisseria gonorrhoeae. Because of excellent bioavailability, oral use is the preferred route in most circumstances and in fact 750mg orally has a preferred pharmacodynamic profile than 400mg iv. Concomitant administration of iron, aluminium, calcium or magnesiumcontaining medicines can significantly reduce the gastrointestinal absorption of orally administered quinolones. Therefore, a gap of at least two hours should be allowed between these agents. Dairy foods containing large amounts of calcium will also reduce absorption. Quinolones damage the joints of immature animals and therefore should be used with caution in children under 14 years. Considerable experience in cystic fibrosis has shown that they can be used safely in the appropriate clinical situation. Quinolones are inappropriate for first line empiric therapy of common infections such as cellulitis, pharyngitis, otitis media, sinusitis, respiratory tract infections or acute osteomyelitis. Newer fluoroquinolones (moxifloxacin, gatifloxacin) with increased activity against Streptococcus pneumoniae (including drug-resistant strains) are now available in New Zealand (although not Pharmac funded). These drugs have increased activity against Gram-positive bacteria (including streptococci) and wide activity against Gram-negative aerobes (but inferior to ciprofloxacin against pseudomonas). They have good activity against anaerobes and most pathogens causing atypical pneumonia. Resistance is already beginning to be seen with these newer agents, which may limit their future. Currently, the role for these newer fluoroquinolones is extremely limited.
Macrolides
The macrolides include erythromycin, roxithromycin, clarithromycin and azithromycin. They have a wide spectrum of activity covering Gram-positive cocci, Legionella, Bordetella, Corynebacteria, Gram-negative cocci, Mycoplasma, Chlamydia and both Gram-positive and Gram-negative anaerobes. They are not active against Gramnegative rods. The newer macrolides have more reliable absorption and longer halflives, allowing less frequent dosing. They attain high intracellular concentrations that confer theoretical benefits in the treatment of intracellular pathogens. They also cause adverse effects less frequently than erythromycin. Erythromycin in all of its oral formulations has variable absorption and frequent GI side effects. Serious adverse effects are very rare, making it one of the safest antibiotics in clinical use. The only parenteral formulation, erythromycin lactobionate, frequently causes pain and phlebitis. Intravenous doses should be administered slowly to minimise local reactions and also to avoid arrhythmia. Erythromycin should not be given intramuscularly. Several oral preparations are available, including erythromycin base, the stearate, and the estolate forms. Although the blood levels achieved with these forms vary 85
somewhat, when the agents are used against very sensitive organisms, these minor differences are not believed to be clinically significant. Erythromycin ethylsuccinate has different absorption characteristics to other forms of erythromycin and therefore higher oral doses are needed to achieve therapeutic effects. 400mg erythromycin as the ethylsuccinate provides serum concentrations similar to those provided by 250mg erythromycin as the base, stearate or estolate. Unfortunately no one formulation seems to cause substantially less GI upset than others. Erythromycin may produce interactions with other drugs by inhibiting hepatic metabolism vai the cytochrome P450 enzyme system. Waikato District Health Board is now only stocking Erythromycin ethylsuccinate (August 2008) so whenever erythromycin is referred to in this document it is the succinate form. Roxithromycin is an alternative to oral erythromycin. It has good oral bioavailability and may cause less gastrointestinal upset than erythromycin, but is slightly more expensive. It is fully funded on the Pharmaceutical Schedule. Clarithromycin, unlike other macrolides, has a microbiologically active metabolite. It is generally suitable for indications similar to those of erythromycin. It has activity against Mycobacterium avium complex and is used in combination with other agents for the treatment of this infection in patients with AIDS. It is not fully funded (except under special authority for specific indications). Azithromycin has good in vitro activity against a wider range of organisms than erythromycin. It is more active against Haemophilus influenzae. It has good oral bioavailability and in particular rapid and sustained uptake by tissues. Once daily dosage of this drug is generally acceptable. Azithromycin can be used for the usual indications of erythromycin and also for Neisseria gonorrhoea and chlamydial genital tract infections. It is also used for the treatment of cerebral toxoplasmosis in patients with AIDS. Azithromycin has recently been used for uncomplicated typhoid fever (Clin Infect Dis 2004;38:951-957). It is currently fully funded for urethritis and cervicitis due to Chlamydia trachomatis.
Glycopeptides
Vancomycin and teicoplanin are effective only against gram-positive organisms. They play an important role in the treatment of methicillin-resistant organisms and in treating severe infection with susceptible organisms in patients who are hypersensitive to penicillin. Glycopeptides are not as effective as Beta-lactam antibiotics in the treatment of sensitive Staphylococcus aureus. Vancomycin is given by intravenous infusion over at least 1 hour to avoid producing the "red man syndrome". Teicoplanin can be given by intramuscular injection or by slow intravenous injection or infusion. Teicoplanin is considerably more expensive, no more efficacious, with a similar toxicity profile and should only be considered as a second-line agent. As a result of the emergence of Vancomycin-resistant Enterococcus and the theoretical threat of Vancomycin-resistant Staphylococcus aureus, they need to be used very wisely. The following are the recommended indications for use of parenteral glycopeptides: Treatment of proven serious methicillin-resistant staphylococcal infections (S. aureus or coagulase negative staphylococcus); Initial treatment of serious infections with a high probability of being caused by coagulase-negative staphylococcus; Infections related to use of a central line; Infections involving a prosthesis; Sternotomy infections; Treatment of bacterial endocarditis caused by methicillin-resistant S. aureus or 86
coagulase-negative staphylococcus; Treatment of bacterial meningitis caused by flavobacteria or penicillin-resistant pneumococcus (+ cefotaxime); Treatment of central nervous system (CNS) shunt infections caused by methicillinresistant staphylococci (+/- removal of infected appliance, +/- use of rifampicin); Treatment of other infections caused by organisms susceptible only to vancomycin (e.g. Corynebacterium jeikium); Enterococcal infections resistant to ampicillin; and Treatment of serious Gram-positive infections in patients with major penicillin allergy (i.e. anaphylaxis, exfoliative dermatitis or severe urticaria).
Oral Vancomycin should not be used as first line therapy in Clostridium difficile diarrhoea. It should be reserved for severe cases unresponsive to metronidazole.
Lincosamides
Clindamycin is active against Gram-positive aerobes and most anaerobes. Although clindamycin has received a great deal of attention as a cause of C. difficile diarrhoea, this condition is now recognised to complicate almost all antibiotic therapy. It should be used as a second choice in those who cannot tolerate conventional therapy. It also has a role to play in the management of Toxoplasma gondii infection. Both oral and intravenous formulations are available. The oral formulation has 90% bioavailability. The intravenous formulation is expensive but is rarely required in someone with a functioning GI tract.
Linezolid
Linezolid is the first in a new class of antibiotics called oxazolidinones. It is effective against Gram-positive organisms including MRSA, coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant strains of Streptococcus pneumoniae. Dosing is twice daily. Myelosuppression is common with prolonged administration and haematology should be monitored weekly. Peripheral neuropathy has also been seen with prolonged therapy. The drug is also known to have monoamine oxidase inhibitory activity. It is available in both oral and IV formulations. It is extremely expensive and is not on the WDHB formulary or PHARMAC funded. Its usage within WDHB will only be after discussion with the Infectious Diseases Service. The major value of this new therapy will probably be in the long-term management of chronic infections with multi-resistant Gram-positive organisms. Currently, other options usually exist for this indication. A monitoring programme to avoid adverse reactions has recently been published in Antimicrob Agents Chemother 2006;50:1599602.
