lOMoARcPSD|4225041

Antibiotics-Notes - Antibiotic notes

Medicine (Queen's University Belfast)

StuDocu is not sponsored or endorsed by any college or university

Downloaded by bava tharini (medicophile@yahoo.com)

Beta Lactams
Penicillin’s
Benzylpenicillin (I.V.)
Associated bacteria: Beta- haemolytic Streptococci-
Gram positive coccus
Clinical use: Bacterial meningitis, severe soft tissue
infections and septic arthritis
Other: Susceptible to beta-lactamases, poor GI
absorption therefore given I.V.
Flucloxacillin (P.O./ I.V.)
Associated bacteria: Staphylococcus aureus - Gram
positive coccus
Clinical use: Skin and soft tissue infections, device
related infections, endocarditis, bone and joint
infection, cellulitis
Other: Stable against staphylococcal beta
lactamase
Amoxicillin (P.O./ I.V.)
Associated bacteria: Streptococcus pneumoniae
and Enterococcus faecalis- Gram positive coccus
Clinical use: Pneumonia (community acquired),
URTI, LRTI, UTI, intra-abdominal infections, Otitis
media
Other: Broad spectrum
lOMoARcPSD|4225041
Combination antibiotics Bacterial cell wall
Co-amoxiclav (P.O./ I.V.) Peptidoglycan layer of bacterial cell wall is formed
Associated bacteria: Staphylococcus aureus,
by cross linked monomers NAMA (n-acetyl muramic
acid) and NAG (n-acetyl glucosamine). The cross
Enterococcus faecalis (Gram positive coccus) and linking is catalysed by transpeptidase (PBP).
Proteus mirabilis (Gram negative rod)
Clinical use: Intra-abdominal infections and severe
ENT infections/ paranasal
Other: Combination drug: Amoxicillin and
Clavulanic acid (beta lactamase inhibitor)
Tazocin (I.V.)
Associated bacteria: Pseudomonas aeruginosa
Clinical use: Severe sepsis with unknown origin and
pyrexia in neutropenic cancer chemotherapy
patients
Other: Combination drug: Pipercillin and Mode of Action
Tazobactam (beta lactamase inhibitor)
Beta- lactam ring in all
Penicillin’s binds to the
transpeptidase
(penicillin binding
Adverse effects protein) to inhibit its
cross-linking activity of
 Hypersensitivity reactions – skin rash/fever
NAMA and NAG. The
 Anaphylaxis (Type 1 IgE mediated reaction)
cell wall becomes more permeable, leaking its
 Antibiotic associated diarrhoea (oral)
contents out leading to cell death.
Also inactivate the inhibitor of autolytic enzymes in
the cell wall, leading to cell lysis (Bacteriocidal).
Downloaded by bava tharini (medicophile@yahoo.com)

Cephalosporins
Chemically related to Penicillin’s, therefore a similar
mode of action. Antibiotic resistance has increased,
especially in Gram negative bacteria –
Chromosomal gene coding for beta-lactamase that
is more active in hydrolysing Cephalosporins.
Therefore, Cephalosporin use has decreased.
Most need to be given parenterally (not orally or
rectally). Renal excretion
All cephalosporins are intrinsically resistant to
enterococcus species. This is a drawback as these
organisms live in the gut and these antibiotics are
sometimes given to cover intra-abdominal
infections.
Second and third generation cephalosporins exist:
Second generation: Cefuroxime
Associated bacteria: Staphylococcus aureus, beta-
haemolytic streptococcus (gram positive coccus)
and Klebsiella pneumoniae (gram negative rod)
Clinical use: Surgical prophylaxis (rarely used now)
Third generation ‘t’:
Cefotaxime
 Clinical use: Meningitis
Ceftazidime
 Clinical use: Bronchiectasis infections
lOMoARcPSD|4225041
Ceftriaxone
Associated bacteria: Streptococcus pneumoniae
(Gram positive coccus), Neisseria meningitidis and
Haemophilus influenzae (Gram negative cocci).
These are the three principle causes of meningitis
Clinical use: First line treatment for Bacterial
Meningitis.
Soft tissue infection, particularly as Outpatient
Parenteral Antimicrobial Therapy (OPAT).
Other: Can be given once daily I.V.
Adverse Effects
 10% cross-sensitivity with Penicillin’s: A
sensitivity reaction to a drug that
predisposes a person to react similarly to a
different, but related, drug.
 Occasional nephrotoxicity and alcohol
intolerance
Monobactam
Aztreonam (I.V.)
Associated bacteria: Only effective against gram
negative aerobic rods i.e. Pseudomonas
Clinical use: Used in combination with gram
positive active agents for patients with penicillin
allergy
Downloaded by bava tharini (medicophile@yahoo.com)
Adverse effects: GI upset, rare cross sensitivity
Other: Resistant to most beta lactamases. Avoid in
pregnancy unless benefits outweigh risk.
Only beta lactam that can be given in Penicillin
allergy.
Carbapenems
Meropenem (I.V.)
Beta-lactam: Interfere with synthesis of the
bacterial cell wall peptidoglycan.
Clinical use: Tend to be reserved for resistant
infection under Infectious Diseases guidance.
Severe Septic shock 2g 8 – hrly. Very broad
spectrum. ICU, Cancer patients
Adverse effects: GI upset, cross sensitivity
Carbapenem resistance a major concern so this
drug is given as last resort to a lot of very
vulnerable patients.
Ertapenem (I.V.)
Associated bacteria: Klebsiella pneumoniae (gram
negative rod)
Clinical use: UTIs, OPAT
Other: well tolerated and can be given o.d.
Glycopeptides

