Clearance of quinupristin-dalfopristin (Synercid) and their main metabolites during continuous veno-venous hemofiltration (CVVH) with or without dialysis.

BACKGROUND: Quinupristin-dalfopristin (Q/D) is often utilized in critically ill patients, some of whom require CVVH. This study was undertaken to determine the clearance of O/D and their main active metabolites (RPR 100391, RP 69012, RP 12536) via CVVH in the swine model. METHODS: Q/D 7.5 mg/kg was intravenously administered over 0.5 h to 12 swine after induction of acute renal failure by ligation of the renal arteries. At 0.5 h post injection, the CVVH procedure was initiated and continued for 8 hours at the following pump rates: (1)100 mL/min, (2)180 rnL/min, and (3)100 mL/min with dialysis (flow rate: 1 L/h). Blood and ultrafiltrate samples were collected at 1 h intervals and assessed by a validated HPLC method. RESULTS: Plasma analysis suggests rapid metabolism to the main active metabolites which are appreciably cleared as demonstrated by high clearance and sieving coefficient estimates. Mean clearance estimates for RP 69012, RP 100391, and RP 12536 are 729, 777, and 578 mL/h in the 100 mL/min CVVH group, 772, 785, 685 mL/min in the 180 mL/min CVVH group, and 753, 791, 616 mL/min in the 100 mL/min CVVH group with 1 L/h dialysis, respectively. CONCLUSION: These data reveal that Q/D is rapidly metabolized and the metabolites are cleared to a large extent via CVVH. Due to the considerable contribution of the metabolites to overall in vivo activities, additional studies are required to fully quantify their removal before final dosage modifications for patients undergoing CVVH can be recommended.

Effects of adjunctive treatment with combined cytokines in a neutropenic mouse model of multidrug-resistant Enterococcus faecalis septicemia.

STUDY OBJECTIVE: To examine whether the antienterococcal efficacy of a regimen of gentamicin plus vancomycin combined with granulocyte colony-stimulating factor (G-CSF) is enhanced by concurrent therapy with interferon-gamma (IFN-gamma). SETTING: Hospital laboratory. INTERVENTION: Mice rendered neutropenic by cyclophosphamide were intraperitoneally inoculated with a gentamicin- and vancomycin-resistant Enterococcus faecalis isolate. MEASUREMENTS AND MAIN RESULTS: Infected animals were randomized into treatment groups that received G-CSF alone or in combination with various dosages of IFN-gamma. Additional groups of animals received vancomycin; G-CSF, G-CSF plus vancomycin, IFN-gamma, and G-CSF; or vancomycin with both cytokines. Addition of IFN-gamma to G-CSF regimen resulted in no significant change (p>0.05) in survival, compared with treatment with G-CSF alone. Also, the antienterococcal efficacy of antibiotic plus G-CSF was not modified by coadministration of IFN-gamma. CONCLUSION: This study suggests that adjunctive application of combined cytokines may not be more beneficial than only G-CSF in combination with an antibiotic to treat multidrug-resistant enterococcal infection.

Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations.

Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.

In vitro and in vivo influence of adjunct clarithromycin on the treatment of mucoid Pseudomonas aeruginosa.

Recent in vitro and in vivo data have substantiated the beneficial effects of macrolides/ azalides for use against Pseudomonas aeruginosa. While macrolides/azalides are not very potent in vitro antimicrobial agents against this pathogen, they appear to have an adjunctive role by either altering the course of infection owing to their inhibition of biofilm production or modulation of the host anti-inflammatory response, or both. To determine the in vitro and in vivo effects of clarithromycin as adjunctive therapy with ceftazidime against a mucoidproducing strain of P. aeruginosa, we performed a standard time-kill experiment and a pneumonia model in mice, respectively. Time-kill studies were performed over a 24 h period with varying concentrations of clarithromycin and ceftazidime alone or in combination. Synergic activity was noted with the use of 0.5 x MIC of ceftazidime combined with either 0.5 or 2 x MIC of clarithromycin. Neutropenic mice were infected with 10(8) cfu of mucoid P. aeruginosa intranasally to produce pneumonia and subsequently treated with oral clarithromycin (100 mg/kg) and/or sc ceftazidime (1500 mg/kg) as monotherapy or in combination. The addition of 5 days of clarithromycin to the ceftazidime regimen significantly improved survival as compared with the beta-lactam alone (48% versus 32%, P = 0.04). While a statistically significant difference was not detected with the addition of 3 days of clarithromycin therapy, a trend towards improved survival was noted with this regimen (38% versus 32%). These data demonstrate the adjunctive potential of clarithromycin when administered in combination with an antipseudomonal agent for the treatment of mucoid-producing Pseudomonas in acute respiratory infection.

