Use of fenofibrate in the management of protease inhibitor-associated lipid abnormalities.

Human immunodeficiency virus (HIV) protease inhibitors are associated with several metabolic abnormalities including hypercholesterolemia and hypertriglyceridemia. Fenofibrate is a new lipid-lowering agent for adults with very high triglyceride levels that was administered to two HIV-positive patients who were taking protease inhibitors and developed hypertriglyceridemia. Starting dosages were 134 and 201 mg/day, and were increased to 268 mg/day in both patients. Triglyceride levels decreased from 1450 to 337 mg/dl (76.8%) and from 1985 to 322 mg/dl (83.8%), respectively, after 10 months of therapy. High-density lipoprotein levels increased in both patients.

Impact of different statistical methodologies on the evaluation of the in-vitro MICs for Bacteroides fragilis of selected cephalosporins and cephamycins.

The purpose of this study was to assess the effect of different MIC statistics on the in-vitro evaluation of cefoxitin, cefotetan, ceftizoxime, cefotaxime, desacetylcefotaxime, and cefotaxime:desacetylcefotaxime (1:1 ratio) against clinical isolates of Bacteroides fragilis from the Medical University of South Carolina. MICs were determined by the agar dilution method following NCCLS guidelines. Statistical analyses included arithmetic and geometric means, median, mode, MIC50, MIC90, and range. Differences between antimicrobial agents were determined using parametric and nonparametric methods. Consistent with previous in-vitro studies on anaerobes with these agents, a wide range in the MICs was observed. The arithmetic mean MIC was lowest for cefotetan, but the geometric mean MIC was lowest for ceftizoxime. Using the MIC90, cefotetan was at least a two-fold dilution more active than the other agents. After natural logarithmic transformation of the MIC data, analysis of variance with the Scheffé post-hoc test demonstrated that the MICs of ceftizoxime were significantly lower than those of cefoxitin (P < 0.001), cefotetan (P < 0.05), cefotaxime (P < 0.05), and desacetylcefotaxime (P < 0.001). Median and mode MICs were lowest for ceftizoxime and cefotaxime:desacetylcefotaxime. Using published breakpoints, cumulative percent susceptibility was similar for all agents studied. In this analysis of the antimicrobial susceptibility of B. fragilis in our institution, the in-vitro activity of the cephalosporins and cephamycins tested appeared to be very similar when all statistical data were evaluated. Since apparent in-vitro activity may be influenced by the statistic evaluated, we suggest that all MIC data be reported to allow for a more complete analysis of microbiological potency.

Evaluation of cephalosporins/cephamycins with antianaerobic activity by integrating microbiologic and pharmacokinetic properties.

When evaluating antimicrobial agents, in vitro microbiologic activity and pharmacokinetics are important factors, but these data are usually not assessed simultaneously. The purpose of the study was to compare cefoxitin, cefotetan, ceftizoxime, cefotaxime (CT), desacetylcefotaxime (DACT), and CT/DACT (1:1 ratio) by integrating their microbiologic activity against clinical isolates of Bacteroides fragilis with their pharmacokinetic properties. Minimal inhibitory concentrations (MIC) were determined by the agar dilution method. Steady-state serum concentration--time profiles were simulated for 2-gm doses in a 70-kg patient using ADAPT software and pharmacokinetic data from published studies. Serum protein binding (%) of each agent was also obtained from published studies and used to calculate the unbound serum concentration--time profiles. As estimates of pharmacodynamic activity, time below the MIC (T less than MIC) and percentage of the dosing interval below the MIC (% INT less than MIC) were calculated for individual isolates using total and unbound serum concentrations. Data analysis included MIC50, MIC90, range, breakpoint susceptibility, and analysis of variance for T less than MIC and % INT less than MIC (Scheffé post-hoc test, P less than 0.05). The MIC90 of cefotetan was at least a twofold dilution lower than the other agents. However, using unbound (pharmacologically active) serum concentrations, T less than MIC and % INT less than MIC for ceftizoxime (at a simulated eight-hour dosing interval) were significantly smaller than with the other antibiotic regimens. Integration of in vitro and pharmacokinetic data may provide additional information to assist in the evaluation of antimicrobials. For B fragilis from our institution, the pharmacodynamic profile of unbound ceftizoxime is superior to the other antianaerobic cephalosporins/cephamycins tested.

Oral antibiotic therapy of dermatologic conditions.

Oral antibiotics that may be useful in dermatology can be classified as beta-lactams (penicillins and cephalosporins), tetracyclines, macrolides, or quinolones; other options are clindamycin, trimethoprim-sulfamethoxazole, rifampin, and metronidazole. Proper understanding of the mechanisms of action and resistance, pharmacology, antimicrobial spectra, and adverse effects of these drugs will enable the clinician to obtain the best results.

Factors affecting antimicrobial susceptibility of Fusobacterium species.

Fifteen clinical isolates of Fusobacterium species were studied to determine their quality of growth on five agar media, their susceptibility to penicillin, cephalothin, cefoxitin, and cefotaxime, the inoculum effect, and the presence of L forms and beta-lactamase. Wilkins-Chalgren agar supported confluent growth best, but Fusobacterium nucleatum exhibited poor growth on all agar media. Most isolates exhibited poor reproducibility of MIC results with repeated agar dilution testing. However, most isolates were susceptible to all antibiotics at the breakpoint concentrations. No inoculum effect was observed, but preparation of an inoculum at a 0.5 McFarland nephelometric standard produced a lower than expected number of CFU (10(6) CFU) in some isolates. L forms were frequently seen. No beta-lactamase was found. The variability in MICs seen with beta-lactam antibiotics was not found when clindamycin was tested. MIC studies with Fusobacterium spp. may be complicated by poor growth on agar media, poor reproducibility, and small inoculum size.

