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Antibiotics

Terms in this set (96)

What are the patient factors to consider when prescribing antibiotics?
Site and source of infection
Likely cause of infection at site
RF for specific infections/resistant organisms
Immune status of patient

Organ dysfunction
Special patient groups - children, pregnant
History of adverse events
Other medication
Co-morbidities
What the antibiotic factors to consider when prescribing antibiotics?
Spectrum of activity
Method of administration
Penetration to site of infection
Bacteriocidal vs static
Metabolism, excretion
Side effect profile
Optimum dosing - maximise efficacy, minimise SE, need for monitoring some agents
Cost
What is MIC?
Minimum Inhibitory Capacity - the concentration under standard conditions at which no visible growth of bacteria in broth/on plate

Disc diffusion - zone of inhibition around ABx - susceptibility gauged by zone diameter
What are the pharmaco-dynamic determinants of outcome by ABx treatment?
Different parameters predict response to therapy for different ABx classes

Time > MIC - beta-lactams, vancomycin, macrolides
Cmax/MIC ratio - aminoglycosides
AUC-24 hours/MIC ratio - fluoroquinolones
What are the agents that act on the cell wall?
Beta-lactams - penicillins, cephalosporins, carbapenems
Bind to penicillin binding proteins - inhibit cell wall synthesis
What are the penicillins?
Benzyl-penicillin
Penicillin V
Flucloxacillin
Amoxicillin/ampicillin
Piperacillin
Benzyl-penicillin
IV only
Streptococci, neisseria meningitidis, some anaerobes
Penicillin V
Streptococci, some anaerobes
po
Flucloxacillin
Staph aureus, streptococci, some anaerobes
Amoxicillin
Streptococci, Neisseria meningitidis, some anaerobes, some limited enterobacteriaceae, H influenzae, enterococci, listeria
Piperacillin
Anti-pseudomonal penicillin
Same as amoxicillin
Enhanced enterobacteriaceae activity, pseudomonas
What are beta-lactamase inhibitors-beta-lactam combinations?
Restore function of beta-lactam where resistance has been mediated by beta-lactamases
Augmentin (amoxicillin and clavulanic acid)
Tazocin (piperacillin and tazobactam)
Augmentin
Active against staph aureus
Enhanced activity - Enterobacteriaceae and anaerobes
Tazocin
Pseudomonas cover
Active against staph aureus
Enhanced activity -Enterobacteriaceae and anaerobes
What are the 3 generations of cephalosporins?
1st - cefalexin, cefradine
2nd - cefuroxime
3rd - cefotaxime, ceftazidime
Cefradine, Cefalexin
Staph aureus, streptococci, limited enterobact cover
1st gen
Cefuroxime
Increased spectrum and potency against enterobact
2nd gen
Cefotaxime, Ceftazidime
Greater increased spectrum and potency vs enterobact
Reduced activity gram positives
3rd gen
Ceftazidime
Pseudomonas
Carbapenems
V broad spectrum
Enterobact (and multi-drug resistance), pseudomonas, staph and streptococci, anaerobes

Meropenem, imipenem
What is the % of penicillin allergies?
Often reported - only 10% respond to challenge
0.4% or less are actually true type 1 reactions
What are the adverse reactions against beta-lactams?
Allergy
Antibiotic associated diarrhoea, other GI upset
Reduced seizure threshold, neutropenia, liver enzyme abnorms, interstitial nephritis
Glycopeptides
Gram-pos cocci and bacilli (incl MRSA)
Vancomycin, teicoplanin
Cell wall active agents
When are glycopeptides used IV?
Serious infections with:
known/suspected infection with multi-resistant gram pos bacteria (eg MRSA)
Beta-lactam allergy, known/suspected infection with gram-pos bacteria - skin/soft tissue, joint/bone, prosthetic, or endocarditis infections
What are the ADRs with glycopeptides?
Nephrotoxicity
Ototoxicity
Allergy
Cytopenias
Red man syndrome

Levels are monitored (to ensure therapeutic levels achieved)
Aminoglycosides
-mycins (streptomycin, gentamicin, amikacin, tobramycin)

