Page 824 - Basic _ Clinical Pharmacology ( PDFDrive )

810 SECTION VIII Chemotherapeutic Drugs

of skin and soft tissue infections. There are limited clinical data evidence supporting increased efficacy is lacking. In clinical tri-
supporting the use of dalbavancin for uncomplicated catheter- als, daptomycin was noninferior in efficacy to vancomycin. It
associated bloodstream infections, though it is not approved for can cause myopathy, and creatine phosphokinase levels should be
use in this setting. Dalbavancin was originally approved as a two- monitored weekly. Pulmonary surfactant antagonizes daptomycin,
dose, once-weekly intravenous regimen (1000 mg infused on day and it should not be used to treat pneumonia. Daptomycin can
1 and 500 mg infused on day 8), but a subsequent phase 3 study also cause an allergic pneumonitis in patients receiving prolonged
comparing the two-dose regimen with a single, 1500-mg intra- therapy (>2 weeks). Treatment failures have been reported in
venous dose showed that the single-dose regimen is noninferior. association with an increase in daptomycin MIC during therapy.
The results of this study allowed for updated labelling, making Daptomycin is an effective alternative to vancomycin, and its role
both dalbavancin and oritavancin appropriate for single-dose continues to unfold.
treatments for complicated skin and soft tissue infections. A prac-
tical difference between the two is the infusion time: dalbavancin
can be administered over 30 minutes, while oritavancin must be FOSFOMYCIN
infused over 3 hours. Neither requires dose adjustment in mild
to moderate renal or hepatic impairment, and neither is removed Fosfomycin trometamol, a stable salt of fosfomycin (phosphono-
by dialysis. mycin), inhibits a very early stage of bacterial cell wall synthesis.
An analog of phosphoenolpyruvate, it is structurally unrelated to
any other antimicrobial agent. It inhibits the cytoplasmic enzyme
■ OTHER CELL WALL- OR enolpyruvate transferase by covalently binding to the cysteine resi-
due of the active site and blocking the addition of phosphoenol-
MEMBRANE-ACTIVE AGENTS pyruvate to UDP-N-acetylglucosamine. This reaction is the first
step in the formation of UDP-N-acetylmuramic acid, the precur-
DAPTOMYCIN sor of N-acetylmuramic acid, which is found only in bacterial cell
walls. The drug is transported into the bacterial cell by glycero-
Daptomycin is a novel cyclic lipopeptide fermentation product of phosphate or glucose 6-phosphate transport systems. Resistance is
Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is due to inadequate transport of drug into the cell.
similar to that of vancomycin except that it may be active against Fosfomycin is active against both Gram-positive and Gram-
vancomycin-resistant strains of enterococci and S aureus. In vitro, negative organisms at concentrations ≥ 125 mcg/mL. Susceptibil-
it has more rapid bactericidal activity than vancomycin. The pre- ity tests should be performed in growth medium supplemented
cise mechanism of action is not fully understood, but it is known with glucose 6-phosphate to minimize false-positive indications of
to bind to the cell membrane via calcium-dependent insertion of resistance. In vitro synergism occurs when fosfomycin is combined
its lipid tail. This results in depolarization of the cell membrane with β-lactam antibiotics, aminoglycosides, or fluoroquinolones.
with potassium efflux and rapid cell death (Figure 43–10). Dap- Fosfomycin trometamol is available in both oral and par-
tomycin is cleared renally. The approved doses are 4 mg/kg/dose enteral formulations, although only the oral preparation is
for treatment of skin and soft tissue infections and 6 mg/kg/dose approved for use in the USA. Oral bioavailability is approxi-
for treatment of bacteremia and endocarditis once daily in patients mately 40%. Peak serum concentrations are 10 mcg/mL and
with normal renal function and every other day in patients with 30 mcg/mL following a 2-g or 4-g oral dose, respectively. The
creatinine clearance of less than 30 mL/min. For serious infec- half-life is approximately 4 hours. The active drug is excreted
tions, many experts recommend using 8–10 mg/kg/dose. These by the kidney, with urinary concentrations exceeding MICs for
higher doses appear to be safe and well tolerated, although most urinary tract pathogens.

L-Asp D-Ala L-Asp Gly D-Ser 3-MeGlu (L-theo)
= O
L-Orn Gly L-Thr O C L-Kyn

L-Asp L-Asn L-Trp NH

= O

Decanoic acid

FIGURE 43–9 Structure of daptomycin. (Kyn, deaminated tryptophan.)