Nitroimidazoles
Metronidazole has a spectrum of activity that encompass Gram-negative anaerobes such as Bacteroides fragilis, Gram-positive anaerobes such as Clostridium species and anaerobic protozoa including Trichomonas vaginalis, Giardia lamblia and Entamoeba histolytica. Metronidazole is available as an intravenous preparation; however excellent absorption means that tablets or suppositories can often be used instead. Tinidazole, is no longer funded within New Zealand (Aug 2008). These agents may cause a disulfiram-like reaction with alcohol. Recommended dosage for metronidazole is 400mg orally or 500mg IV with a 12-hourly dosing schedule. This is based on pharmacokinetic data and minimum inhibitory concentrations of the pathogens involved, rather than formal clinical studies.
Rifampicin
Apart from its important role as an anti-tuberculous and anti-leprosy agent, rifampicin is 87
used to eradicate nasopharyngeal carriage of N. meningitidis, H. influenzae and S. aureus, and as an adjunct to other antibiotics in serious staphylococcal infection. Rifampicin causes red discoloration of body fluids and occasional influenza-like symptoms and hepatotoxicity. It interferes with oral contraceptive metabolism.
Antiviral Drugs
Purine Nucleoside Analogues
Aciclovir is active against Herpes simplex virus and to a lesser extent Varicella-zoster virus. It is the drug of choice for severe infections caused by these viruses. Intravenous doses should be administered slowly. Valacyclovir and famciclovir, which have longer half-lives, are no longer funded in New Zealand. Ganciclovir is used for the treatment of serious cytomegalovirus infections in immunocompromised patients. Unfortunately, it has dose-dependent bone marrow suppressive effects. The drug also has demonstrated mutagenicity in mammalian cells and carcinogenic potential in animals. Solutions for iv infusion must therefore be prepared in a biohazard cabinet (currently prepared at Waikato Hospital by Baxter).
Neuraminidase Inhibitors
Zanamivir and Oseltamivir can shorten the duration of influenza symptoms by about one day if commenced within 48 hours of the onset of symptoms. Both drugs are neuraminidase inhibitors. Zanamivir is produced in a diskhaler format (and should be used with caution in severe asthmatics) while Oseltamivir is an oral medication. The advantages of one over the other are still to be clarified by further trials. These agents are not funded by Pharmac.
Antiretroviral Drugs
The last decade has seen an explosion in the number of anti-retroviral therapies specific for HIV infection become available. There were seven nucleoside analogue reverse transcriptase inhibitors (NRTIs), two non-nucleoside reverse transcriptase inhibitors (NNRTIs), six protease inhibitors and an HIV fusion inhibitor currently funded for use within New Zealand as at August 2008. Antiretroviral prescribing can only be undertaken by named specialist. At the time of publication only Dr Jane Morgan and Dr Graham Mills were approved to initiate antiretroviral therapy.
Antifungal Agents
The number of systemic antifungal agents has grown considerably during the last decade. The newer agents are usually confined to specific infections in the setting of immunocompromised individuals.
Polyenes
Amphotericin is a polyene compound that remains the treatment of choice for most serious fungal infections having the broadest spectrum of any antifungal compound currently marketed. The major action of amphotericin B is to damage the membrane of fungal cells. It has significant and serious side effects, predominantly renal toxicity. Consultation with an infectious diseases physician or clinical microbiologist is advised concerning its use. Liposomal amphotericin is less toxic but is extremely expensive (up to $3000 per day dependent on dose used). Evidence of increased efficacy against fungal infection compared with the standard preparation of amphotericin is anecdotal only. It is likely to be used only in extremely exceptional circumstances after prior use of standard amphotericin when significant toxicity has occurred and alternative 88
antifungal agents are not appropriate. Amphotericin has a long half-life (up to 15 days). It is initially given once daily, although once control of fungal sepsis has been achieved, alternate day dosing can be used. Dosage modifications of amphotericin B are not required in patients with renal insufficiency, in keeping with the low renal excretion of the drug. Hypersensitivity to amphotericin is common and consists of headache, fever, severe rigors, chills, malaise, muscle and joint aches, and hypotension. Symptoms subside within 4 hours after discontinuance. The occurrence of this side effect decreases with continued therapy. Intravenous hydrocortisone (50-100 mg) and promethazine can be given prior to commencing the amphotericin infusion, although the hypersensitivity reactions are, in part, dose-related. The patients should be closely observed during the first dose, but daily incrementation of the dose is not necessary. Regular monitoring of serum electrolytes, renal function and full blood count is essential. Amphotericin is usually infused in 500 ml 5% dextrose, although for volume-restricted patients, amphotericin B can be given in a concentration of 0.5mg/ml of 5% dextrose. It is typically infused via a central line as peripheral venous administration may predispose patients to develop phlebitis because of the irritant effect of amphotericin B. IV administration of 0.5 to 1L sodium chloride 0.9% prior to the amphotericin infusion is strongly recommended. When commencing amphotericin, a slow infusion is recommended over 6 hours. If the patient tolerates this for two successive doses without any evidence of an allergic response occurring, then the infusion can be shortened down to a 2 - hour infusion for subsequent doses. Amphotericin is nephrotoxic, although impaired renal function is generally reversible after discontinuation of therapy. Irreversible renal damage is rare. One must be cautious about using amphotericin in combination with aminoglycosides, vancomycin, cisplatin or cyclosporin.
Imidazoles
Clotrimazole, econazole, ketoconazole and miconazole are broad-spectrum antifungal drugs, which are used in mucocutaneous candidiasis, dermatophytosis and tinea versicolor. Clotrimazole has some activity against trichomonas, and ketoconazole shampoo is used in the treatment of seborrhoeic dermatitis and dandruff. Ketoconazole is active against a variety of fungal infections, particularly yeasts. It has acid-dependent oral absorption (similar to itraconazole) and is not significantly excreted in the urine. Hepatotoxicity may occur and liver function tests need to be monitored monthly. It blocks steroid synthesis and may lead to hypoadrenalism and reduction in testosterone levels. Ketoconazole has significant interactions with other drugs that are metabolised in the liver by CYP3A4 isoforms of the cytochrome P450 enzymes.
Triazoles
Fluconazole has a narrow spectrum of antifungal activity, and clinical use is usually limited to treatment of Candida species. It has good tissue penetration, including penetration into the central nervous system. It is well absorbed following oral administration. Itraconazole absorption is increased with acidic drinks and food. Itraconazole has a similar spectrum to fluconazole, except for increased activity against filamentous fungi such as Aspergillus species. 89
Itraconazole has significant interactions with other drugs that are metabolised in the liver by the cytochrome P450 enzymes. Fluconazole has a lesser effect on the same pathway. Voriconazole and Posaconazole are newer triazole antifungals structurally related to fluconazole with a spectrum of action similar to itraconazole. They can be used for the treatment of invasive aspergillosis, and serious infection with Candida species, Scedosporium species and Fusarium species. Voriconazole is available both as oral and intravenous preparations, with an oral bioavailability of 96%. As voriconazole is eliminated via a cytochrome P450 pathway, the potential for drug interactions is high. Voriconazole is expensive and should be restricted to patients with proven invasive aspergillosis intolerant or unresponsive to amphotericin . Voriconazole is active against Aspergillus species, Scedosporium apiospermum and Fusarium species. Posaconazole (currently only available in an oral formulation) is active against Candida and Aspergillus species. It also has activity against Coccidioides immitis, Fusarium, Histoplasma, Zygomycetes and phaeohyphomycetes.
Caspofungin
Caspofungin is the first in a new class of antifungal agents called the echinocandins, which inhibit -1,3-D-glucan synthesis in the cell wall in a novel way. It is used in the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies, such as amphotericin or voriconazole. It is administered by slow IV infusion. It is not available in oral formulation.
