Antibacterial Antiviral Antifungal Antiparasitic Pharmacophore: active chemical moiety of the drug which binds to the microbial receptor

Biochemical processes commonly inhibited: Cell wall synthesis in bacteria/fungi Cell membrane synthesis Synthesis of 30s and 50s ribosomal subunits Nucleic acid metabolism Function of topoisomerases, viral proteases, viral integrases, viral envelope fusion proteins Folate synthesis in parasites Parasitic chemical detoxification processes

 Classification of antibiotic based on: Class and spectrum of microorganism it kills Biochemical pathway it interferes with Chemical structure of its pharmacophore

 PHARMACOKINETIC BASIS OF ANTIMICROBIAL THERAPY Ability of drug to penetrate the site of infection = crucial consideration in choosing an antimicrobial agent for therapy Penetration of a drug depends on:
Physical barriers Chemical properties of the drug Presence of multi-drug transporters

 Physical barriers Layers of epithelial and endothelial cells Type of junctions formed between these cells Octanol-water partition coefficient of antimicrobial agent
Measure of the hydrophilicity/hydrophobicity of the agent Hydrophobic agents-concentrate in the bilipid cell membrane bi-layer Hydrophilic agents-concentrate in the blood, cytosol and other aqueous compartments

octanol-water partition coefficient > likelihood of crossing physical barriers erected by layers of cells More charged/larger moleculepoorer penetration CNS Guarded by BBB
Tight junctions that connect endothelial cells of cerebral microvessels to one another Protein transporters Antibiotics that are polar at physiologic pHpoor penetration

 integrity during active bact. Infectionsmarked in penetration Eye : poor penetration of drug from plasma Standard Tx: direct instillation Other compartments requiring special penetration Endocardial vegetations/biofilm on artificial heart valves, IV caths, artificial hips, ORIF devices

 Variability in Drug Response Between-patient variability

Same dose of drug given to multiple patientsdifferent pharmacokinetic parameters

Inter-occasion/within-patient variability
Same dose administered to same patient on different occasionsdifferent conc.-time profile of the drug

 Causes: Genetic variability Weight, height, age Comorbid conditions renal/liver dysfunction Residual variability due to unexplainable factors

 Susceptibility Testing ID and isolation of organism choice of antibioticsusceptibility testing done to narrow down the list of antimicrobials to be used Bacteria
Dilution tests
MIC (minimum inhibitory conc.): lowest conc. Of the agent that prevents visible growth after 18-24 hrs of incubation

 Fungi
Same as used for bacteria MIC-depends on drug and type of yeast

Viruses
HIV phenotypic assaysgenotypic tests

Parasites
Similar to bacteria, fungi, viruses

 Basis for selection of dose and dosing schedule Susceptibility of the organism to the antimicrobial agent
Ex. Vancomycin
Resistance MIC >2.0 mg/L MRSA 61% success rate w/ MIC 0.5 mg/L 28% for MIC 1.0 11% for MIC 2.0

Actual drug concentration achieved at site of action-most impt

Dose-poor measure due to between-patient and w/in-patient variability

 Optimal dose of antibiotic for a patient=dose that achieves IC80 to IC90 exposures at site of infection Optimal microbial kill by the antibiotic may be best achieved by maximizing antimicrobial effect Some classes of antimicrobials kill best when concentration persists above MIC for longer durations of dosing interval
Beta-lactams 5-fluorocytosine Drug should be dosed more frequently or t prolonged by other drugs

 Some drugs depend on peak concentration

Aminoglycosides
Highly effective once daily

Rifampin
Long duration of post-antibiotic effect Administer combined doses on a >intermittent basis(OD)maximize effect Also toxicity

 TYPES AND GOALS OF ANTIMICROBIAL THERAPY Prophylactic Preemptive Empirical Definitive/suppressive

 Prophylactic therapy Treating patients not yet infected/not yet developed the disease Goal: prevent infection
Prevent devt of a potentially dangerous dse in those w/ evidence of infection

Main principle: targeted therapy Used in immunocompromised patients

Therapy based on pathogens that are major causes of morbidity AIDS-CD4 count <200 cells per mm3

 Chemoprophylaxis Prevent wound infection after surgery Antimicrobial activity must be present at the wound site at the time of its closure

1st dose begun w/in 60 min

before surgical incision, D/C w/in 24 hrs Antibiotic must be active against the most likely contaminating microorganisms for that type of surgery

 Pts at risk for infective endocarditis for w/c prophylaxis is recommended Those w/ prosthetic material used for heart valve repair/replacement Previous infective endocarditis CHD(unrepaired cyanotic heart dse, w/in 6 mos of repair of heart dse w/ prosthetic material, residual defects adjacent to prosthetic material) Postcardiac transplant patients w/ heart valve defects

