abx ppt (mel)

8/2/2019 ABX ppt (Mel)

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ANTIBIOTICS

ID REVIEW

2010

Mark Hull

St Pauls Hospital


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Introduction

Many ways to choose antibiotics:

Empiric therapy in sick pt, aiming at most likely/mostserious organisms

Directed therapy if organism known

Host factors : pregnancy, renal failure, immunecompromise, allergies Antibiotics aimed at certain site eg. CNS

Environmental factors: travel, exposures, IDU, wherept lives etc

Agent factors: type of bacteria suspected at that site,resistance patterns for institution,


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Classification

Easiest to classify by means of action in destroyingbacteria:

I. cell wall synthesis inhibitors

Penicillins, Cephalosporins, Carbapenems, Glycopeptides II. Protein synthesis inhibitors

Aminoglycosides, Tetracyclines, Macrolides, Clindamycin

III. Anti-metabolites

Sulphonamides

IV. Nucleic acid agents

Quinolones, metronidazole


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I. Cell wall agents -1. Penicillins

Penicillins one of the first groups ofb-lactam antibioticsnamed because of chemical structure (all other wall agents arealso part of this supergroup, except vancomycin)

Penicillins act by binding to penicillin-binding proteins in thecell wall of bacteria Once bound they block transpeptidationie. Stop crosslinking of cell

wall

This leads to loss of wall integrity and osmotic lysis

The action against cell wall means very important in fightinggram positive infections

Resistance now common due to either altered binding proteins(as in S. pneumoniae) or b lactamase enzymes which cleavethe antibiotic .


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Cell wall agents - penicillins

Group mimics the generational classification ofcephalosporins:

Penicillin V, G.original penicillins

Pen V =PO, Pen G =IV, Benzathine Penicillin = IM Useful still against Group A Strep (Eg. GAS pharyngitis or

necrotizing fasciitis)

Useful against Strep species, - usually dont use as first lineagainst S.pneumoniae until sensitivity proven (increasing

rates of resistance)

Used to treat Syphilis

Useful against some gram negatives (Neisseria) if sensitive


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Cell wall agents - penicillins

Ureidopencillins

Eg. Piperacillin, ticarcillin

Even wider spectrum than others:

Gram positives, gram negatives(Pseudomonas) andanaerobes

Combined with tazobactam ( b lactamase inhibitor)extends spectrum even further

So, great empiric antibiotic for

sepsis,

nosocomial infection, or in an immune compromised host

Intra abdominal infections


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Cell wall agents2. cephalosporins

1- 4 generations

Similar in structure to penicillins so work againstsame bacteria, also bactericidal

Not useful against enterococci, listeria 1st generation:

Cefazolin (ancef), Cephalexin (keflex =PO)

Gram positives and some gram negatives: Proteus

mirabilis,E.coli, Klebsiella Remember PEcK

Useful for cellulitis, pre op coverage, occasionally UTI


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Cell wall agents - cephalosporins

2nd generation:

Eg. CefuroximePO/IVuseful for pneumonia

Lose a little gram positive coverage

Increased gram negatives: PEcK plus:H.influenzae,Enterobacter, Neisseria, Serratia

Therefore: HEN PEcKS

Subgroup: cefotetan, cefoxitin (called the

cephamycins) cover anaerobes Remember: Cefaclor (Ceclor) associated with serum

sickness


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3rd generation:

Lose more gram positive coverage ( so not great againstskin orgs)

But better gram negativeuseful for serious infections

Ceftriaxone, cefotaxime penetrate BBB

Ceftriaxone used as empiric coverage for Neisseria inmeningitis (as well as covering S.pneumoniae if notresistant to penicillins).

Has long half life, so can be dosed once daily for non-meningitis infections.

Ceftazidime covers Pseudomonas


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4th generation:

Cefepime

Powerful broad-spectrum coverage against gram

positives, negatives

Less anaerobic coverage than Pip-tazo

Covers Pseudomonas

Reserved here for serious nosocomial infections


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Cell wall agents3. Carbapenems

Similar to penicillin derivatives

Eg. Imipenem, Meropenem, Ertapenem

Broad spectrum coverage: gram positives, gram

negatives (Pseudomonas), and anaerobes

Again reserved for serious sepsis, nosocomial

infections

Cross-reactivity in pts with pen allergy


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Cell wall agents4. glycopeptides

Vancomycin

Large, bulky molecule that inhibits cell wall polymerizationat step before the penicillins