Flucytosine
Flucytosine is a fluorinated pyrimidine analogue, with antifungal properties. It is available for oral or parenteral use although it is unregistered in New Zealand and requires a Section 29 application. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High serum levels, which often occur with renal impairment, are associated with bone marrow toxicity and monitoring of serum concentrations is therefore advised.
Terbinafine
Terbinafine is fungicidal for many dermatophytes. It is well absorbed from the gut and is of value in treating fungal infections of the skin and nail. It should be used with caution in patients with hepatic diseases. It may be used topically.
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2.
Staphylococci
3h 4h 3h 3h
Pseudomonas 0h N/A 6h 6h
The relationship between tissue levels and serum levels. As most infections occur in tissues and the common bacterial pathogens are extracellular, interstitial fluid concentrations at the site of infection are the prime determinants of efficacy. Most tissue sites within the body can be described as having a large capillary surface area across which antimicrobials diffuse into a relatively small volume of interstitial fluid. Drug concentrations at these sites will show little lag and therefore antibiotic levels will be very close to serum concentrations. Some tissue sites such as blister, pleural, peritoneal and synovial fluids have a lower ratio of surface area to volume than most other tissues. Concentrations at these sites will therefore lag behind those in serum, resulting in lower peak concentrations but higher trough levels. Two major patterns of bactericidal activity are now recognised. These are termed "concentration-dependent killing" and "time-dependent killing". An understanding of these concepts will have a major impact on how antibiotics are prescribed. Concentration-dependent bactericidal activity is characterised by a greater extent and rate of bactericidal activity with higher drug concentrations. Figure 1 demonstrates this characteristic. This pattern of killing is observed with the aminoglycosides, fluoroquinolones, and metronidazole.
4.
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Concentration
K3 K2 K1
......
MIC
Time
Fig 1: Concentration Dependent Bactericidal Activity Rate of Kill K3 > K2 > K1 Time-dependent bactericidal activity is characterised by a saturation of the rate of killing at concentrations near the MIC. Thus, high concentrations will not kill the organism faster or more extensively than low concentrations. The duration of exposure rather than the concentration is the major determinant of the extent of killing. This pattern of bactericidal activity is seen with beta-lactams, vancomycin, macrolides and clindamycin. Figure 2 demonstrates this characteristic. Furthermore, animal studies have revealed that maximal efficacy for an antibiotic with time-dependent bactericidal activity can be achieved when serum levels are above the MIC for only 60% of the dosing interval, and as low as 25% for some organisms.
Concentration
K0 K0 K0
....
MIC
Time
Fig 2: Time-Dependent Bactericidal Activity Rate of Kill K0 is constant The pharmacodynamic characteristics described reveal that the time course of antimicrobial activity varies markedly for different antimicrobials and can not be based solely on half-life of the antibiotic or the MIC data for a particular organism. It is with this in mind that the dosing guidelines for various antibiotics have been defined. Much of this pharmacodynamic data is relatively new, differing from some of the traditional dosing approaches used in the past. 92
The aminoglycosides demonstrate concentration-dependent killing. Clinical studies show that a high peak serum concentration relative to the Minimum Inhibitory Concentration (MIC) of the micro-organism being treated, is the major determinant of the clinical response to the aminoglycosides. This optimisation of the Peak : MIC ratio, can best be obtained by the extended interval" administration of aminoglycosides, which result in high peak concentrations of the drug (peak target ~ 20 g/ml). In addition, these drugs also exhibit a post-antibiotic effect, which is a period of time after complete removal of the antibiotic during which there is no growth of the target organism. Although "extended interval" dosing of aminoglycosides may result in a period of up to 12 hours during which there are no detectable serum concentrations of the drug, this property of the aminoglycosides allows for extended interval dosing without compromising therapeutic efficacy. The principal goal to achieve good efficacy in aminoglycoside therapy is therefore to achieve a peak of 10 20 mg/L. Some patients, such as children, have very rapid clearance. Other patients, such as those with burns, have unusually high volume of distribution and require higher mg/kg doses. These cases may be recognised when levels 8-12 hr post dose are unexpectedly low. A secondary alternative goal is to achieve an area under the curve of 70-100 mg/L.h. Toxicity Toxicity may still occur in some cases where target levels have been adhered to, particularly after prolonged courses and in pre existing renal failure. This obligatory small risk is usually offset by aminoglycosides high potency, relative absence of resistance, narrow spectrum, low cost and efficient once daily administration. However, for courses longer than 7 days, specialist advice should be sought to weigh the risks and benefits. The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within both the renal cortex and the perilymph of the inner ear. Uptake and accumulation of aminoglycosides into renal cortical tissue demonstrates saturable kinetics. This makes peak aminoglycoside concentrations unimportant when considering tissue accumulation of the drug. Less frequent dosing of aminoglycosides allows for trough levels of the drug to fall well below the threshold for binding to their tissue receptors. This also allows for the back-diffusion of aminoglycosides from the renal cortex and inner ear, which may theoretically limit drug toxicity. The major goal for avoiding aminoglycoside toxicity is therefore to achieve a low trough level, preferably below 1 mg/L for gentamicin and tobramycin.
AMINOGLYCOSIDES: DOSING AND MONITORING Contraindications Previous vestibular or auditory toxicity due to aminoglycoside Serious hypersensitivity reaction to aminoglycoside (rare) Precaution if used > 48-72 hr Pre existing conductive hearing problem or vestibular problem 93
Neuromuscular disorders Chronic liver disease or cholestasis (bilirubin > 90 micromole/L) Chronic renal failure or deteriorating renal function
Alternative agents 3rd and 4th generation cephalosporins eg ceftriaxone, ceftazidime or cefepime (the latter two for Pseudomonas) Fluroquinolones eg ciprofloxacin (not moxifloxacin) Carbapenems eg meropenem or ertapenem (use is restricted for ecological and stewardship reasons). Dual agent therapy With another active agent for severe Pseudomonal infection With penicillin or amoxicillin for endocarditis Administration IV infusion over 30 min. Neuromuscular blockade may occur with rapid administration. The standard dose size is 5 mg/kg of dosing weight Dosing weight is ideal body weight or an adjusted obese dosing weight (see below). Round the dose to the nearest 20 or 40 mg for adults. Adjustment within the range 3 7 mg/kg may be required for specific patients (see below). An initial stat dose of 5 mg/kg may be given safely to most patients and subsequent doses adjusted the next day. The standard dose interval is 24 hr In most cases, adjusting the interval is the preferable way to manage dosing. Use the nomogram below to adjust the interval. Adjustment within the range 16-48 hr may be necessary, guided by monitoring levels. Intervals in multiples of 12 hr are most convenient and foolproof. If intervals beyond 48 hr are indicated, change to another agent. Renal function is the main determinant of dosing interval. 8 hrly dosing may be used in specific situations such as endocarditis synergy and for neonates, in pregnancy and >20% burns. Close monitoring and dose by dose adjustment is required in renal failure (CrCl < 0.5 mL/s) and alternative agents are preferred.
