FIGURE 43–10 Proposed mechanism of action of daptomycin. Daptomycin first binds to the cytoplasmic membrane (step 1) and then forms complexes in a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of cellular potassium, possibly by pore formation, and membrane depolarization. This is followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis does not occur.
Fosfomycin is approved for use as a single 3-g dose for treatment of uncomplicated lower urinary tract infections (UTI) in women. Limited data in case reports have suggested efficacy in males with UTI and prostatitis; in these cases, a 3-g dose has been given every 3 days for 9 days when treating UTI or 21 days for prostatitis. There are no supportive data for using fosfomycin to treat pyelonephritis. The drug appears to be safe for use in pregnancy.
Bacitracin is a cyclic peptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943. It is active against Gram-positive microorganisms. Bacitracin inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. There is no cross-resistance between bacitracin and other antimicrobial drugs.
Bacitracin is highly nephrotoxic when administered systemically and is only used topically (Chapter 61). Bacitracin is poorly absorbed, and topical application results in local antibacterial activity. Bacitracin, 500 units/g in an ointment base (often combined with polymyxin or neomycin), is used for the treatment of infections due to mixed bacterial flora in surface lesions of the skin or on mucous membranes. Bacitracin is commonly associated with hypersensitivity and should not be applied to wounds for the purpose of preventing infection.
Cycloserine is an antibiotic produced by Streptomyces orchidaceous. It is water soluble and very unstable at acid pH. Cycloserine inhibits many Gram-positive and Gram-negative organisms, but it is used almost exclusively to treat tuberculosis caused by strains of Mycobacterium tuberculosis resistant to first-line agents. Cycloserine is a structural analog of d-alanine and inhibits the incorporation of d-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts l-alanine to d-alanine, and d-alanyl-d-alanine ligase. After ingestion of 0.25 g of cycloserine blood levels reach 20–30 mcg/mL—sufficient to inhibit many strains of mycobacteria and Gram-negative bacteria. The drug is widely distributed in tissues. Most of the drug is excreted in active form into the urine. The dosage for treating tuberculosis is 0.5 to 1 g/d in two or three divided doses.
Cycloserine causes serious, dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions. If oral dosages are maintained below 0.75 g/d, such effects can usually be avoided.
• Penicillin G Prevents bacterial cell wall synthesis by binding to and inhibiting cell wall transpeptidases
Penicillin V: Oral, low systemic levels limit widespread use
Benzathine penicillin, procaine penicillin: Intramuscular, long-acting formulations
Nafcillin, oxacillin: Intravenous, added stability to staphylococcal β-lactamase, biliary clearance