Daptomycin is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is similar to that of vancomycin except that it may be active against vancomycin-resistant strains of enterococci and S aureus. In vitro, it has more rapid bactericidal activity than vancomycin. The precise mechanism of action is not fully understood, but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux and rapid cell death (Figure 43–10). Daptomycin is cleared renally. The approved doses are 4 mg/kg/dose for treatment of skin and soft tissue infections and 6 mg/kg/dose for treatment of bacteremia and endocarditis once daily in patients with normal renal function and every other day in patients with creatinine clearance of less than 30 mL/min. For serious infections, many experts recommend using 8–10 mg/kg/dose. These higher doses appear to be safe and well tolerated, although evidence supporting increased efficacy is lacking. In clinical trials, daptomycin was noninferior in efficacy to vancomycin. It can cause myopathy, and creatine phosphokinase levels should be monitored weekly. Pulmonary surfactant antagonizes daptomycin, and it should not be used to treat pneumonia. Daptomycin can also cause an allergic pneumonitis in patients receiving prolonged therapy (>2 weeks). Treatment failures have been reported in association with an increase in daptomycin MIC during therapy. Daptomycin is an effective alternative to vancomycin, and its role continues to unfold.
Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), 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 enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial cell by glycerophosphate or glucose 6-phosphate transport systems. Resistance is due to inadequate transport of drug into the cell.
Fosfomycin is active against both Gram-positive and Gram-negative organisms at concentrations ≥ 125 mcg/mL. Susceptibility tests should be performed in growth medium supplemented with glucose 6-phosphate to minimize false-positive indications of resistance. In vitro synergism occurs when fosfomycin is combined with β-lactam antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin trometamol is available in both oral and parenteral formulations, although only the oral preparation is approved for use in the USA. Oral bioavailability is approximately 40%. Peak serum concentrations are 10 mcg/mL and 30 mcg/mL following a 2-g or 4-g oral dose, respectively. The half-life is approximately 4 hours. The active drug is excreted by the kidney, with urinary concentrations exceeding MICs for most urinary tract pathogens.
FIGURE 43–9 Structure of daptomycin. (Kyn, deaminated tryptophan.)