ANTIBIOTICS

ID REVIEW 2010 Mark Hull St Pauls Hospital

Introduction
Many ways to choose antibiotics: Empiric therapy in sick pt, aiming at most likely/most serious organisms Directed therapy if organism known Host factors : pregnancy, renal failure, immune compromise, allergies
Antibiotics aimed at certain site eg. CNS

Environmental factors: travel, exposures, IDU, where pt lives etc Agent factors: type of bacteria suspected at that site, resistance patterns for institution,

Classification
Easiest to classify by means of action in destroying bacteria: 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

I. Cell wall agents -1. Penicillins

Penicillins one of the first groups of b-lactam antibiotics named because of chemical structure (all other wall agents are also part of this supergroup, except vancomycin) Penicillins act by binding to penicillin-binding proteins in the cell wall of bacteria
Once bound they block transpeptidation ie. Stop crosslinking of cell wall This leads to loss of wall integrity and osmotic lysis

The action against cell wall means very important in fighting gram positive infections Resistance now common due to either altered binding proteins (as in S. pneumoniae) or b lactamase enzymes which cleave the antibiotic .

Cell wall agents - penicillins

Group mimics the generational classification of cephalosporins: 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 line against S.pneumoniae until sensitivity proven (increasing rates of resistance) Used to treat Syphilis Useful against some gram negatives (Neisseria) if sensitive

Cell wall agents - penicillins

Antistaphylococcal penicillins
Cloxacillin, methicillin Great against S. aureus infections bacteremia, endocarditis, arthritis etc Very narrow spectrum b lactamase resistant Now problem with resistance (MRSA)

Aminopenicillins
Ampicillin, amoxicillin Good against gram postives enterococcus, listeria But extended spectrum so action against some gram negative rods (E.coli, H. influenzae, Proteus) If combined with clavulin (blactamase inhibitor) =wider spectrum useful for sinus infections, otitis media,

Cell wall agents - penicillins

Ureidopencillins
Eg. Piperacillin, ticarcillin Even wider spectrum than others: Gram positives, gram negatives (Pseudomonas) and anaerobes 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

Cell wall agents 2. cephalosporins

1- 4 generations Similar in structure to penicillins so work against same 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

Cell wall agents - cephalosporins

2nd generation: Eg. Cefuroxime PO/IV useful 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

Cell wall agents - cephalosporins

3rd generation:
Lose more gram positive coverage ( so not great against skin orgs) But better gram negative useful for serious infections

Ceftriaxone, cefotaxime penetrate BBB

Ceftriaxone used as empiric coverage for Neisseria in meningitis (as well as covering S.pneumoniae if not resistant to penicillins). Has long half life, so can be dosed once daily for nonmeningitis infections.

Ceftazidime covers Pseudomonas

Cell wall agents - cephalosporins

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

Cell wall agents 3. 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

Cell wall agents 4. glycopeptides

Vancomycin
Large, bulky molecule that inhibits cell wall polymerization at step before the penicillins Bactericidal, great gram positive coverage

Used now for MRSA, Coagulase negative Staphylococcus (CNS), Enterococci Oral use for C. difficile Adverse effects: red man syndrome from rapid infusion and histamine release
Also Nephrotoxicity, rare ototoxicity with long term exposure

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 rises animal models show reversible skeletal muscle effects

Licensed for skin and soft tissue infection Rx

And MSSA/MRSA endocarditis

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 positives enterococcal endocarditis Tobramycin has good activity against Pseudomonas

Watch nephrotoxicity, ototoxicity check levels

Protein synthesis inhibitors 30S

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 children bone,tooth probs Not safe in pregnancy

Protein synthesis inhibitors - 50S

Chloramphenicol
Broad coverage, but side effects (anemias, gray baby syndrome) mean not 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- atypicals and Moraxella, H.flu, Legionella
ALSO for Chlamydia Rx

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 foot infections.
IV used for necrotizing fasciitis.

high risk C.difficile.

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

Protein synthesis inhibitors 50S

Oxazolidinones Linezolid
Binds 50S, interferes with initiation complex formation with 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 SSRI serotonin syndrome

Also long term use associated with peripheral/optic neuropathy

IV. Nucleic acid-targeting agents DNA gyrase inhibitors

Quinolones Eg. Ciprofloxacin, levofloxacin, moxifloxacin
Prevents supercoiling of DNA by binding DNA gyrase (topoisomerase II) Bactericidal Great gram negative agents useful for UTIs, GI infections Cipro covers Pseudomonas Levofloxacin/ moxifloxacin = respiratory quinolones gain gram positive coverage (S.pneumoniae) but loses gram negative strength (would not use against pseudomonas)

Beware of people with suspected TB these agents also cover TB, dont use if treating CAP but think TB in differential

Other DNA agents

Metronidazole (flagyl)
Toxic metabolite binds DNA Bactericidal Great anaerobic coverage- 1st line for C. difficile, some parasites (Giardia, trichomonas) Can cause disulfiram reaction so not used with ETOH

Rifampin
Binds DNA-dependent RNA polymerase Good gram positive coverage Side effects: Orange tinged tears etc, induces P450 so drug interactions

V. Antimetabolites
Sulfonamides
Block folic acid synthesis in bacteria which is vital for synthesis of DNA, amino acids

Trimethoprim
Blocks folate pathway by inhibiting dihydrofolate reductase

Usually these groups are used in combination:

Eg. TMP-SMX, Septra Good gram negative coverage so useful for UTIs, prostatic infections, some pneumonia coverage PCP in HIV

Summary
Gram positive agents:
Penicillins (Pen GAS) (Clox MSSA) Cephalosporins Vancomycin Clindamycin

Gram negative agents:

Aminoglycosides Quinolones Sulphonamides

Summary
Anaerobic agents:
Piptazo Imipenem Clindamycin Metronidazole

Anti-Pseudomonal agents:
Piperacillin, Ceftazidime, Cefepime, Imipenem, Tobramycin, Ciprofloxacin

Summary
Skin 1st gen cephalosporins Cloxacillin (if known MSSA) Clindamycin (usually for Pen allergic) Vancomycin/Daptomycin/Linezolid MRSA Lung Cefuroxime mild cases +/- Macrolide Ceftriaxone and Macrolide (CAP requiring hospital) Moxifloxacin (CAP outpt/inpt)

Summary
Urine TMP-SMX (Septra) Cipro Keflex Nitrofurantoin Ceftriaxone (pyelonephritis/hospitalized) Sepsis Piptazo, Carbapenems, Cefipime, +/- MRSA agent