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Monitoring Courses over 7 days: consult with infectious diseases specialist as to the benefits versus risks. Consider monitoring renal function, vestibular and auditory function. Toxicity (particularly ototoxicity) may occur with long term use even if serum gentamicin levels are satisfactory. It is not necessary to measure drug levels if renal function is normal and the course is < 48 hr. Frequency of monitoring Initial test: after 24-72 hr of treatment Long term monitoring: weekly with additional 3 x weekly serum creatinine Recheck aminoglycoside levels if renal function improves or declines significantly. Dose adjustment: remeasurement is often useful at 24 48 hr intervals until a stable satisfactory dose is established. The preferred time to measure levels is 8 12 hr post dose. Suitable when renal function is mildly impaired ie CrCl > 0.5 mL/s Usually gives a measurable non zero figure. Will pick up cases with slow clearance and those with large Vd. Minor errors in recording the administration and sampling times wont severely affect interpretation. Target level 2-7 mg/L, depends on time of sampling relative to last dose. See nomogram. Measure peak and trough levels if difficulty is encountered. eg unusual Vd or body composition, changing or unpredictable renal function, if significant drug accumulation is suspected Peak sample: 30 min after end of 30 min infusion. Target: gent and tobra 10-20 mg/L, amikacin 40-60 mg/L Trough sample: within 2 hr of next dose. Target: gent & tobra < 1mg/L, amikacin < 4 mg/L For 8 hrly dosing, gent & tobra targets are peak: 5-10, trough <2 (4x time this for amikacin). How to adjust doses Try for simple, conventional dose sizes and intervals to minimise administration errors. The Clinical Microbiologist or Infectious Diseases Physician is available to discuss cases. First, try to adjust the interval, using the nomogram. Second, adjust the dose size if necessary. Third, take peak and trough levels if a satisfactory result is not achieved after a couple of days (sooner if problems are anticipated). Fourth, change to an alternative agent if satisfactory levels cant be readily achieved.
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Calculation of Dose Size Use Ideal Body Weight (IBW) to calculate the dose, or the actual body weight (if less than IBW).
IBW (male) = 50kg + 0.9kg for each cm >150cm in height IBW (female) = 45.5kg + 0.9kg for each cm >150cm in height If an individual is > 20% above IBW, dosing should be based on the obese dosing weight (ODW) which is calculated: ODW = IBW + 0.4 (Actual BW IBW).
Ideal Body Weight Chart Height Males (kg) 155 cm / 52 55 160 cm / 54 60 165 cm / 56 64 170 cm / 58 68 175 cm / 510 73 180 cm / 60 78 185 cm / 62 82 190 cm / 64 87 195 cm / 66 91
Females (kg) 50 55 60 64 69 73 78 82 87
Aminoglycoside Starting Doses for Special Cases Special Cases Starting Dose for Extended Interval Dosing (24 48 hrly) mg/kg/day for gent or tobra For amikacin, multiply by 4 Neonates incl premature 3 Infants and Children < 10 y 7 10 - 29 y 6 30 - 60 5 > 60 y 4 Endocarditis, Streptococcal 3 (gentamicin only) and Enterococcal
Determination of Initial Dosing Interval The initial dosing interval is determined from an estimate of creatinine clearance. An estimate of creatinine clearance (CrCl) is made using the modified Cockcroft formula (Intensive Care Med 1993, 19:39).
CrCl (ml/sec) = (140 - age) x ideal body weight (IBW) in kg ( x 0.85 if female) serum creatinine (mol/L) x 50
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A creatinine clearance calculator is also available on the Intranet under Clinical Guidelines/Utilities. The initial dose interval is then selected according to guidelines below: Initial Dosing Interval 5mg/kg for gentamicin and tobramycin. Amikacin doses are 4x those. q24 h q36 h q48 h Consider alternative antibiotic. One stat dose then seek specialist advice.
Nomogram for Dose Interval Adjustment Start with the time the sample was taken after the most recent dose, read up to the measured aminoglycoside level and adjust the dose interval to that shown. If the measured level is undetectable, next time measure the peak level; increasing to 7mg/kg may be helpful.
Note: This nomogram may be used for either gentamicin or tobramycin and is calibrated for a dose of 5 mg/kg. For amikacin, multiply mg by 4. Source: Therapeutic Guidelines Antibiotic 13th ed 2006.
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Vancomycin Dosing
Vancomycins bactericidal effect appears to depend on the area under the curve. Vancomycins reputation for lower potency compared to beta lactams may stem partly from under dosing with standard regimens in patients with good renal clearance. The practical way to assure optimum dosing is to measure trough levels. Current recommendations are that trough levels should be 10 20 g/ml in those patients receiving 12-hourly dosing. The MIC values for most Staphylococcus aureus are 0.5-1 g/ml and for Enterococci and Coagulase Negative Staphyloccci may range up to 2 g/ml. In cases of serious infection, the MIC should be checked because at levels of 2 or 4 g/ml vancomycin will not be so effective. With MRSA, small moderately resistant subpopulations (heterogenous Vancomycin Intermediate S aureus, hVISA) may occur, which are difficult to detect in the laboratory and may result in therapeutic failure. Prolonged, subtherapeutic vancomycin dosing appears to allow such strains to emerge in an individual patient during treatment. If the patient does not improve on vancomycin, repeat cultures should be obtained and the case discussed with the laboratory so the organism may be sent to a reference laboratory to check for occult resistance. Fully Vancomycin Resistant Enterococci (VRE) and S. aureus (VRSA) due to VanA or VanB have MIC 32 g/ml. VRE has been recognised in recent outbreaks within Auckland hospital (2007) and Waikato hospital (2008). Vancomycin must be given intravenously for systemic infections. It is not absorbed when given orally and IM injections cause tissue necrosis. Ototoxic and nephrotoxic effects of this drug are now considered to be minimal and not related to specific serum concentrations. However, vancomycin appears to potentiate the ototoxicity and nephrotoxicity of aminoglycosides. Careful monitoring is required when administering vancomycin together with an aminoglycoside or other drugs that are known to be cause ototoxicity or nephrotoxicity.
Usual Dose
The usual adult starting dose is 1g iv 12 hourly. Vancomycin should be infused slowly over at least one hour to avoid anaphylactoid reactions and the red man syndrome.
Dosing Interval As vancomycin is cleared solely by the kidney, an assessment of the patients renal function is required for determining the appropriate dosing interval. The initial dosage interval will be determined from an estimate of creatinine clearance, based on the patients age, weight and serum creatinine.
Creatinine Clearance (ml/sec) > 1.0 0.35 1.0 < 0.35 Dosing Interval q12 h q24 h Repeat dose when Vanc level is 1020g/ml
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Monitoring
The primary aim of vancomycin monitoring is to ensure that dosing is adequate. Peak levels are not performed, since they are not useful in predicting efficacy and do not predict toxicity. Trough levels should only be performed in a few select patient populations who have been on vancomycin therapy for greater than 72 hours, including: - Patients with high (e.g. burn patients) or low (<0.9ml/sec) creatinine clearance. - Patients receiving concurrent treatment with other nephrotoxic drugs (e.g. aminoglycosides, amphotericin B). - Patients with infections at sites where there is reduced penetration of vancomycin (e.g. endocarditis, meningitis, pneumonia). When trough levels are taken, the aim is to maintain a trough level of 10-20 g/ml. Trough levels should be drawn immediately before the next dose.
Metronidazole Dosing
Metronidazole, a nitroimidazole derivative, is a well-established antimicrobial for the prevention and treatment of anaerobic infections. Despite having a long serum elimination half-life of about 8 hours (range 6-12 hours), metronidazole has traditionally been administered every 6-8 hours. It has never been determined that such a frequency is necessary. Furthermore, dosing metronidazole every 6-8 hours will lead to drug accumulation after prolonged use, especially if there is liver impairment. It has been shown that a dose of 500mg every 12 hours is sufficient to maintain serum concentrations of the drug above the minimal inhibitory concentration (MIC) of most anaerobic pathogens for the duration of the dosing interval. There is also some limited data to suggest that metronidazole may have a post-antibiotic effect against certain anaerobic bacteria. Metronidazoles bactericidal activity is based on concentrationdependent killing. All dosing recommendations in this booklet are based upon daily or twelve hourly dosing of metronidazole. Metronidazole has excellent oral bioavailability (95-100%) and the iv route should only be used when oral or rectal administration is not possible.
