Kenneth C. Lamp

In vitro pharmacodynamic effects of concentration, pH, and growth phase on serum bactericidal activities of daptomycin and vancomycin.

Clinical trials with daptomycin were halted in December 1990 because of treatment failures including two resistant Staphylococcus aureus strains. High protein binding of daptomycin (> 90%) and the lower-than-expected concentrations in serum with the dosage regimen of 3 mg/kg of body weight every 12 h may have contributed to these failures. To evaluate the effect that higher concentrations would have on bactericidal activity measured by time-kill curves, peak and trough concentrations were estimated for dosage regimens of 3, 5, and 10 mg/kg every 12 h. MICs, MBCs, and killing curves for daptomycin and vancomycin were performed by using the estimated concentrations with four S. aureus strains obtained from patients who failed daptomycin therapy for endocarditis. MICs and MBCs of daptomycin demonstrated a greater inoculum effect than those of vancomycin; MICs and MBCs of daptomycin increased three- to fourfold, but those of vancomycin increased only one- to twofold when the inoculum was increased from 5 x 10(5) to 5 x 10(7) CFU/ml. No pH-dependent effect on MICs or MBCs was seen. Strenuous experimental conditions were chosen: high inoculums (5 x 10(7) CFU/ml), extremes of pH (6.4, 7.4, and 8), and stationary and exponentially growing organisms; and all experiments completed in the presence of pooled human serum. Daptomycin exhibited concentration-dependent killing and statistically faster kill rates than vancomycin against stationary- or exponential-growth-phase organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. The results indicate that the use of higher dosage regimens with compounds similar to daptomycin may be capable of overcoming the effects of pH, high inoculum, and protein binding.

Ofloxacin Clinical Pharmacokinetics

SummaryOfloxacin is a new fluoroquinolone with a spectrum of activity similar to other fluoroquinolones with activity which includes Chlamydia trachomatis, Mycobacterium spp., Mycoplasma spp. and Legionella pneumophila. Through its additional mechanisms of action, ofloxacin may be less susceptible to the development of resistance from Staphylococcus aureus commonly seen with currently available fluoroquinolones. The impact of these findings cannot be evaluated without further clinical experience. The pharmacokinetics of ofloxacin are characterised by almost complete bioavailability (95 to 100%), peak serum concentrations in the range of 2 to 3 mg/L after a 400mg oral dose and an average half-life of 5 to 8h. In comparison with other available quinolones, elimination is more highly dependent on renal clearance, which may lead to more frequent dosage adjustments in patients with impaired renal function. Ofloxacin appears less likely to affect the pharmacokinetics of drugs (e.g. theophylline) which commonly interact with fluoroquinolones such as ciprofloxacin and enoxacin. The properties of ofloxacin make it a therapeutic alternative to currently available fluoroquinolones.

Pharmacodynamics of Once-Daily Amikacin in Various Combinations with Cefepime, Aztreonam, and Ceftazidime against Pseudomonas aeruginosa in an In Vitro Infection Model.

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

Teicoplanin and daptomycin bactericidal activities in the presence of albumin or serum under controlled conditions of pH and ionized calcium

Teicoplanin and daptomycin bactericidal rates (BRs) were measured from standard kill curves in supplemented Mueller-Hinton broth (B), B with 3 g of albumin per dl (BA), B with 50% pooled human serum (BS), and in broth to simulate free concentrations (BF) under controlled physiologic conditions of pH (7.4) and ionized calcium (1.15 to 1.17 mM) against two clinical Staphylococcus aureus strains. Total concentrations of teicoplanin and daptomycin, respectively, were 45 and 12.5 micrograms/ml in B, BA, and BS and 4.5 and 1.25 micrograms/ml in BF. All BRs are reported as log10 CFU per milliliter per hour. There was a trend for the teicoplanin BR to be inhibited by serum for strain 67 (BR in B was -0.26 +/- 0.08 versus a BR in BS of -0.19 +/- 0.08 [P > 0.05]). The teicoplanin BRs for strain 135 were unaffected by the type of medium used (range, -0.17 to -0.20). For both strains, daptomycin BRs were adversely affected by lower concentrations, albumin, and serum. The BR of daptomycin was significantly faster in B (-4.53 +/- 1.92) (P < 0.05) than it was in BF (-0.58 +/- 0.04), BA (-1.68 +/- 0.28), or BS (-1.02 +/- 0.16) against strain 67. BA and BS resulted in BRs more than twice that in BF (P > 0.05). Against strain 135, daptomycin again produced the highest BR in B; however, the BRs in BF, BA, and BS were almost identical, indicating that only free daptomycin was active. After correcting for the influence of protein binding, pH, and ionized calcium, teicoplanin appeared to be inhibited by serum, and daptomycin demonstrated enhanced BRs against different S. aureus strains in the presence of albumin or serum.