 Prophylaxis recommended for above patients if:

Dental procedures Manipulation of gingival tissue/periapical region of teeth Perforation of oral mucosa Single dose of oral Amoxicillin 30 min 1 hour before procedure
IV Ampicillin or Ceftrixone Macrolide /Clindamycin - allergic

 Post-exposure prophylaxis Meningococcal meningitis prevention after exposure: Rifampin Prevention of Gonorrhea/Syphilis Macrolides after contact w/ Pertussis HIV exposure-4 weeks therapy

 Pre-emptive therapy Delivery of therapy prior to development of symptomsaborts impending dse Short and defined duration of therapy Tx for CMV after hamatopoietic stem cell transplants and after solid organ transplantation

 Empirical Tx in symptomatic patient 1st determine if drug is indicated Gram staining of infected secretion/body fluid
Most valuable and time tested method for ID of bacteria

Definitive Tx w/ Known Pathogen Monotherapy-preferred risk of toxicity and selection of antimicrobial-resistant pathogens

 Combination Tx Prevent resistance to monoTx Accelerating rapidity of microbial kill Enhance therapeutic efficacy by use of synergistic interactions or enhancing kill Reducing toxicity

 MECHANISMS OF RESISTANCE TO ANTIMICROBIAL AGENTS 2 major factors

Evolution
For survival Aided by poor therapeutic practices Indiscriminate use of antibiotics

Clinical/environmental practices

 Resistance due to: Reduced entry of antibiotic into pathogen Enhanced export of antibiotic Release of microbial enzymes that destroy antibiotic Alteration of microbial proteins that transform prodrugs to active Alteration of target proteins Development of alternative pathways to those inhibited by antibiotic

 Resistance due to reduced entry of drug into pathogen Porins-protein channels through which antibiotics pass through outer membrane of gm bacteria Absence Mutation porin channel slow/prevent Loss drug entry into cell
resistance

 Resistance due to drug efflux 5 major systems of efflux pumps

Multidrug and toxic compound extruder (MATE) Major facilitator superfamily (MFS) transporters Small multidrug resustance (SMR) system Resistance modulation division (RND) exporters ATP binding cassette (ABC) transporters

 Efflux pumps-prominent mech. Of resistance for parasites, bacteria and fungi Ex. P. falciparum resistant to chloroquine, quinine, mefloquine, halofantrine, lumefantrine
Mediated by ABC transporter encoded by P. falciparum multidrug resistance gene 1 (Pfmdr1)

 Resistance due to destruction of antibiotic Drug inactivation Ex. Drug resistance to aminoglycosides and -lactam antibiotics
due to production of an aminoglycoside-modifying enzyme or lactamase

 Resistance due to affinity of drug to altered target structure Single point or multiple point mutations
affinity of drug for its target Due to: mutation of natural target(fluoroquinolone resistance) Target modification (macrolides and tetracyclines)

 Acquisition of a resistant form of the native, susceptible target (MRSA due to production of low affinity PCN-binding protein) Resistance due to Incorporation of drug Org not only becomes resistant but starts requiring it for growth Ex-Vancomycin resistant Enterococcus
Due to prolonged exposure to Vancomycin

 Resistance due to Enhanced Excision of incorporated drug Zidovudine Hetero-resistance and Viral Quasi species Subset of total microbial population is resistant, despite susceptibility of total population on testing

 Evolutionary Basis of Resistance Emergence Mutation selection Occur in the gene encoding:
Target protein no longer binds the drug Protein involved in drug transport Protein impt for drug activation/inactivation Regulatory gene or promoter affecting expression of the target

Not caused by drug alone Random events that give a survival advantage when drug is present

 Hypermutable phenotypes Ability to protect genetic information from disintegrating Flexibility to allow genetic changes leading to adaptation
essential for life

 Accomplished by: Insertion of correct base pair by DNA polymerase III Proofreading by the polymerase Postreplicative repair Defect in any of these repair mechanisms high degree of mutations May include mutations in genes causing antibiotic resistance Ex - MDRTB

 Resistance by External Acquisition of Genetic Elements Horizontal transfer of resistance determinants from a donor cell(another bact. Species)

 SUMMARY Success of antimicrobial tx

Proper selection of drug based on microbiological results and susceptibility testing Knowledge of drug penetration into infected compartment Knowledge of compartmental pharmacokinetics

 PENICILLIN Thiazolidine ring connected to a -lactam ring, attached to a side chain

PCN nucleus chief structural requirement for biological activity Side chain-determines many antibacterial and pharmacological char. Of a particular type of PCN

