Inhibition of cell wall synthesis

Drug
Penicillin G IV or IM Penicillin V PO (Natural penicillin) Nafcillin IV Oxacillin - IV Dicloxacillin PO (Antistaphylococcal penicillin)
MOA of beta-lactams - binds to transpeptidase (aka penicillin binding protein) irreversibly - inhibits peptidoglycan polymer crosslinking creates holes in cell wall cell lysis / death

Mechanism of action

Indications / Resistance / Exceptions

Penicillin (beta-lactam)
- very short half-lives - need frequent dosing - spectrum: streptococci, Treponema pallidum (syphilis) - main uses: susceptible streptococcal infections, syphilis (drug of choice penicillin G) - most bacteria has become resistant - has bulky R group that inhibits beta-lactamases - spectrum: MSSA, streptococci - main uses: susceptible staphylococcal infections (cellulitis, endocarditis) - hepatic elimination (Nafcillin) - Amoxicillin > Ampicillin for bioavailability - use Ampicillin PO if you want to kill bug in gut - use against Gram Neg Rods (E. coli, Klebsiella, H. flu) (more hydrophilic) - spectrum: streptococci, enterococci, Listeria monocytogenes (drug of choice), Helicobacter pylori - main uses: URI, UTI (in pregnant women - less toxic), peptic ulcer disease, enterococcal infection (drug of choice) - susceptible to beta-lactamases - penetrate wall of Pseudomonas aeruginosa - spectrum: like Ampicillin and Amoxicillin (even better for Gram Neg Rods) + Pseudomonas (very hydrophilic) - main uses: hospital acquired pneumonia, nosocomial infection - susceptible to beta-lactamases (better as a definitive vs. empirical therapy or used with beta-lactamase inhibitors)

Adverse Effects

AE of beta-lactams - hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses) - cross-allergenicity - phlebitis and neutropenia with Nafcillin (irritating to veins, need central line) - more diarrhea with Ampicillin (b/c more bugs killed in gut) - thrombocytopenia with Piperacillin and Ticarcillin - Methicillin cause interstitial nephritis

Ampicillin IV or PO Amoxicillin PO (Aminopenicillin)

- good tissue penetration - time dependent - bactericidal (mostly) - renal elimination (mostly) - Ureidopenicilins have saturable renal and biliary elimination

Piperacillin (Ureidopenicilin) (more frequently used) Ticarcillin [Carboxypenicilin also Carbenicillin (only one that is PO)] (Antipseudomonal penicillin) Piperacillin/Tazobactam (Zosyn) Vit Z Ampicillin/Sulbactam (Unasyn) Amoxicillin/Clavulanate (Augmentin) PO
- beta-lactam + - beta-lactamase inhibition

Beta-lactam / beta-lactamase inhibitor combination

- spectrum: (BROAD!) parent drug + most beta-lactamase producing bacteria, streptococci, MSSA, enterococci, Gram Neg Rods (better than parent drug alone), anaerobes - main uses: GI infection, abscesses, hospital acquired pneumonia, serious nosocomial infection, diabetic wound infection (not against MRSA) - Ampicillin/Sulbactam and Amoxicillin/Clavulanate are NOT active against Pseudomonas -resistance can still occur

- hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses)

1st generation cephalosporin (beta-lactam) Cefazolin IV (most common used) Cephalexin PO

- bactericidal (mostly) - renal elimination - no CNS penetration (NOT used in meningitis) - poor activity against enterococci, GN cocci - spectrum: MSSA, streptococci, some Gram Neg Rods, E. Coli, Klebsiella pneumoniae (not MRSA) - main uses: surgical prophylaxis, cellulitis, UTI (in pregnant women) - less beta-lactamase susceptible than most penicillins (6 membered-ring vs. 5 in penicillin) - hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses) - cross-hypersensitivity

2nd generation cephalosporin (beta-lactam) Cefuroxime IV or PO Cefaclor PO Cefoxitin IV