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Beta-Lactam Dosing
Beta-lactam antibiotics are frequently given in inappropriately high dosages. The treatments of meningitis and endocarditis are the only indications for "high" dosage, as serum levels may not necessarily reflect levels in the infected tissue. For most other infections, the magnitude of the peak level is no longer deemed relevant. Timedependent killing means that the time above the MIC is the determinant of success. Examples of this would include ceftazidime for a sensitive Pseudomonas aeruginosa where 1g 8 hourly is more than adequate and ceftriaxone for systemic gram-negative infections where 1g 24 hourly is satisfactory.
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Method of dosage adjustment: D = Dose adjustment I = Dosage interval adjustment. 2 Monitoring of levels recommended to determine precise dosage requirements. 3 Dosage for intraperitoneal administration. 4 Dosage in mg/L of filtrate removed. 5 nd = no data. 6 n/a = not applicable. 7 No supplement means that the dose given is the same as for GFR< 0.2 ml/sec. 8 Dose after means that the dose given is the same as for GFR < 0.2 ml/sec and it should be withheld until after dialysis on days of dialysis.
* +
Agents (often) used in combination, see also companion agent Monitor for myelosuppression
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Aciclovir Amikacin2 Amoxycillin Amoxycillin/ Clavulanate Amphotericin Azithromycin Aztreonam Benzylpenicillin Cefaclor Cefepime Cefotaxime Cefotetan Cefoxitin Cefpirome Ceftazidime Ceftriaxone Cefuroxime Cephalexin Cephalothin Cephamandole Cephazolin Chloramphenicol Chloroquine
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Ciprofloxacin Clarithromycin Clindamycin Co-trimoxazole2,+ Doxycycline Erythromycin Ethambutol Flucloxacillin Fluconazole Flucytosine Fusidic acid Ganciclovir+ Gatifloxacin Gentamicin2 Imipenem/cilastatin Isoniazid Itraconazole Ketoconazole Mebendazole Mefloquine Metronidazole Meropenem Minocycline Moxifloxacin
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Nalidixic acid Nitrofurantoin Norfloxacin Phenoxymethylpenicillin Piperacillin I Piperacillin I Tazobactam Praziquantel Pyrazinamide D Pyrimethamine+ Quinine I Rifabutin Rifampicin Roxithromycin + Sulphadiazine I Sulphamethoxazole*,+ I 2 Teicoplanin After dose on day 4 (I) Terbinafine D Tetracycline I Ticarcillin I Tinidazole Tobramycin2 D&I Trimethoprim Vancomycin2 I
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HEPATIC INSUFFICIENCY
Although many antibiotics are metabolised in the liver and a few are excreted, to a significant extent, in the bile, precise guidelines for dosing in hepatic insufficiency are unavailable. There is no test of hepatic function, equivalent to creatinine clearance for renal insufficiency, on which to base dosage adjustments. It is prudent to avoid drugs with known hepatotoxicity when possible in those with hepatic failure. For manufacturers recommendations consult www.medsafe.govt.nz
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OBESE PATIENTS
Antibiotic dosing is routinely adjusted for weight, but does not often take account of the variable proportions of tissues that comprise the bodys mass. The effect of obesity on the pharmacokinetics of antimicrobials is not very well understood. The volume of distribution of antibiotics in fat is only about 0.3 to 0.4 that of other tissues. The dosing weight is therefore often calculated as the ideal body weight plus 0.3-0.4 the difference between actual and ideal body weight. Since there is likely to be considerable individual variation, in the case of potentially toxic drugs e.g. aminoglycosides, levels should be measured and doses adjusted accordingly.
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Drugs in Pregnancy
During the first 2 weeks of development, the embryo is thought to be resistant to any teratogenic effects of drugs. The critical period of embryonic development, when the organ systems develop starts at about 17 days after conception and is complete by 60 to 70 days. Exposure to certain drugs during this period can cause major birth defects. However, some drugs can interfere with functional development of organ systems and the central nervous system in the second and third trimesters and produce serious consequences. All drugs should be avoided if possible in the first 12 weeks of pregnancy. If drugs are to be prescribed, the benefits to the mother and/or foetus must be considerable. Discrepancies between recommendations on the safety of antimicrobials in pregnancy are a reminder that all prescribing involves risks and benefits that are often difficult to quantify. Manufacturers' recommendations tend to err on the side of caution and their warnings frequently reflect theoretical concerns or insufficient data rather than proven toxicity. No antimicrobial is absolutely contraindicated in all circumstances in pregnancy but the table below may allow choice of a safer alternative or raise the possibility of deferring treatment. Refer to the Description of Foetal Risk Categories (below) when prescribing any antimicrobial medications for women who are pregnant or lactating.
B1 Studies in animals have not shown evidence of an increased occurrence of foetal damage. B2 Studies in animals are inadequate or may be lacking, but available data show no evidence of any increased occurrence of foetal damage. B3 Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans. C Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for foetal risk or lacking as well. However, potential benefits may justify the potential risk. Positive evidence of risk. Investigational or postmarketing data shows risk to the foetus. Nevertheless, potential benefits may outweigh the potential risk. Contraindicated in pregnancy. Studies in animals or humans, or investigational or postmarketing reports have shown foetal risk that clearly outweighs any possible benefit to the patient. Drugs that have such a high risk of causing permanent damage to the foetus should not be used in pregnancy or when there is a possibility of pregnancy.
D X
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Drugs in Lactation
The benefits of breastfeeding are sufficiently important to recommend that breastfeeding should be discontinued or discouraged only when there is substantial evidence that the drug taken by the mother will be harmful to the infant and that no therapeutic equivalent can be given. Most antimicrobial drugs are only excreted to a minimal extent in breast milk, and in most cases the dosage to which the infant is ultimately exposed is very low and is well below the therapeutic dose level for infants. For this reason there are few antimicrobial drugs that are totally contraindicated whilst breastfeeding.
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ANTIBACTERIALS Penicillins Cephalosporins Beta-lactamase inhibitors (e.g. clavulanate) Erythromycin (Do not use estolate during pregnancy - increased risk of maternal hepatoxicity) Clindamycin Nitrofurantoin Roxithromycin Aminoglycosides (Potential for foetal 8th nerve toxicity) Chloramphenicol (Avoid near term - risk of Grey Baby syndrome) Clarithromycin (Foetal toxicity in primates) Fusidic acid Metronidazole and other nitroimidazoles (Avoid during first trimester) Rifampicin (Neonatal bleeding, give Vitamin K if used during last few weeks of pregnancy) Trimethoprim (Avoid use in first trimesterteratogenic) Nalidixic acid Vancomycin Tetracyclines (Discoloration of teeth, inhibition of bone growth, maternal hepatotoxicity) Sulphonamides e.g. cotrimoxazole, sulphamethoxazole (Avoid near term - risk of kernicterus) Fluoroquinolones e.g. ciprofloxacin, norfloxacin (Damage to developing cartilage in animal models)
Safe Caution high dose IV Safe Safe Caution high dose IV Safe
A A B1 D A B3 C B2
Safe, monitor infant for diarrhoea Avoid in premature infants. Caution with G6PD deficiency infants Safe Safe Not recommended Safe Safe Produces a bitter taste in milk Withhold breast-feeding for 24hrs after high dose or IV Safe
B3 A B2 D
Safe
B3
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ANTIFUNGALS Amphotericin B Fluconazole Itraconazole Ketoconazole ANTIVIRALS Aciclovir Ganciclovir Antiretrovirals (Therapy for HIV infection has not been associated with foetal risk and prevents transmission. Expert advice recommended).