Bind 30s subunit of ribosomes -> conformational change -> interrupts translation and translocation of mRNA
Gentamycin
Gram-neg bacilli (incl pseudomonas)
Staphylococci
Streptococci - resistance if monotherapy - but synergistic killing when combined with cell wall active agents like beta-lactams
Adverse events - aminoglycosides
Significant toxicity with narrow therapeutic index (drug levels required)
Nephrotoxic, ototoxic
Neuromuscular blockade
Allergy uncommon
Properties of aminoglycosides
Bactericidal
Concentration dependent killing
Post-ABx effect
Cross bbb poorly, low conc in bronchial secretions, v high conc in urine
Clinical use aminoglycosides
Combination regimes with beta-lactam
Gram-negative sepsis
Complicated UTI
Neutropenic sepsis
Synergistic killing in strep/enterococcal endocarditis
Action of fluroquinolones
Inhibit DNA gyrase and topoisomerase - inhibit bacterial DNA synthesis
Bactericidal
Excellent oral bioavailability

Ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin
Ciprofloxacin
Aerobic gram negative (incl pseudomonas)
Staphylococci
Atypical bacteria - legionella, mycoplasma
Levofloxacin
Enhanced activity vs streptococci and anaerobes
Clinical usage of ciprofloxacin
Pseudomonal infection if oral therapy appropriate
Complicated UTI, prostatitis
Abdominal infections
Clinical usage of levofloxacin
Pneumonia (beta-lactam allergy)
Legionnaire's disease
Adverse events fluoroquinolones
ABx-assoc diarrhoea
Tendon rupture
CNS SE including seizures
Not for children (except CF) and pregnancy - risk arthropathy
Macrolides
Bind 50s ribosomal sub-unit- inhibit bacterial protein synthesis

Erythromycin, clarithromycin, azithromycin, clindamycin
Eryth/Clarithromycin
Staph and streptococci
Moraxella, Haemophilus
'Atypical pathogens'
Clindamycin
Staph and streptococci, anaerobes
Clinical usage macrolides
Empirical treatment pneumonia (with beta-lactam)
Chlamydia, non-gonococcal urethritis
Skin and soft tissue infection (beta-lactam allergy)
Adverse events macrolides
GI upset
ABx--associated diarrhoea
Other SE infrequent
Tetracyclines
Bind 30s ribosomal subunit - inhibit protein synthesis
Bacteriostatic
Generally well tolerated - contraindicated children and pregnant

Broad spectrum (gram pos, gram neg, atypical) - usefulness limited by development of resistance
Rifampicin
Inhibits DNA-dependent RNA polymerase
TB treatment regimen, staph aureus
Fusidic acid
Inhibits protein synthesis
Staph aureus
Nitrofurantoin
UTI
Trimethoprim
Inhibits folate metabolism
UTI
Metronidazole
Anaerobic cover
Free radical production - DNA and protein damage
Linezolid
Gram pos bacteria incl MRSA, VRE
Inhibits protein synthesis
Daptomycin
Alters integrity of bacterial cell membrane
Gram pos bacteria including MRSA
Tigecyline
Reduced resistance (similar to tetracyclines)
Broad spectrum - MRSA, VRE, gram-negs
What are the causes of CAP?
Streptococcus p
Haemophilus influenzae
Mycoplasma p
Legionella pneumophilia
Treatment CAP
Mild - amoxicillin +/- clarithromycin
Moderate/severe - augmentin + clarithromycin