PCN G-greatest antimicrobial activity

Only natural PCN used clinically

 MOA: Inhibition of bacterial cell wall synthesis Mech. Of Bacterial Resistance Structural differences in PBPs(PCN-binding proteins)targets of drug
Found in bacterial cell wall

Development of high-molecular-weight PBPs w/ decreased affinity for PCN Inability to penetrate site of action Active efflux pumpsremove antibiotic from its site of action before it can act

 Enzymatically ( lactamases)
4 classes Class A: extended spectrum (ESBLs) Degrade PCN, some cephalosporins, carbapenems Most worrisome: KPC carbapenemase in Enterobacteriaceaeresistant to Carbapenems, PCN all extended spectrum cephalosporins Class B: Zn+ dependent enzymes Destroy all - lactams except Aztreonam

 Class C: active against cephalosporins Class D: Cloxacillin-degrading enzymes

Gm + bacteria-produce and secrete a large amount of lactamase Most enzymes: penicillinases

 Other factors that influence activity Microorganisms adhering to implanted prosthetic devices (catheters, artificial joints, prosthetic heart valves)produce biofilmsmuch < sensitive to antibiotic Tx
Density of bacterial population influence Age of infection activity of lactams

Presence of proteins/other constituents of pus, low pH, low O2 tensiondoes not decrease ability of - lactams to kill bacteria

 Classification of PCN Table 53-1 Penicillin G and V Readily hydrolyzed by PCNase Active against sensitive strains of gm + cocci Ineffective against most S. aureus PCNase resistant PCNs Nafcillin, oxacillin, cloxacillin, dicloxacillin 1st line for PCNase producing S. aureus and S. epidermidis

 Ampicillin, Amoxicillin Extended spectrum including gm (-) org: H. influenzae, E. coli, P. mirabilis Ther. Conc of PCN-achieved readily in tissues and secretions (joint, pleural fluid and bile) Low conc-prostatic secretions, brain tissue, intraocular fluid

 PENICILLIN G and V Antimicrobial activity

Similar for aerobic gm + org PCN G-5-10> more active against Neisseria sp Many bacteria previously sensitive to PCN G are now resistant
Viridans streptococci S. pneumoniae S. aureus S. epidermidis PCNase producing gonococci

Not effective against amebae, plasmodia, rickettsiae, fungi or viruses

 Absorption Oral admin of PCN G

1/3 of dose absorbed pH 2 of gastric juice destroys antibiotic Rapid absorption Max conc in bld achieved in 30-60 min Ingestion of food interferes w/ absorption administered 30 min before meals or 2 hours after

 Oral admin of PCN V More stable in acidic medium Better absorbed from GIT Parenteral admin of PCN G Peak plasma conc. w/in 15-30 min PCN G benzathine
Releases PCN G slowly from area of injection Produces low but persistent conc. In the blood

 Distribution Conc. Vary in different fluids and tissues Sig. amounts = liver, bile, kidney, semen, joint fluid, lymph and intestine Penetration into CSF
Normal meninges-does not readily enter CSF Acutely inflamed meninges-penetrates into CSF easilytherapeutically effective against susceptible org Probenecid-elevates conc. Of PCN in CSF by inhibiting active transport processno secretion of PCN from CSF into bloodstream

 Excretion Mainly by kidney Small part-bile and other routes

 Therapeutic Uses Pneumococcal infections

DOC for sensitive strains of S. pneumoniae

Pneumococcal pneumonia
3rd gen cephalosporin/20-24 M units PCN G daily by continuous IV infusion Tx continued for 7-10 days

Pneumococcal meningitis
Only if sensitive to PCN

Strep pharyngitis
Caused by S. pyogenes PCN V 500 mg q 6H x 10D

 Infections caused by other Streptococci Viridans grp-most common cause of infectious endocarditis PCN-sensitivedaily doses of 12-20 M units of IV PCN G for 2 weeks + Gentamicin 1 mg/kg q 8H Infections w/ Anaerobes Sensitive to PCN G exceptB. fragilis

 Staphylococcal Infections Resistant due to penicillinase Meningococcal Infections PCN G-DOC High doses IV Does not eliminate carrier stateineffective for prophylaxis Gonococcal Infections > resistant Ceftriaxone

 Syphilis 1o, 2o, and latent syphilis of <1 yr duration

PCN G procaine 2.4 M units/day Implus Probenecid 1 g/day orally for 10 days OR Weekly IM doses of 2.4 M units of PCN G benzathine

70-90% of pts w/ 2o syphilis develop JarischHerxheimer reaction

Hrs after 1st injection w/ PCN Chills, fever, headache, myalgias, arthralgias Syphilitic cutaneous lesionsbecome more prominent, edematous and brilliant in color