Uncertain Safe Uncertain Uncertain Safe Insufficient data Contraindicated in HIV positive women
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Advantages
Eliminates the risk of adverse events associated with intravenous therapy, such as phlebitis and increased fluid burden. Increases patient comfort and acceptance of therapy and permits increased patient mobility. Increases the potential for completion of treatment as an outpatient, allowing earlier discharge from hospital. Decreases the risk and severity of allergic reactions. Reduces treatment costs.
Guidelines
Patients eligible for conversion from parenteral to oral therapy should meet the following criteria: Patient is tolerating oral or NG nutrition or is receiving medication by mouth or NG tube. Patient has a functional gastrointestinal tract. Signs and symptoms related to the infection have resolved or are improving. Patient does not fall within the parameters of exclusion as described below. Patients should be excluded from immediate consideration for Switch Therapy if they meet any of the following criteria: - Patient has an infection in which the continuation of parenteral therapy is indicated, such as endocarditis, meningitis, line sepsis or Staphylococcus aureus, or Enterococcus spp. bacteraemia. - Patient has febrile neutropenia. Response to oral medication may be unreliable e.g. in the presence of continuous NG suction, malabsorption syndrome, ileus, protracted vomiting and severe diarrhoea. Treatment should be reinstated with the original parenteral regimen if continued improvement in the patient's clinical status is not apparent on oral therapy. 111
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ANTIBACTERIALS Penicillins Amoxycillin Amoxycillin/clavulanate Flucloxacillin Penicillin V Cephalosporins Cephalexin Cephradine Cefaclor Fluoroquinolones Ciprofloxacin Gatifloxacin Moxifloxacin Macrolides Erythromycin base Erythromycin stearate Roxithromycin Tetracyclines Doxycycline Minocycline Tetracycline
60-89 60 50 35-70
1 1 0.5 0.5
17 18 95 35
Yes Yes No No
90 90 50
15-18 16 13
Yes No No
69-85 96 89
20-40 20 50
Yes No No
18-45 18-45 80
0.3-1.0 0.4-1.9 6
1.4 12
70-74 90%
No Yes No
18 11-26 8.5
93 76 65
Yes Yes No
Miscellaneous Clindamycin Metronidazole Trimethoprim / Sulphamethoxazole ANTIVIRALS Aciclovir ANTIFUNGALS Fluconazole Ketoconazole
5.3 5 10 2/40
85-94 20 44/ 70
15-30
200
0.3-0.9
2.2-5.0
9-33
Yes
90 Variable
4.5-8 10 3-4.5
24 6.5-9.6
11-12 84-99
Yes Yes
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Route(s) of Administration
Intravenous administration is the optimal method to ensure adequate tissue levels during the operative procedure. In certain instances rectal or oral administration is appropriate.
for most surgical procedures lasting less than 4 hours. A second dose may be necessary under the following circumstances: A delay in starting the operation. If the operation is prolonged so that it continues beyond four hours. In specific circumstances e.g. amputation of an ischaemic limb. Giving more than 1 or 2 doses postoperatively is not advised, except where specifically recommended. Established infection should of course be treated. Note: Prophylactic antibiotics are only one factor that determines the risk of infection. Other factors of equal or even greater importance are surgical technique, the duration of surgery, the duration of pre-operative stay, shaving the operation site (if this must be done, do so immediately pre-operatively), repeat surgical procedure, obesity, immune compromise and a variety of other host factors (eg diabetes). Excessively long courses of 'prophylactic' antibiotic, whether before or after surgery, select for resistant organisms and may increase the risk of infection. The practice of continuing prophylactic antibiotics until surgical drains have been removed is both illogical and of unproven benefit.
Choice of Antibiotic
There are several considerations when selecting an antimicrobial regimen for prophylaxis: Antibiotics should have a spectrum of activity, which includes the pathogens most frequently responsible for wound infection following a given operation. The antibiotics need not be active against every micro-organism present in the initial bacterial inoculum, as some of the micro-organisms may not contribute to the development of wound infection. Consideration should be given to the serum half-life of the antibiotic and local hospital antimicrobial susceptibility patterns. Routine use of vancomycin prophylaxis is strongly discouraged to prevent selection pressure for VRE and VRSA. However, vancomycin should replace the cephalosporin or penicillin component of a regimen when preoperative patients are infected or colonised with an MRSA strain either currently or in the recent past. The following tables contain surgical prophylaxis regimens that have been approved for use by the respective Clinical Directors at Waikato Hospital.
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Likely Pathogens
Suggested Regime(s)
Metronidazole (child:12.5mg/kg up to) 500mg IV, ending the infusion at the time of induction plus Cephazolin (child: 25mg/kg up to) 1g IV at the time of induction. A second dose of cephazolin is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred Severe penicillin allergy Gentamicin 3mg/kg IV (based on lean body mass) and metronidazole 500mg IV at induction
Clean surgery Hernia (with prosthetic material), varicose veins Thyroid and Parathyroid surgery Staphylococcus aureus, Staphylococcus epidermidis Staphylococcus aureus, Staphylococcus epidermidis Staphylococcus aureus, Staphylococcus epidermidis (occasional anaerobes) Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred Flucloxacillin 1g IV at induction.
Breast surgery
Note: Not all GI surgery needs prophylaxis. There is no indication for prophylaxis in uncomplicated cholecystectomies in patients younger than 60 as the biliary tract is normally sterile when elective operations for stone-related disease are undertaken.
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Likely Pathogens
Staphylococcus aureus, Staphylococcus epidermidis (occasional gram-negative bacilli) This carries a small but important risk of clostridial infection. Staphylococcus epidermidis, Staphylococcus aureus Aerobic Gram-negative organisms Staphylococcus epidermidis, Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus aureus
Suggested Regime(s) Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred. Use Cephazolin 1g IV at induction plus metronidazole 500mg (child: 12.5mg/kg up to 500mg) IV ending at the time of induction and then 12 hourly for 24 hours. Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred. Cephazolin 1g IV at induction only. Cephazolin 1g IV at induction only. Allow 5 minutes to elapse between administration of antibiotic and application of a tourniquet. Severe penicillin allergy Vancomycin 500mg infused over at least one hour
CARDIOTHORACIC SURGERY
EAR, NOSE AND THROAT SURGERY Head And Neck Rhinoplasty +/- cartilage graft Ear or sinus surgery with potential for dural breach Contaminated major ear or sinus surgery
1
Mixed anaerobic and anaerobic upper respiratory tract flora Staphylococcus species Mixed aerobic and anaerobic upper respiratory tract flora Mixed aerobes and anaerobic upper respiratory tract flora
Amoxycillin/clavulanate 1g/200mg IV at induction Flucloxacillin 1g IV at induction Amoxycillin/clavulanate 1g/200mg IV at induction Amoxycillin/clavulanate 1g/200mg IV at induction
The value of routine prophylaxis for the insertion of shunts, ventricular drains or pressure monitors remains unproven.
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Likely Pathogens
Suggested Regime(s)
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ENDOCARDITIS PROPHYLAXIS
A revolution in the recommendations for endocarditis prophylaxis has occurred during the last few years highlighted by the 2007 publication of the American Health Association Prevention of endocarditis guidelines - Circulation 2007;116:1736-1754. These evidence based guidelines are radically different from previous guidelines and have markedly reduced the indications for endocarditis prophylaxis acknowledging that the frequency, magnitude and duration of bacteraemia from dental and other procedures is in fact very similar to that which occurs from everyday activities. As a result, the need for specific endocarditis prophylaxis around dental and other operative procedures has been markedly reduced. The Waikato DHB has therefore created new endocarditis prophylaxis guidelines, adapted from the recommendations made within the AHA guidelines and 2008 NICE guidelines (http://www.nice.org.uk/CG064). There are likely to be further refinements once Australasian guidelines have been developed.