Non-beta lactams but active against cell
wall
Large polar, hydrophilic
molecules -therefore they
don’t penetrate or cross
the cell membranes well.
So, if you give them I.V. they tend to stay largely in
the blood, and they will be filtered into the kidneys.
Likewise, if you give them orally, they tend to stay
in the GIT.
Mode of Action
At the bacterial cell these drugs embed themselves
into the cell membrane of bacteria where they
block the transport of peptidoglycan monomers
(NAMA) from the cell cytoplasm (where they are
synthesised) to the cell wall.
Inhibit cell wall synthesis
Vancomycin and Teicoplanin (P.O. / I.V.)
Associated bacteria: Clostridium difficile
Clinical use: Only oral administration of vancomycin
is for severe Clostridium difficile colitis. I.V.
administration for MRSA (Methicillin Resistant Stap
Aureus). Teicoplanin only given I.V.
Adverse effects: rash, ototoxicity, nephrotoxicity
Other: No useful activity against gram negatives.
Can give combinations of aztreonam and
vancomycin for broad cover in penicillin allergic
patients.
lOMoARcPSD|4225041
Usually given orally but can be give I.V. but risk of
Bacterial Protein phlebitis.
Poor penetration in synovial fluid and concentrates
Synthesis inhibitors in phagocytes.
Adverse effects: GI upset, hypersensitivity, QT
Macrolides, Aminoglycosides and
prolongation
Tetracyclines
Drug interactions: inhibit metabolism of ciclosporin
Mode of Action and theophylline.
Site of action: bacterial ribosome -inhibiting the
production of bacterial proteins.
Prevent transfer of bacterial tRNA from A-site to P-site
on the ribosome, thus preventing elongation of
polypeptide chain (bacteriostatic).
Macrolides
Erythromycin and Clarithromycin (P.O. /
I.V.)
Associated bacteria: Legionella pneumophila,
Chlamydia trachomatis, Mycoplasma pneumonia
Aminoglycosides
(Gram negative rods) – cell wall deficient.
Gentamicin
These three bacteria cause atypical pneumonia
Associated bacteria: Pseudomonas aeruginosa,
Clinical use: Used to replace beta lactams in Klebsiella pneumonia (Gram negative rods)
penicillin allergy. Cover for ‘atypical’ causes of Gentamicin in septic shock
Clinical use: Gram negative sepsis. (Highly polar –
pneumonia
I.V. administration
Other: Clarithromycin better tolerated than Combination therapy: Meropenam
Adverse effects: Ototoxic (deafness, vertigo, ataxia)
Erythromycin. Clarithromycin has a longer T1/2 and I.V. 8hrly, Gentamicin I.V. o.d. and
and nephrotoxic (usually reversible)
better bio-availability. Vancomycin b.d.
Reversibly bind to 50S subunit of ribosome.
Downloaded by bava tharini (medicophile@yahoo.com)

Other: Narrow therapeutic window – can
accumulate in kidneys. Must reduce dose in renal
impairment.
MOA: Requires oxygen-dependent transport
mechanism to enter bacteria therefore ineffective
against anaerobes.
Binds to 30S ribosomal subunit – induces
misreading of mRNA, lyses polysomes and
interferes with initiation complexes of peptide
formation.
Measure serum trough levels after first dose and
when it reaches < 1mg/L, second dose can be
administered. Monitor U&E.
Tetracyclines
Doxycycline (P.O.)
Associated bacteria: Staphylococcus aureus,
Streptococcus pneumonia (Gram positive cocci),
lOMoARcPSD|4225041
Legionella pneumophila and Chlamydia trachomatis Ciprofloxacin (P.O. / I.V.)
(Cell wall deficient)
Associated bacteria: Klebsiella pneumonia, Proteus
Clinical use: Usually given orally as an alternative mirabilis, Pseudomonas aeruginosa (Gram negative
for community acquired pneumonia or cellulitis. rods)
Covers typical and atypical pneumonia. RTIs
Broad cover, particularly against gram negatives
Oral- MRSA
Clinical use: Oral – pseudomonas, gram negative
Avoid in pregnancy UTIs
and children
Adverse effects: Drives resistance and associated
Adverse effects: with hospital outbreaks of Clostridium difficile.
Tetracycline teeth
(stains bones and
teeth yellow because it chelates calcium ions)
Levofloxacin (P.O. / I.V.)
Agents acting on Associated bacteria: Streptococcus pneumoniae
(Gram positive cocci), Legionella pneumophila and
Nucleic Acid Chlamydia trachomatis (Cell wall deficient)
Clinical use: typical and atypical causes of
Synthesis pneumonia. Respiratory Quinolone. Excellent
activity against streptococcus pneumoniae and
causes of ‘atypical’ pneumonia
Quinolones
Adverse Effects
Ciprofloxacin, Levofloxacin,
 GI upset and C. difficile risk
Moxifloxacin  Hypersensitivity
 Convulsions (rare)
Mode of Action  QT – prolongation
 Inhibits CYP450 – toxicity
Inhibit bacterial DNA gyrase
 Tendon damage (rare)
(Topoisomerase II) – preventing
supercoiling of DNA double helix,
transcription and replication. Metronidazole
Downloaded by bava tharini (medicophile@yahoo.com)

