A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa, and for treatment of mixed aerobic and anaerobic infections. Carbapenems are active against many penicillin-nonsusceptible strains of pneumococci. Carbapenems are highly active in the treatment of Enterobacter infections because they are resistant to destruction by the β-lactamase produced by these organisms. Clinical experience suggests that carbapenems are also the treatment of choice for serious infections caused by extended-spectrum β-lactamase-producing Gram-negative bacteria. Ertapenem is insufficiently active against P aeruginosa and should not be used to treat infections caused by this organism. Imipenem, meropenem, or doripenem, with or without an aminoglycoside, may be effective treatment for febrile neutropenic patients.
The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to seizures. Meropenem, doripenem, and ertapenem are much less likely to cause seizures than imipenem. Patients allergic to penicillins may be allergic to carbapenems, but the incidence of cross-reactivity is thought to be less than 1%.
Vancomycin is an antibiotic isolated from the bacterium now known as Amycolatopsis orientalis. It is active primarily against Gram-positive bacteria due to its large molecular weight and lack of penetration through Gram-negative cell membranes. The intravenous product is water soluble and stable for 14 days in the refrigerator following reconstitution.
Mechanisms of Action & Basis of Resistance
Vancomycin inhibits cell wall synthesis by binding firmly to the d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide (Figure 43–8). This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.
Resistance to vancomycin in enterococci is due to modification of the d-Ala-d-Ala binding site of the peptidoglycan building block in which the terminal d-Ala is replaced by d-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus
Bacterial cell wall Periplasmic space Cytoplasm Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G = N-acetylglucos-amine (N-Ag) M = N-acetylmuramic acid (N-Am) G M M M MG G G G MG M G M G M M M M G M G M G M G G G M M M MG G G G +Transpeptidase Crosslinking Cytoplasmic membrane
Vancomycin binds the D-Alanine D-Alanine terminus of the amino acid peptide, inhibiting crosslinkage. MG M G M M GG+Vancomycin V A N No crosslinking V A N V A N