Cardiac Conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis is reasonable
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair. Prior episode(s) of infective endocarditis. Specific congenital heart disease only - Unrepaired cyanotic CHD, including palliatie shunts and conduits - Completely repaired congenital heart defect with prosthetic material or device during the first 6 months after the procedure - Reparied CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device Cardiac transplantation recipients who develop cardiac valvulopathy Prophylaxis is not reasonable or recommended any longer in all of the following circumstances: - Native valvular heart disease (except for those with previous infective endocarditis) - Previous rheumatic fever - Mitral valve prolapse or Hypertrophic cardiomyopathy - Previous coronary artery bypass graft surgery - Presence of a cardiac pacemaker - There is also no role for antibiotic prophylaxis in those with prosthetic joints.
Dental Procedures for which Prophylaxis is reasonable when the above highest risk cardiac conditions are present
All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa.
Respiratory Procedures for which Prophylaxis is reasonable when the above highest risk cardiac conditions are present are
Invasive procedures of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy Invasive respiratory tract procedures to treat an established infection eg drainage of abscess or empyema (Note: these individuals are likely to already be on antibiotics)
Endocarditis prophylaxis solely to prevent IE is no longer recommended for any GI or GU procedures. It is important to state that antibiotic therapy remains important in treating active infections. 119
Antibiotic Regimens
Antibiotics are aimed at Streptococcus viridans species.
Standard regimen:
Amoxycillin 2g (children 50mg/kg up to 2g) po 30 to 60 minutes before the procedure.
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SPLENECTOMY
After splenectomy, people are at risk of severe infection, particularly from a small range of encapsulated bacteria. About 70% of these post splenectomy sepsis episodes occur in the first 5 years. Adults may be at less risk than children. The most common organisms are Streptococcus pneumoniae and Haemophilus influenzae type B, with Neisseria meningitidis and S. aureus causing a few cases only. Malaria is a recognised risk which travellers should be warned about.
Vaccination
This should ideally be done 2 weeks before an elective splenectomy. Post splenectomy, response is believed to be better if given more than 2 weeks after the operation. Recommended vaccinations include: Pneumococcal 23-valent, 5 yearly. For children, a 7-valent vaccine should soon be available which is more efficacious, but the dose is too low for adults. Haemophilus influenzae Type B. This should be given as per routine schedule for children, but is unlikely to benefit adults who have a much lower incidence of disease, presumably due to pre-existing immunity. This vaccine doesnt protect against the non-typable H. influenzae, which causes adult respiratory tract infections. Meningococcal vaccine. The incidence of serogroup C and A disease in New Zealand at present (2008) is very low, therefore vaccination against these strains is likely to be of very little benefit. It is possible that the New Zealand custom-made serogroup B vaccine would be beneficial and patients with splenectomy are eligible under the Meningococcal vaccination program. Influenza vaccine seems sensible and could be offered annually.
Prophylactic Antibiotics
Penicillin for a few years has been used, but there is no consensus that it is worthwhile, particularly for adults. There are no guidelines for dose, but amoxycillin has theoretical advantages with better coverage of Haemophilus and better pharmacokinetics from oral dosing. For the motivated, informed patient who wishes to use prophylaxis, amoxycillin 250 mg daily (20mg/kg daily for children <5 years) for 3 - 5 years would be reasonable, although there is no evidence-based literature to support this.
APPENDICES
Outpatient Intravenous Therapy
To ensure the safe and co-ordinated care of a patient who is discharging into the community on IV therapy the Community Resource Nurse (CRN) must be contacted. (The ward Clinical Nurse Leader will be able to do this). The CRN will facilitate discharge planning. There are 23 District Nurses based within WDHB, and all are able to manage IV therapy.
If antibiotic-organism combinations have not been reported, this implies that these combinations are not usually recommended. Advice and occasionally additional testing are available on request.
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Acinetobacters (0.6%)
These are frequently multiresistant and require aminoglycosides.
Enterococci (7.0%)
These are intrinsically more resistant than streptococci. A penicillin is the agent of choice. There has not been any evidence of vancomycin resistance in the Waikato.
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Pseudomonas aeruginosa2
% susceptible
Beta-lactamase Ampicillin Amoxicillin clavulanate Ticarcillin clavulanate PipericillinTazobactam Cephalothin Cefotaxime / Ceftriaxone5 Ceftazidime5 Cefepime Meropenem6 Amikacin Gentamicin Tobramycin Norfloxacin Ciprofloxacin Nitrofurantoin Tetracycline Co-trimoxazole Trimethoprim
% neg Total % susc Total % susc Total % susc Total %susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total
43 1849 79 1848 85 1838 98 1842 51 1838 98 1838 98 1839 98 1840 100 1816 100 1840 95 1853 96 1849 95 1847 95 1846 97 1847
88 144 95 143 100 141 100 142 96 141 97 181 97 181 97 181 100 142 100 141 100 145 99 144 100 143 100 144 0 143
0 183 92 183 92 182 97 182 88 181 97 181 97 181 97 181 100 180 99 182 94 184 93 182 99 184 99 182 27 182
0 90 0 89 64 89 87 90 0 89 79 89 66 89 100 89 100 88 98 89 77 91 79 89 88 90 87 89 47 90
0 252 0 254 86 253 98 303 0 254 1 253 92 329 95 304 97 300 98 260 87 334 97 333 91 258 88 334 0 254
BLNAR3
79 1850 77 1848
97 144 94 143
87 184 84 184
75 91 74 90
75 91 74 90
3 290 0 252
88 25
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Enterobacter cloacae1
Serratia marcescens1
Klebsiella pneumoniae
Eshcerichia coli
Proteus mirabilis
1.Penicillin and cephalosporin susceptibilities are not routinely reported for these species because they have the ampC gene which can become derepressed leading to development of resistance. Results reported are from isolates tested at time of isolation. 2.Susceptibilities reported for P.aeruginosa include non mucoid isolates from cystic fibrosis patients. 3. Beta-lactamase negative isolates only tested. 2.0 % of 206 isolates were Beta Lactamase Negative, Ampicillin Resistant. 4. Beta-lactamase positive isolates only tested. 5. See notes on Extended Spectrum Beta Lactamase organisms. 6. Phenotypic testing by Vitek II. No genetic or EDTA inhibition testing for carbapenemases has been performed.
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Gentamicin Synergy
Fusidic acid Mupirocin Co-trimoxazole
Chloramphenicol
% susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total % susc Total
100 69 3 2365 802 2542 75 36 84 2397 84 2545 98 2368 100 2407 99 2396 1 332 23 404 73 43 63 363 51 336 59 332 100 438 60 401
23 13 41 21
70 67
8 12
100 68
921 12
63 67 81 2560 983 455 99 2392 100 249 100 2394 99 2202 72 365
31 13
100 64
25 12
98 2394
88 332
30 67
62 12
1. Note that this is just one isolate of Vancomycin Resistant Enterococcus. 2. This figure includes duplicate isolates from some patients. See notes on Resistant Isolates: MRSA. Methicillin resistance among patients with S.aureus bacteremia was 6.7% in 2006. Methods in routine use may fail to detect heterogenous vancomycin resistance. 3. Only MRSA were tested against mupirocin.