Beneficial effect of adjunctive azithromycin in treatment of mucoid Pseudomonas aeruginosa pneumonia in the murine model.

While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.

Protective effect of trovafloxacin, ciprofloxacin and ampicillin against Streptococcus pneumoniae in a murine sepsis model.

Trovafloxacin is a new fluoroquinolone that has potent microbiological activity against the pneumococcus, including penicillin-resistant strains. To evaluate the protective effect of trovafloxacin, ciprofloxacin and ampicillin against penicillin-susceptible, -intermediate and -resistant strains of Streptococcus pneumoniae, an intraperitoneal, immunocompetent mouse model of sepsis was used. The minimum lethal dose (MLD) for each isolate was determined in duplicate. A single sc dose of each antibiotic was administered over a wide range of doses 1 h after the ip inoculation of the test isolate at the MLD. The assessment of the protective dose for 50% of the population (PD50) for each antimicrobial/bacteria combination was performed in triplicate and the PD50 value was calculated at the end of 5 days. Results showed that trovafloxacin provided PD50 values that were significantly lower than those of ciprofloxacin for all isolates. For the penicillin-susceptible and -intermediate isolates, the PD50 values of ampicillin were significantly lower than those for either of the fluoroquinolones studied; however, trovafloxacin was statistically superior to both ciprofloxacin and ampicillin against the penicillin-resistant strain. Therefore, regardless of penicillin susceptibility, trovafloxacin has potent activity against Streptococcus pneumoniae and may be a viable alternative for the treatment of penicillin-resistant isolates.

In vitro synergistic activities of tobramycin and selected beta-lactams against 75 gram-negative clinical isolates.

The microdilution checkerboard technique was utilized to distinguish synergistic activity between tobramycin and four beta-lactams: piperacillin-tazobactam, ticarcillin-clavulanate, ceftazidime, and ceftriaxone. Beta-lactam-aminoglycoside combinations were tested against 75 clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumanii, Citrobacterfreundii, Serratia marcescens, and Enterobacter cloacae. Despite in vitro susceptibilities, all isolates demonstrated either synergism or indifference; no antagonism was observed. Against pathogenic gram-negative nosocomial isolates, a greater percentage of synergy was consistently observed with combination regimens containing tobramycin and piperacillin-tazobactam or ticarcillin-clavulanate than with the cephalosporin-containing regimens.

Oral bioavailability and pharmacokinetics of ciprofloxacin in patients with AIDS.

Few reports on the effects of AIDS on the absorption of orally (p.o.) administered agents exist. To help fill this informational gap, we administered ciprofloxacin to 12 patients with AIDS by two dosing regimens (400 mg given intravenously [i.v.] and 500 mg given p.o. every 12 h) in a randomized, crossover fashion. Pharmacokinetic parameters were determined by noncompartmental methods. Mean values (+/- standard deviations [SD]) for p.o. ciprofloxacin were as follows: peak concentration of drug in serum (Cmax), 2.94 +/- 0.51 microg/ml; time to Cmax, 1.38 +/- 0.43 h; area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 12.13 +/- 3.21 microg x h/ml; and half-life (t(1/2)), 3.86 +/- 0.48 h. Mean values (+/- SD) for i.v. ciprofloxacin were as follows: Cmax, 3.61 +/- 0.82 microg/ml; time to Cmax, 1.0 h; AUC(0-12), 11.92 +/- 2.92 microg x h/ml; and t(1/2), 3.98 +/- 0.94 h. The mean percent absolute bioavailability for ciprofloxacin was calculated to be 82% +/- 13%, similar to the value for healthy volunteers. We conclude that ciprofloxacin when administered p.o. to patients with AIDS is well absorbed, as evidenced by excellent bioavailability and is not affected by gastrointestinal changes in the absence of infectious gastroenteritis and severe diarrhea.

Influence of adjunct azithromycin on the mortality of experimental Pseudomonas aeruginosa sepsis.

