STEPTRACKERPHARMACOLOGY + MICROBIOLOGY | ANTIMICROBIALS | HIGH-YIELD REVIEW

Cell Wall & Membrane Antibiotics

β-lactams block the last step of peptidoglycan cross-linking; glycopeptides block an earlier step; a few drugs attack the membrane. Resistance and spectrum follow the structure.

FOCUS ON
β-lactams bind penicillin-binding proteins (transpeptidases) → no cross-linking → autolysis; bactericidal, time-dependent. Resistance: β-lactamases, altered PBPs (MRSA PBP2a, S. pneumoniae), porins (Pseudomonas). Penicillin G/V (strep, syphilis, Actinomyces); antistaphylococcal (nafcillin, oxacillin, dicloxacillin — MSSA; nafcillin interstitial nephritis); aminopenicillins (ampicillin, amoxicillin — Listeria, Enterococcus, H. influenzae, E. coli; rash with EBV); antipseudomonal (piperacillin-tazobactam). Cephalosporins (1st cefazolin → 5th ceftaroline MRSA); none cover Listeria, Enterococcus, atypicals. Carbapenems (meropenem, imipenem + cilastatin; ertapenem no Pseudomonas): broadest; seizures. Aztreonam: gram-negative only, safe in penicillin allergy. Vancomycin: binds D-Ala-D-Ala; MRSA, C. difficile (oral); vancomycin infusion reaction (histamine), nephro/ototoxicity; resistance D-Ala-D-Lac (VRE). Daptomycin: membrane depolarization; not pneumonia (surfactant); ↑ CK. Polymyxins: membrane detergent; nephro/neurotoxic. Fosfomycin (UTI), bacitracin (topical).
DRUG · GROUP
SPECTRUM HIGHLIGHTS
USE
ADVERSE · NOTES
Penicillin G · V · benzathine
Streptococci, T. pallidum, N. meningitidis, clostridia, Actinomyces
Syphilis, strep pharyngitis, rheumatic fever prophylaxis
Hypersensitivity, Jarisch-Herxheimer reaction, hemolytic anemia
Nafcillin · oxacillin · dicloxacillin
β-lactamase-resistant; MSSA
Skin infections, osteomyelitis, MSSA bacteremia
Interstitial nephritis, hepatitis (oxacillin); no MRSA
Ampicillin · amoxicillin (± clavulanate/sulbactam)
Extended: H. influenzae, E. coli, Listeria, Proteus, Salmonella, enterococci
Otitis, sinusitis, bites (amox-clav), Listeria meningitis, endocarditis prophylaxis
Rash (esp. with mononucleosis), C. difficile, diarrhea (clavulanate)
Piperacillin-tazobactam
Gram-negatives incl. Pseudomonas, anaerobes
Hospital-acquired, intra-abdominal, febrile neutropenia
AKI with vancomycin
1st–2nd gen cephalosporins
Cefazolin (gram + , E. coli, Klebsiella); cefoxitin/cefotetan (+ anaerobes), cefuroxime
Surgical prophylaxis, MSSA, cellulitis
Cefotetan disulfiram-like, hypoprothrombinemia
3rd gen cephalosporins
Ceftriaxone (CSF, gonorrhea, Lyme CNS), cefotaxime, ceftazidime (Pseudomonas)
Meningitis, pneumonia, gonorrhea, pyelonephritis
Ceftriaxone biliary sludge; avoid in neonates with Ca²⁺ IV, hyperbilirubinemia
4th–5th gen cephalosporins
Cefepime (Pseudomonas, gram +) · ceftaroline (MRSA)
Nosocomial, febrile neutropenia · MRSA skin/pneumonia
Cefepime neurotoxicity in renal failure
Carbapenems
Meropenem, imipenem-cilastatin (broadest), ertapenem (no Pseudomonas/Acinetobacter)
ESBL organisms, severe polymicrobial infections
Seizures (imipenem), C. difficile; carbapenemase resistance
Aztreonam
Monobactam: aerobic gram-negatives incl. Pseudomonas
Gram-negative infection in severe penicillin allergy
No gram-positive or anaerobic activity
Vancomycin
Gram-positives incl. MRSA, C. difficile (oral), enterococci
MRSA, empiric meningitis, C. difficile colitis
Vancomycin infusion reaction (slow rate, antihistamine), nephrotoxicity, ototoxicity, DRESS
Daptomycin
Gram-positives incl. MRSA, VRE
Bacteremia, endocarditis, skin
Myopathy (↑ CK), eosinophilic pneumonia; inactivated by surfactant
Polymyxin B · colistin
Gram-negatives (membrane LPS); salvage for MDR
Carbapenem-resistant organisms
Nephrotoxicity, neurotoxicity, respiratory arrest
Fosfomycin · bacitracin
Blocks MurA · blocks peptidoglycan carrier recycling
Uncomplicated cystitis · topical
Bacitracin nephrotoxic systemically

Picture it — where antibacterials act

DNA30S50SPABA → DHF → THFCell wallβ-lactams, vancomycinbacitracin, fosfomycinMembranedaptomycin, polymyxinsGyrase / topo IVfluoroquinolonesDNA damagemetronidazoleFolate synthesissulfonamides → TMP30Saminoglycosidestetracyclines50Smacrolidesclindamycin, linezolidchloramphenicolRNA polymeraserifampin
Antibacterial target mapWall and membrane drugs act at the envelope; fluoroquinolones and metronidazole attack DNA; rifampin blocks RNA polymerase; aminoglycosides and tetracyclines bind the 30S subunit; macrolides, clindamycin, linezolid and chloramphenicol bind the 50S subunit; sulfonamides and trimethoprim block two steps of folate synthesis.

Schematic diagrams, not to scale.

Mechanism — β-lactam vs vancomycin

NAM-NAG + D-Ala-D-Ala tail
→
Vancomycin caps D-Ala-D-AlaBlocks transglycosylation
→
β-lactam blocks PBP transpeptidaseNo cross-links
→
Weak wall → lysis

Coverage gaps to remember

DRUG
MISSES
ALTERNATIVE
Cephalosporins
Listeria, enterococci, atypicals, MRSA*
Ampicillin, vancomycin
Ertapenem
Pseudomonas
Meropenem
Aztreonam
Gram +, anaerobes
Add vancomycin, metronidazole
Daptomycin
Lung infections
Vancomycin, linezolid

* Ceftaroline covers MRSA.

How it's tested

COMMON CONFUSIONVancomycin infusion reaction (flushing from histamine) is rate-related, not an allergy — slow the infusion and premedicate.
THE TRAPNeonatal meningitis needs ampicillin added to a cephalosporin — Listeria and enterococci are intrinsically resistant to cephalosporins.
YOUR APPROACHOrganism → is it covered (gram +/−, anaerobe, Pseudomonas, MRSA)? → resistance mechanism → toxicity and allergy.

If you see… think…

Diffuse rash after amoxicillin for "strep throat" with splenomegaly → EBV mononucleosis
Fever, chills, myalgia hours after penicillin for syphilis → Jarisch-Herxheimer reaction
Flushing of the upper body during IV vancomycin → vancomycin infusion reaction
MRSA resistance mechanism → altered PBP2a (mecA)
VRE resistance mechanism → D-Ala-D-Lac
Antibiotic inactivated by surfactant → daptomycin
Seizure on a carbapenem → imipenem
Gram-negative coverage in anaphylactic penicillin allergy → aztreonam
Cephalosporin covering MRSA → ceftaroline
Interstitial nephritis on an antistaphylococcal penicillin → nafcillin/methicillin