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Staphylococcus aureus
% susceptible
Enterococcus faecalis
Enterococcus faecium
Streptococcus pneumoniae
Susceptibility to Penicillin (invasive sites) or Amoxycillin (non-invasive sites) is reported according to the following criteria: Susceptible Amoxycillin M.I.C Penicillin M.I.C Invasive Isolates (total = 48 ) Total No. of Isolates tested Penicillin Ceftriaxone Erythromycin 48 8 43 No. isolates susceptible (%) 42 (87.5) 8 (100) 40 (93.0) No. isolates with intermediate susceptibility (%) 6 0 0 No. isolates resistant (%) 0 0 3 <2 <0.06 Intermediate susceptibility 4 0.12-1 Resistant >8 >2
Non Invasive Isolates (total = 120) Total No. of Isolates tested Ampicillin Erythromycin 120 118 No. isolates susceptible (%) 114 (95.0) 92 (78.0) No. isolates with intermediate susceptibility (%) 5 1 No. isolates resistant (%) 1 25
Neisseria gonorrhoeae There were 158 isolates of N.gonorrhoeae cultured in 2006. This was an increase from 101 isolates in 2005.
Total No. of Isolates tested Penicillin Ceftriaxone Ciprofloxacin 154 153 152 No. isolates susceptible (%) 71 (46.1) 153 (100.0) 104 (68.4) No. isolates with intermediate susceptibility (%) 80 (52.0) No. isolates resistant (%) 3 (1.95) 48 (31.6)
One isolate of N.gonorrhoeae was Beta Lactamase positive. Ciprofloxacin resistance has increased dramatically, from 3.5% in 2004 to 16.5% in 2005 and 31.6% in 2006.
Mycobacterium tuberculosis
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During 2006, 35 patients were culture positive for Mycobacterium tuberculosis. Critical concentration susceptibility for the first line agents Streptomycin, Isoniazid, Rifampicin and Ethambutol was performed using the Bactec MGIT 960. Pyrizinamide susceptibility is tested by Waynes method for pyrazinamidase detection. The only resistance found was one isolate with low level and one with high level resistance to Isoniazid.
MRSA
The prevalence of MRSA infections and patient colonisation has been stable since 2003. In 2006, a total of 105 patients had culture positive S.aureus bacteraemia. Of these, 6.7% (7 patients) were MRSA. Six of these 7 bacteraemias were due to the EMRSA 15 strain. Total S. aureus bacteremia cases MRSA Percent 2003 124 2004 130 2005 107 2006 105
9 7.3%
9 6%
9 8.4 %
7 6.7 %
At Emergency Dept, MRSA comprised 7.7% of the 433 cases of S. aureus infection diagnosed by culture. Strain EMRSA 15 WSSP WR/AK1 other BORSA Number of patients 16 11 3 1 1 Previously known MRSA 4/16 4/11 2/3
There were two multi-drug resistant organisms isolated during 2006. Both were community-acquired. One patient had a highly resistant E.coli from a urine specimen. This was not found to be an ESBL through further laboratory testing. The other isolate was a Morganella morganii in catheter urine from a patient with long term catheterisation. Report prepared by: Kay Stockman Manager/Technical Advisor Microbiology Dept. With contributions from: Dr Chris Mansell, Microbiologist Kathryn Coley, Mycobacteria Laboratory Specialist Ruth Barratt, Infection Control
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MRSA MANAGEMENT
The control of MRSA is important because the alternatives to beta-lactams are more toxic, more expensive and less effective. New Zealand is in the fortunate position where beta lactams can be confidently used as initial treatment in conditions where S. aureus infection is suspected. In 2005, 6% of S. aureus from blood cultures at Waikato Hospital was MRSA, although this figure fluctuates depending on local outbreaks. In many parts of the world, over 30% of S. aureus is MRSA. Patients found to be positive are isolated or cohorted and receive appropriate treatment and follow up. Fortunately, only a limited number of strains of MRSA are currently circulating within the Waikato region. At the time of writing (August 2005) most MRSA encountered in the Waikato can be treated with cotrimoxazole if oral therapy is required. Typical Antibiotic Susceptibility of MRSA Strains in the Waikato 2005 Cotrimoxazole
Erythromycin
Ciprofloxacin
Flucloxacillin
Fusidic Acid
WSPP 1 & 2
Mupirocin
MRSA Strain
Vancomycin
Comments
EMRSA 15
AKH4 WR/AK1
R R
R S
R S
R S
S V
S R
S S
Common in the community. Readily controllable by standard MRSA procedures. Doesnt cause outbreaks in our hospitals. Present in the community. Particularly transmissible and difficult to control. Causes the majority of hospitalacquired cases in the Waikato. This strain caused outbreaks at Waikato Hospital in late 2004. Uncommon at present, not endemic at Waikato Hospital. Often resistant to mupirocin. Prevalence has declined since mupirocin over the counter sales stopped.
The management of MRSA outbreaks is directed by the Infection Control Team and may vary for each particular outbreak. The location, type of clinical service, staffing and strain of MRSA will influence strategies for isolation, screening and decolonisation.
MRSA Screening
Screening is directed by the Infection Control Team. Guidelines about how to collect specimens are available in the Infection Control Manual, which is held on each ward and on the hospital intranet. Frequently, MRSA is detected in routine clinical specimens and may reflect active infection or colonisation. To detect colonisation in staff or patients, request MRSA screen and the laboratory will test by a more sensitive method and not look for other organisms. Often, swabs from several sites on the one patient will be processed as one for this purpose.
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Isolation Procedures
Detailed instructions for managing MRSA-colonised or infected patients are in the Infection Control Manual, available on the Waikato Hospital intranet and in hard copy in clinical areas. The mainstay of isolation is contact precautions. Where appropriate, they may be cohorted into multibed rooms with other MRSA patients. Where their medical conditions allow, efforts are made to discharge carriers from hospital. Patients with infectious conditions such as MRSA may be placed at the end of operating lists to reduce the possibility of cross-infection. Management of specific patients may vary at the direction of the Infection Control Team.
Clearance
It is seldom possible to clear MRSA completely from a person with active infection or unhealed lesions.
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HCV
Risk of infection is approximately 3%. Exposed person is monitored for development of Hepatitis C, particularly asymptomatic infection. If infection occurs, treatment of acute Hepatitis C may be initiated. 133
HIV
Risk of infection is approximately 0.3%, but less if the source is having effective antiretroviral treatment. Antiretroviral prophylaxis can have life-threatening complications, while HIV infection can now be managed to preserve length of survival and quality of life. Prophylaxis should generally not be given unless a definite exposure has occurred. The ideal time frame for administration is thought to be within 2 hours, but sometimes longer delays are unavoidable. Only a specialist experienced in the treatment of patients with HIV as approved and named by the Ministry of Health may prescribe antiretroviral prophylaxis. The people to contact (through Waikato Hospital telephonist) are, in order: - Dr Graham Mills, Infectious Disease Physician. - Dr Jane Morgan, Sexual Health Physician. - Auckland Hospital Infectious Disease Service (available 24hr). Please persist in making contact with one person on this list if source blood is HIV positive.
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* Not every case of acute gastroenteritis is necessarily notifiable - only those where there is a suspected common source or from a person in a high risk category, (e.g. food handler, child care worker, etc.) or single cases of chemical, bacterial, or toxic food poisoning such as botulism, toxic shellfish poisoning (any type) and disease caused by verocytotoxic E. coli.
Diseases Notifiable to Medical Officer of Health (Other than Notifiable Infectious Diseases) Lead absorption equal to or in excess of Cysticercosis 15g/dL (0.72mol/L) ** Taeniasis Poisoning arising from chemical Trichinosis contamination of the environment Decompression sickness **Blood lead levels to be reported to the Medical Officer of Health (15g/dL or 0.72mol/L) are for environmental exposure. Where occupational exposure is suspected, please notify OSH through the NODS network.
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