- bactericidal (mostly) - no CNS penetration (NOT used in meningitis) - poor activity against enterococci - spectrum: Gram Pos (worse than 1st), Gram Neg (better than 1st) (not MRSA) - main uses: URI, LRI, surgical prophylaxis, gonorrhea - less beta-lactamase susceptible than most penicillins (6 membered-ring vs. 5 in penicillin) - hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses) - cross-hypersensitivity

3rd generation cephalosporin (beta-lactam)

- poor activity against enterococci (extended-spectrum beta-lactamase) - less antistaphylococcal activity than 2nd gen. - better Gram Neg activity than 2nd gen. - better antistreptococcal activity than 2nd gen. - main uses: meningitis, community acquired pneumonia (drug of choice Cegtriaxone), hospital acquired pneumonia (drug of choice - Ceftazidime), Lyme disease (Ceftriaxone), SSTI, UTI, febrile neutropenia (Ceftazidine) (not MRSA) - Ceftazidime: NO Gram Pos activity, has Pseudomonas activity - less beta-lactamase susceptible than most penicillins (6 membered-ring vs. 5 in penicillin)

Ceftriaxone IV Cefotaxime IV Ceftazidime IV

- bactericidal (mostly) - ability to penetrate the BBB (except cefoperazone and cefixime) - renal elimination (Cefotaxime, Ceftazidime) - Ceftriaxone: renal and biliary elimination

- hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses) - biliary sludging (obstruction) in neonates with Ceftriaxone can cause jaundice - cross-hypersensitivity

4th generation cephalosporin (beta-lactam)

- poor activity against enterococci - GOOD empirical treatment (combo activity of 1st and 3nd generations) - BAD definitive treatment - spectrum: (BROAD!) MSSA, streptococci, Gram Neg Rods, Pseudomonas (not MRSA) - main uses: febrile neutropenia, hospital acquired pneumonia, nosocomial infection - less beta-lactamase susceptible than most penicillins (6 membered-ring vs. 5 in penicillin)

Cefepime IV Broadest of all cephalosporins

- bactericidal (mostly) - renal elimination

- hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - seizures (in high doses) - cross-hypersensitivity

Monobactam (beta-lactam)
- resistant to beta-lactamase produced by GNR (Klebsiella, Pseudomonas, and Serratia) - Synergistic with aminoglycosides -renal elimination - renal elimination - low susceptibility to beta-lactamases - active against Gram Neg Rods, Pseudomonas - not cross-reactive with other beta-lactam allergies except for Ceftazidine - main uses: gram neg infections in pts with allergies to other betalactams - hypersensitivity (type I more important & III) - nausea/vomiting/diarrhea - vertigo and headache - rare hepatotoxicity - seizures (in high doses)

Aztreonam IV

Carbapenems (beta-lactam) Imipenem/Cilastatin IV

- NOT 1st line of drugs - stable to most beta-lactamases - spectrum: MSSA, streptococci (not penicillin resistant), enterococci, Gram Neg Rods (drug of choice for acinetobacter sp.), Pseudomonas, anaerobes - main uses: nosocomial infection, mixed aerobic/anaerobic infection, febrile neutropenia - spectrum and main use: same as above - except: NOT active against Pseudomonas, enterococci, acinetobacter sp. - Drug of choice for extended-spectrum beta-lactamase (ESBL) producing GNRs

Meropenem IV

-often used with aminoglycosides - currently drug of choice for enterobacter - Imipenem metabolite is toxic; Cilastatin inhibits this metabolism (renal dihydropeptidase) -very broad spectrum

- hypersensitivity (type I more important & III) - nausea (rate dependent)/ vomiting/diarrhea - seizures (in high doses, esp. with Imipenem)

