Page 825 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 811

Daptomycin

Ca 2+
Step 1

Ca 2+ Step 2 Step 3
Ca 2+

K +

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 treat- skin or on mucous membranes. Bacitracin is commonly associated
ment of uncomplicated lower urinary tract infections (UTI) in with hypersensitivity and should not be applied to wounds for the
women. Limited data in case reports have suggested efficacy in purpose of preventing infection.
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 CYCLOSERINE
to treat pyelonephritis. The drug appears to be safe for use in
pregnancy. 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
BACITRACIN is used almost exclusively to treat tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to first-line agents. Cycloser-
Bacitracin is a cyclic peptide mixture first obtained from the Tracy ine is a structural analog of d-alanine and inhibits the incorpora-
strain of Bacillus subtilis in 1943. It is active against Gram-positive tion of d-alanine into peptidoglycan pentapeptide by inhibiting
microorganisms. Bacitracin inhibits cell wall formation by inter- alanine racemase, which converts l-alanine to d-alanine, and
fering with dephosphorylation in cycling of the lipid carrier that d-alanyl-d-alanine ligase. After ingestion of 0.25 g of cycloserine
transfers peptidoglycan subunits to the growing cell wall. There blood levels reach 20–30 mcg/mL—sufficient to inhibit many
is no cross-resistance between bacitracin and other antimicrobial strains of mycobacteria and Gram-negative bacteria. The drug is
drugs. widely distributed in tissues. Most of the drug is excreted in active
Bacitracin is highly nephrotoxic when administered systemi- form into the urine. The dosage for treating tuberculosis is 0.5 to
cally and is only used topically (Chapter 61). Bacitracin is poorly 1 g/d in two or three divided doses.
absorbed, and topical application results in local antibacterial Cycloserine causes serious, dose-related central nervous system
activity. Bacitracin, 500 units/g in an ointment base (often com- toxicity with headaches, tremors, acute psychosis, and convul-
bined with polymyxin or neomycin), is used for the treatment of sions. If oral dosages are maintained below 0.75 g/d, such effects
infections due to mixed bacterial flora in surface lesions of the can usually be avoided.