Bactericidal, great gram positive coverage

Used now for MRSA, Coagulase negativeStaphylococcus (CNS), Enterococci

Oral use for C. difficile

Adverse effects: red man syndrome from rapidinfusion and histamine release

Also Nephrotoxicity, rare ototoxicity with long termexposure


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II. Cell Membrane agents

Lipopetides

Daptomycin

Binds to cell membrane of Gram positives only Leads to membrane depolarization, K release and cell death

Active against Staph including CNS, MRSA

Active against Enterococcus, including VRE

Some anaerobes

IV only 4mg/kg/d, renally cleared

Watch for CK risesanimal models show reversible skeletalmuscle effects

Licensed for skin and soft tissue infection Rx And MSSA/MRSA endocarditis


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III. Protein synthesis Inhibitors-30S

30S ribosome agents

Aminoglycosides (bactericidal)

Eg. Gentamicin, tobramycin, amikacin

Bind 30S cause misreading of mRNA Best used against gram negative infections

great for gram negative sepsis as are cidal

Cant work against anaerobes

Synergy against gram positivesenterococcal endocarditis Tobramycin has good activity against Pseudomonas

Watch nephrotoxicity, ototoxicitycheck levels


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Protein synthesis inhibitors30S

Tetracyclines (static)

Blocks incoming tRNA so halts protein synthesis

Best used against unusual, intracellular infections:

Rickettsia (rocky mountain spotted fever)

Chlamydia,

Lyme disease

Also good for acne, mycoplasma Not safe in childrenbone,tooth probs

Not safe in pregnancy


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Protein synthesis inhibitors - 50S

Chloramphenicol

Broad coverage, but side effects (anemias, gray baby syndrome) meannot commonly used

Macrolides

Bind 50S ribosome, prevent translocation of growing protein chain Eg. Erythromycin, azithromycin, clarithromycin

Erythro used for pen allergy (strep)

Clarithromycin covers CAP,sinusitis,H.pylori, Legionella

Azithromycin also used for respiratory infections- atypicalsand Moraxella, H.flu, Legionella

ALSO for Chlamydia Rx


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Protein synthesis inhibitors - 50S

Lincosamides (Clindamycin)

Bacteriostatic

PO/IV formulation

Oral has excellent bio availability

Covers gram positives and anaerobes

Good for cellulitis, abscess, some use for diabetic footinfections.

IV used for necrotizing fasciitis.

high riskC.difficile.

Remember: buy AT 30, CE(erythro)L at 50


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Protein synthesis inhibitors50S

Oxazolidinones

Linezolid

Binds 50S, interferes with initiation complex formationwith mRNA

Spectrum of activity

Staph, including MRSA, CNS

Enterococcus, including VRE

Good PO bioavailability (also in IV form)

Adverse effects include cytopenias (after 14d) Thrombocytopenias, Neutropenia

Drug interaction with SSRIserotonin syndrome

Also long term use associated with peripheral/optic neuropathy


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Other DNA agents

Metronidazole (flagyl)

Toxic metabolite binds DNA

Bactericidal

Great anaerobic coverage- 1st line for C. difficile, someparasites (Giardia, trichomonas)

Can cause disulfiram reactionso not used with ETOH

Rifampin

Binds DNA-dependent RNA polymerase

Good gram positive coverage

Side effects: Orange tinged tears etc, induces P450 so druginteractions


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V. Antimetabolites

Sulfonamides

Block folic acid synthesis in bacteria which is vital forsynthesis of DNA, amino acids

Trimethoprim

Blocks folate pathway by inhibiting dihydrofolatereductase

Usually these groups are used in combination:

Eg. TMP-SMX, Septra

Good gram negative coverage so useful for UTIs, prostaticinfections, some pneumonia coverage

PCP in HIV


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Summary

Gram positive agents:

Penicillins (PenGAS) (CloxMSSA)

Cephalosporins

VancomycinClindamycin

Gram negative agents:

AminoglycosidesQuinolones

Sulphonamides


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Summary

Anaerobic agents:

Piptazo

Imipenem

Clindamycin

Metronidazole

Anti-Pseudomonal agents:

Piperacillin, Ceftazidime, Cefepime, Imipenem,

Tobramycin, Ciprofloxacin


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Summary

Skin

1st gen cephalosporins

Cloxacillin (if known MSSA)

Clindamycin (usually for Pen allergic) Vancomycin/Daptomycin/LinezolidMRSA

Lung

Cefuroximemild cases +/- Macrolide

Ceftriaxone and Macrolide (CAP requiring hospital)

Moxifloxacin (CAP outpt/inpt)


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Summary

Urine

TMP-SMX (Septra)

Cipro

Keflex

Nitrofurantoin

Ceftriaxone (pyelonephritis/hospitalized)

Sepsis

Piptazo, Carbapenems, Cefipime, +/- MRSA agent

abx ppt (mel)

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