Pro-drug: activated in low oxygen conditions. Nitro
group reduced to reactive products. Metronidazole
would be toxic to human cells, but it is only
activated in low oxygen conditions. This is how it
has ‘selective toxicity’.
Associated bacteria: Clostridium difficile (Gram
positive rod), anaerobic species.
Clinical use: First line for C. difficile colitis, Intra-
abdominal infections, Oral infections.
Other: P.O. / I.V. Combination with cefuroxime in
surgical prophylaxis
Nitrofurans
Nitrofurantoin (P.O)
Inhibits bacterial enzymes in protein synthesis and
is DNA toxic. (Acts on nucleic acid synthesis)
Associated bacteria: Enterococcus faecalis (Gram
positive cocci), E. coli (Gram negative rod)
Clinical use: UTIs (Not pseudomonal or proteus)
lOMoARcPSD|4225041
Other: Therapeutic levels are only attained in the Associated bacteria: Enterococcus faecalis (Gram
urine. Not effective in renal failure - BNF says avoid positive cocci), E. coli (Gram negative rod)
if GFR is <45ml/min.
Clinical use: Uncomplicated UTIs e.g. cystitis
Adverse effects: Peripheral neuropathy, Haemolytic
Other: Can be combined with Sulfamethoxazole
anaemia, Pulmonary fibrosis, hypersensitivity and
(Co-trimoxazole) to treat pneumocystis pneumonia.
GI upset.
Action on Nucleoside Folate antagonist. Blocks the bacterial folate
synthesis pathway by inhibiting the enzyme
Precursors dihydrofolate reductase. Required to produce
pyrimidines and purines and subsequently
deoxyribonucleic acid.
Trimethoprim (P.O.)
Antibiotic Resistance
Downloaded by bava tharini (medicophile@yahoo.com)

Inherent resistance: Naturally occurring e.g.
bacteria with absent cell was are inherently
resistant to beta-lactam antibiotics. Bacteria
may have underlying genes that can be induced
in response to environmental factors. Microbe-
microbe survival competition.
Acquired resistance: Can occur via;
spontaneous mutation and clonal expansion or
transferable resistance in the form of plasmids.
Extra-chromosomal genetic elements can freely
replicate in the cytoplasm. Plasmids (mobile
genetic elements) seem to be the biggest
problem in resistance development. Plasmids
carry r-genes which can be readily transferred
to another plasmid or chromosome.
Molecular mechanisms
 Altered target site
 Enzymatic degradation
 Alteration of uptake or output of
antimicrobial (efflux pumps)
 Use of alternative pathways for
metabolism and growth.
Decreased permeability
Antibiotics usually enter bacteria via porin
channels in the cell wall. Porin loss/change =
less antibiotic can enter cell.
Enzymatic degradation
lOMoARcPSD|4225041
 Inactivation of beta lactam antibiotics It has been found that HIV positive people have
by beta lactamase producing organisms a greater tendency to become resistant to M.
e.g. S. aureus, N. gonorrhoea, H. tuberculosis. (Particularly bad where both of
influenza. Cleave beta-lactam ring. these diseases are very prevalent).
 Carbapenemase producing
Enterobacteriaceae (CPE) e.g. E. coli and Pseudomonas aeruginosa
Klebsiella. Carbapenemase destroys the  Efflux pump overexpression
antibiotic; Meropenem and Ertapenem.  Low permeability
 ESBL E.coli, OXA-48, KPC, NDM  Beta-lactamase production
 Horizontal transfer – mutations leading
Altered target site
to over expression of efflux pumps and
Glycopeptide resistant Enterococcus (GRE): reduced uptake.
Glycopeptides (Vancomycin and Teicoplanin)
Intrinsic, Adaptive and Acquired resistance.
bind to peptidoglycan precursor molecules to
prevent bacterial incorporation into the cell
wall. Altered precursor molecules prevent
glycopeptide binding.
MRSA (Methicillin Resistant Staph. Aureus):
Altered Penicillin binding protein (PBP),
therefore beta-lactam fails to bind. Associated
with MecA and MecC gene. MecA encodes
beta-lactam-insensitive protein PBP2a.
Mycobacterium Tuberculosis
Multi-drug resistant TB (MDR-TB) – defined as
resistant to Rifampicin and Isoniazid. Multiple
mechanisms of resistance but a degree of
intrinsic resistance from lipid cell wall.
Treatment usually involved a combination of
four drugs.
Downloaded by bava tharini (medicophile@yahoo.com)