 Due to release of spirochetal antigens with subsequent host reactions to the products Persist for a few hours, rash begins to fade w/in 48 hrs Tx: Aspirin, do not D/C Tx

Actinomycosis PCN G-DOC 20 M units IV daily for 6 weeks Clostridial Infections DOC for gas gangrene 12-20 M units/day IV + antitoxin + debridement

 Recurrences of Rheumatic Fever 200,000 units PCN G/V q 12H orally 1.2 M units PCN G benzathine IM once monthly for 1 year

 PENICILLINASE-RESISTANT PENICILLINS Use restricted to treatment of infections known/suspected to be caused by Staph elaborating penicillinase Oxacillin, Cloxacillin, Dicloxacillin
Stable in acidic medium Not substitutes for PCN G, not active against enterococci or Listeria Potent inhibitors of the growth of most PCNase-producing Staph

Dicloxacillin-most active Absorption more effective on an empty stomach

 Administered 1 hour before or 2 hours after meals

Nafcillin
>active than Oxacillin against PCN-resistant S. aureus

 AMINOPENICILLINS Ampicillin, Amoxicillin Bactericidal for both gm+ and gm- bacteria
Meningococci, L. monocytogenes-sensitive Salmonella, Shigella(most strains), Pseudomonas, Klebsiella, Serratia, Acinetobacter, indole+ Proteus resistant

Ampicillin
Stable in acid Well absorbed after oral administration Intake of food prior to ingestion diminishes absorption

 Amoxicillin Absorbed more rapidly and completely from GIT than Ampicillin (major difference) Similar antimicrobial spectrum to Ampicillin
< effective for Shigellosis

 Therapeutic Indications URTI

Active against S. pyogenes, S. pneumoniae, H. influenzae Sinusitis, OM, acute exacerbations of chronic bronchitis, epiglottitis Most active against both PCN-sensitive and PCN-resistant S. pneumoniae Addition of beta lactamase inhibitor-extends spectrum to beta lactamase producing H. influenzae and Enterobacteriaceae

 UTI Ampicillin-effective but w/ inc. resistance Meningitis S. pneumoniae or N. meningitidis 20-30%-resistant Ampicillin + Vancomycin + 3rd gen Cephalosporin L. monocytogenes-Ampicillin (excellent activity)

 Salmonella infections Fluoroquinolone/Ceftriaxone-DOC High doses Ampicillin (12 g/day) for adults

 ANTIPSEUDOMONAL PCNs Carboxypenicillins

Carbenicillin Ticarcillin
Active against P. aeruginosa and Proteus w/c are resistant to Ampicillin Ineffective against S. aureus, E. faecalis, Klebsiella, L. monocytogenes

Ureidopenicillins
Mezlocillin Piperacillin
Superior activity vs P. aeruginosa klebsiella

 Carbenicillin 1st PCN w/ activity vs P. aeruginosa and some Proteus strains resistant to Ampicillin Contains 5 mEq Na+ per gram of drug
May produce CHF due to excess Na+

Carbenicillin Indanyl Sodium Acid stable, avail. For oral admin Only use is for mgt of UTI caused by Proteus spp other than P. mirabilis and P. aeruginosa
Active component excreted rapidly in urine=therapeutic conc.

 Piperacillin Extends spectrum of Ampicillin to include P.aeruginosa, Enterobacteriaceae, Bacteroides spp and E. faecalis + lactamase inhibitor(PiperacillinTazobactam)
Broadest antibacterial spectrum of PCNs

Tx of pts w/ serious infections caused by gmbacteria

Bacteremia, pneumonias, infections ff. burns, UTI caused by P. aeruginosa, Proteus, Enterobacter spp

 Ticarcillin 2-4x > active vs P. aeruginosa vs Carbenicillin < Piperacillin for Pseudomonas Mezlocillin > active against Klebsiella than Carbenicillin > activs vs E. faecalis than Ticarcillin D/C in US

 UNTOWARD REACTIONS TO PCNs Hypersensitivity reactions

Most common Maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, anaphylaxis Extends to other beta-lactams Management
Careful Hx Desensitizations Gradually increasing doses

 Pts w/ life-threatening infections

Continued on PCN despite rashoften resolves as Tx is D/C Give antihistamines or glucocorticoids

 Other Adverse Reactions BM depression Granulocytopenia Hepatitis (Oxacillin and Nafcillin) Pain/sterile inflammatory rxns at sites of IM injections N and V Diarrhea PCN procaine G
Dizziness, tinnitus, headache, hallucinations, seizures Due to rapid release of toxic conc. Of Procaine