The aim of this study was to determine the in vivo influence of azithromycin subinhibitory concentrations on mortality in a peritonitis-sepsis model. One hour after an intraperitoneal injection of Pseudomonas aeruginosa, mice were randomized to receive: ceftazidime, 500 mg/kg SC q4hxtwo doses alone; azithromycin, 20 mg/kg SCxone dose alone; ceftazidime plus azithromycinxone dose; ceftazidime plus azithromycinxtwo doses (1 and 24 h); ceftazidime plus prophylactic azithromycin (three doses at -48, -24, 1 h); or no treatment (control). A significant decrease in the rate of mortality was observed in animals treated with all ceftazidime plus azithromycin groups when compared with those receiving ceftazidime alone. These data indicate a potential role for adjunctive azithromycin therapy in P. aeruginosa infection.

Characterization of bactericidal activity of clindamycin against Bacteroides fragilis via kill curve methods.

Kill curves were determined for five isolates of Bacteroides fragilis with clindamycin at concentrations equal to the MIC or to 4, 16, and 64 times the MIC. Examination of plots of log CFU per milliliter versus time revealed no association between the clindamycin concentration and the rate and extent of the bactericidal activity against B. fragilis at or below 64 times the MIC.

Oral absorption of trimethoprim-sulfamethoxazole in patients with AIDS.

STUDY OBJECTIVE: To determine the bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, randomized, two-way crossover trial. SETTING: Outpatient clinical research center affiliated with a community-based teaching hospital. PATIENTS: Ten individuals diagnosed with the acquired immunodeficiency syndrome (AIDS) with CD4+ counts less than 200 cells/mm3, receiving TMP-SMX one double-strength tablet 3 times/week as prophylaxis for Pneumocystis carinii pneumonia (PCP), and without documented gastroenteropathy or diarrhea agreed to participate in the trial. One patient withdrew from the study secondary to development of symptomatic PCP. Data were available for analysis from the remaining nine subjects. INTERVENTIONS: Participants received TMP 160 mg and SMX 800 mg orally or intravenously during two study periods. Following dose administration, blood samples were collected at predetermined time points over 36 hours. MEASUREMENTS AND MAIN RESULTS: Analysis of TMP-SMX pharmacokinetic parameters (half-life, total body clearance, area under the serum concentration versus time curve, and peak concentration) failed to reveal any significant differences between intravenous and oral preparations. The calculated bioavailabilities of oral TMP and SMX (mean +/- SD) were 102.7% +/- 19.8% and 109.4% +/- 19.4%, respectively. CONCLUSION: The absorption of TMP-SMX is not adversely affected by HIV infection in the absence of HIV-induced gastroenteropathy or diarrhea.

Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections.

Since beta-lactam antibiotics have concentration-independent killing, bacterial eradication is a function of the time the serum drug concentration remains above the drug's MIC (T > MIC). We compared the serum bactericidal titers (SBTs) of ceftazidime given by continuous infusion (CI) or by intermittent bolus dosing (BD) against two clinical isolates each of Pseudomonas aeruginosa and Escherichia coli to determine if CI would allow lower daily dosing while still providing equal bactericidal activity compared with BD. This was an open-labeled, randomized, steady-state, four-way crossover study with 12 healthy volunteers. The ceftazidime regimens were 1 g every 8 h (q8h) BD, 1 g q12h BD, 3 g over 24 h CI, and 2 g over 24 h CI. The areas under the bactericidal curves were calculated by the trapezoidal rule using the reciprocal of the SBT. For all organisms the areas under the bactericidal curves for intermittent versus the CI regimens were the same for equal doses (P > 0.05). For both strains of E. coli all four regimens provided SBTs of > or = 1:2 over the dosing interval and 100% T > MIC. The 1-g q8h BD and q12h BD regimens provided T > MIC of 82 and 52%, respectively, for both P. aeruginosa isolates (MICs, 4 micrograms/ml). In comparison, the 2- and 3-g CI regimens always maintained SBTs of > or = 1:2 and T > MIC over the 24-h period as serum drug concentrations were 12.8 +/- 3.0 and 18.2 +/- 4.5 micrograms/ml, respectively. CI optimizes the pharmacodynamic and pharmacoeconomic profile of ceftazidime by providing adequate antibacterial activity over the 24-h dosing period with a reduction in the total daily dose of the antimicrobial agent.

Intracellular and extracellular penetration of azithromycin into inflammatory and noninflammatory blister fluid.

The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05).