Ertapenem IV

Glycopeptide
- 1st line of drug for MRSA infection - spectrum: Gram Pos aerobes and anaerobes, MRSA, C. difficile - main uses: MRSA infection, Gram Pos infection in pts with severe betalactam allergies - combo with 3rd gen cephra for penicillin resistant pneumococci (PRSP) - ALL Gram Neg are resistant - enterococci are resistant (VRE) - vancomycin resistant staph. aureus (VRSA) - do NOT kill beta-lactam susceptible staphylococci as quickly as beta-lactam (very slowly active against beta-lactamase + bacteria) - resistance due to altered target site

Vancomycin IV or PO (for gut bugs like C. difficile)

- binds to terminal D-ala-D-ala chain of peptidoglycan prevents peptidoglycan elongation - time dependent - poor bioavailability - overutilization

- Red-man syndrome when infused quickly (not an allergy) - corrected by slowing down infusion / give antihistamine - nephrotoxicity, ototoxicity (?) largely a problem with older formulations (Mississippi mud)

Peptide antibiotic Bactitracin topically, locally

- disrupts peptidoglycan translocation prevents next peptidoglycan monomer from connecting to chain - inhibits peptidoglycan monomer synthesis(N-acetylmuramic acid) - may be synergistic with beta-lactam - inhibits enzyme linking D-ala molecules prevents monomer synthesis - inserts into cell membrane of GP organisms (its a lipopeptide) forming channels leakage of cations depolarization and cell death - rapidly bactericidal - concentration dependent - poor bioavailability - distribute well in lungs (but inactivated by surfactant) - renal excretion - bind to cell membrane of GN organism disrupting permeability leakage of cellular components - rapidly bactericidal - concentration dependent - poor bioavailability - renal excretion - spectrum: Gram Pos Cocci and Rods - main use: minor skin infection - highly nephrotoxic limited to topical use

Others Fosfomycin Cycloserine

- main use: simple UTI (in noncompliant pt b/c only 1 dose is needed to treat) - main use: TB (2nd/3rd line drug those that are resistant to 1st line) - diarrhea - significant neurotoxicity (tremors, seizures, psychosis)

Cell-membrane active antibiotics

Daptomycin

- spectrum: GP aerobes and anaerobes similar to vancomycin (but also includes MRSA, VRE, and VRSA) - indicated for skin and skin structure infections and staphylococcal bacteremia

- elevation of creatine kinase (maybe rabdomyolisis) related to frequent dosing

Polymyxins (Colisin, Polymyxin B) often inhaled for colonized MDR organims

- spectrum: many GN organism including MDR pseudomonas aeruginosa (mostly), acinetobacter baumanni, and Klebsiella pneumonia - Inactive against species of serratia and providential - main use: MDR GNR (particularly pneumonia and bacteremia), elimination of colonization in CF patients (inhaled)

- nephrotoxicity (poorly characterized) - neurotoxicity (uncommon)

Gram Positive Bacteria Enterococci Group B Strep S. pneumoniae Group A Strep Listeria S. epidermidis S. aureus N. meningitides

Gram Negative Bacteria H. influenzae Klebsiella Serratia p. aeruginoa E. coli Enterobacter

Anaerobes Mouth Gut b. fragilis

Resistance - enzyme inactivation - reduced membrane permeability - alterations in target sites Cross reactivity of true allergies to beta lactams - PCN <-> cephalosporins 3-5% (more in the 1%) - PCN <-> carbapenems higher, possibly 50% (more like 1%) - PCN, carbapenem, cephalosporin <-> azetronam none - in the face of a true allergy to a needed drug, desensitization can be performed (depending on patients IgE levels) No beta-lactams are active against atypical pneumonia: Micoplasma, Legionella, Chlamydia

Penicillin G, Penicillin V Nafcillin, Oxacillin Ampicillin, Amoxicillin Piperacillin, Ticarcillin 1st generation cephalosporin 2nd generation cephalosporin 3rd generation cephalosporin 4th generation cephalosporin Aztreonam Imipenem/Cilastatin Vancomycin