Beta-lactam allergy/confirmed Legionella - levofloxacin
HAP causes
Gram-neg aerobes - E coli
Pseudomona aeruginosa
Staph aureus
HAP treatment
Tazocin
Vancomycin, rifampicin
Abdominal sepsis causes
Gram neg aerobes (eg E coli)
Anaerobes
Treatment abdominal sepsis
Augmentin
Causes complicated abdominal sepsis
Gram neg aerobes (eg E coli)
Anaerobes
Multi-resistant gram-neg aerobes
Enterococci
Candida
Complicated abdominal sepsis treatment
Tazocin, meropenem and fluconazole
Simple UTI causes
Gram neg aerobes (E coli)
Staph saprophyticus
Enterococci
Simple UTI treatment
Trimethoprim
Nitrofurantoin, cefradine, amoxicillin
UTI in pregnancy - causes
gram neg aerobes (E coli)
Staph saprophyticus
Enterococci
Pregnancy UTI treatment
trimethoprim - not in first trimester
Nitrofurantoin - not in 3rd trimester
Cefradine, amoxicillin
Pyelonephritis causes
Gram neg aerobes (E coli)
Staph saprophyticus
Enterococci
- drug resistance more of a concern
Pyelonephritis treatment
Augmentin and gentamycin
Ciprofloxacin
Skin and soft tissue infection causes
Streptococcus pyogenes
Staphylococcus aureus
Skin and soft tissue infection - treatment
Flucloxacillin
Septic arthritis, osteomyelitis - causes
Staph aureus, streptococci, sometimes gram neg aerobes
Septic arthritis, osteomyelitis - treatment
Flucloxacillin with fusidic acid or rifampicin
Meningitis causes
Neisseria meningitides
Strep pneumoniae
H influenzae
Listeria monocytogenes
Meningitis treatment
Cefotaxime
EUCAST
European committee on antimicrobial susceptibility testing - defines antimicrobial susceptibility and resistance
Clinically susceptible organism
Level of antimicrobial activity associated with high likelihood of therapeutic success
Clinically intermediate organism
Level of antimicrobial activity associated with in-determinate therapeutic effect
Clinically resistant organism
Level of antimicrobial activity associated with high likelihood of therapeutic failure
MIC
Minimum Inhibitory Concentration
Lowest concentration of drug that inhibits visible growth of organism, after appropriate incubation
Intrinsic resistance
Fundamental characteristic of a bacteria
Acquired resistance
New characteristic achieved either by mutation of existing DNA or acquisition of new genetic material
Problem of resistance
Poor outcome for treatment
Intrinsic - determines the activity profile of ABx
Acquired - prediction more difficult, decreases therapeutic options
Mechanisms of resistance
ABx target site modification
ABx-modifying enzymes
Cell wall impermeability, periplasmic membrane - ABx doesn't get to site of action
Efflux - pump ABx out
Spread of resistance
Mutational resistance
Transfer of genetic material
Transfer of organisms
Mutational resistance
Via mutation event - can happen easily
eg rifampicin resistance requires single mutation in gene for target (RNA polymerase)
Transfer of genetic material in spread/acquisition of resistance
Plasmids - transfer between bacteria (conjugation)
Mobile genetic elements - integrons, transposons move genes around the chromosome and to plasmids
S pneumoniae penicillin resistance
Uncommon in UK ~5%
Problem for meningitis rather than RTI
Mechanism penicillin resistance in S pneumoniae
Altered penicillin binding proteins (enzymes involved in cell wall formation - targets for beta-lactams)
'Naturally transformable' - picks up DNA floating in environment and mixes into chromosome
Macrolide site of action
Inhibits protein synthesis (peptides pass through peptide exit channel in 50 S ribosomal subunit - macrolides interact with 23 s rRNA in upper portion of exit channel)
Inhibits 50 s sub-unit assembly
Mechanisms of macrolide resistance
Target site modification of 23 s rRNA
Drug efflux
Target site modification of ribosomal proteins
What is the gene involved in target site modification of 23 s rRNA?
Erm genes (S aureus, pneumoniae, pyogenes)
- encode methylase -methylates A2058

mefA - S pyogenes, S pneumoniae (M phenotype)
msrA - S aureus (MS phenotype)
What are the mutations in ribosomal proteins?
Mutations in L4 or L22 ribosomal proteins (S pneum, pyogenes, aureus)
Non-transferable chromosomal mutation
What is the timeline of beta-lactam resistance in S aureus?
1940 - penicillin - then beta-lactamase appeared in S aureus
1960-70s - beta-lactams developed that were stable to staphylococcal beta-lactamase (cephalosporin, flucloxacillin, co-amoxiclav)
60s - MRSA emerged
1990s MRSA worldwide (>900 strains)
What is resistant to vancomycin?
Enterococci
1st reported 1988

Vancomycin MIC >128 mg/L
Vancomycin mode of action
Binds to terminal D-ala-D-ala of pentapeptide side chains
Prevents transglycosylation and transpeptidation required for polymerisation of PG in cell wall synthesis
S aureus and vancomycin
Reduced susceptibility

Increased use of vancomycin due to increase in MRSA - high level of resistance in enterococci (genes on transposon)
Vancomycin method of resistance
Thickened cell walls - reduced cross-linking
More free D-ala-D-ala side chains
More binding of vancomycin - reduced clearance, does not reach site of action
Beta-lactam resistance
Gram negatives
- beta lactamases
Carbapenem resistance
V broad spectrum
Carbapenemases - resistance
What can doctors do for drug resistance?
Prudent use of anti-microbials - only if has clear benefit (treatment or prophylaxis)
Infection control (hosp/comm)
Infection prevention - vaccine, public health
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