In vitro activity of cefbuperazone compared with that of other new beta-lactam agents against anaerobic gram-negative bacilli and contribution of beta-lactamase to resistance.

Cefbuperazone was compared with other currently available and investigational antibiotics against 278 clinical isolates of anaerobic gram-negative bacilli by an agar dilution method. Cefbuperazone and cefotetan were equally active against Bacteroides fragilis, with 8% of the organisms tested found to be resistant to 32 micrograms of either drug per ml. Cefoperazone, cefotaxime, ceftriaxone, and cefmetazole were less active against these strains; cefoxitin, moxalactam, piperacillin, clindamycin, and metronidazole were more active. None of the agents were consistently active against any of the other anaerobic gram-negative bacilli except imipenem, for which the minimum concentration required to inhibit 90% of all strains tested was 4 micrograms/ml. A 10,000-fold increase in inoculum size caused an increase in the MIC of ceftriaxone, cefotaxime, and cefoperazone but not of cefbuperazone, cefotetan, or cefoxitin. Investigation of the mechanism of resistance to cephalosporin-like agents demonstrated a correlation between the level of resistance and beta-lactamase activity. Cefbuperazone, cefotetan, and cefoxitin were not hydrolyzed, had lower MICs, and were less affected by changes in inoculum size than were cefotaxime, ceftriaxone, and cefoperazone.

Comparison of moxalactam with the combination of clindamycin and an aminoglycoside in the treatment of common surgical infections.

The efficacy and safety of moxalactam were compared with those of a combination of clindamycin and an aminoglycoside in a randomized study of therapy for 60 patients with the following surgical infections: intraabdominal or pelvic infections (12 patients), abscesses (13 patients), and severe infections of extremities (35 patients). These infections were equally distributed between the two treatment groups, except that, according to the randomization process, a majority of patients with intraabdominal infections received moxalactam therapy. Surgery was used as adjunctive therapy when necessary. One adverse reaction--fever and leukocytosis with eosinophilia--was due to continued administration of moxalactam. No significant adverse reaction was observed in the patients treated with the clindamycin-aminoglycoside combination. Although the number of isolated organisms resistant to the antibiotics was similar within each treatment regimen, an alarmingly high percentage of gram-positive cocci were intermediately sensitive to moxalactam in vitro. Even in the presence of resistant organisms, moxalactam therapy was as effective as the clindamycin-aminoglycoside therapy when surgical debridement or drainage was properly timed and executed.

Giardiasis in pregnancy.

Giardiasis in pregnancy can be a debilitating disease with threatens the well-being of mother and fetus, as illustrated by three cases. The usual therapeutic agents are contraindicated in pregnancy. Paromomycin, an oral, poorly absorbed aminoglycoside, is an alternate, potentially less toxic agent for treatment of symptomatic giardiasis in pregnancy. The pharmacologic actions of paromomycin in human beings and its antiprotozoan efficacy are discussed.

In vitro activity of N-formimidoyl thienamycin, moxalactam, and other new beta-lactam agents against Bacteroides fragilis: contribution of beta-lactamase to resistance.

N-Formimidoyl thienamycin (N-F-thienamycin) and moxalactam were compared with other currently available and investigational antibiotics against 100 clinical isolates of Bacteroides fragilis by an agar dilution method. N-F-thienamycin was the most active among the beta-lactam agents tested, with a minimal inhibitory concentration for 90% of isolates (MIC90) of 0.25 micrograms/ml. Moxalactam was next in activity, with an MIC90 of 4 micrograms/ml. N-F-thienamycin was somewhat more active, and moxalactam was slightly less active, than metronidazole and clindamycin. An increase in inoculum size caused an increase in the MIC of N-F-thienamycin, cefoperazone, and cefotaxime. This inoculum effect could influence the usefulness of these drugs in certain clinical conditions. The minimal bactericidal concentration was less than two times the MIC for most agents and less than four times the MIC for all beta-lactam agents at each inoculum size tested. Investigation of the mechanism of resistance to beta-lactam agents demonstrated a correlation between the level of resistance and beta-lactamase activity in each strain tested. N-F-thienamycin and cefoxitin were not hydrolyzed, and moxalactam was less susceptible to hydrolysis than the other beta-lactam antibiotics. Moxalactam and N-F-thienamycin may prove to be useful against infections with B. fragilis.

Perioperative cephalosporin prophylaxis in cesarean section: effect on endometritis in the high-risk patient.

A total of 120 patients who were to be delivered by cesarean section and who were at high risk of postoperative infection received three doses of either cefamandole, cephalothin or placebo perioperatively. Maternal serum levels for both antibiotics were in the therapeutic range. Although both drugs reduced the incidence of febrile morbidity and endometritis, only cefamandole significantly reduced the fever index. Risk factors for postoperative infections were the presence of ruptured membranes, labor, and internal fetal monitoring. Cefamandole beneficially influenced all risk factors while cephalothin was able to reduce only the risk of ruptured membranes. When a new method for obtaining endometrial tissue was utilized, 50% of cultures were negative. There was no difference in the organisms isolated from patients with and without endometritis.

Intravenous metronidazole therapy for Bacteroides fragilis meningitis.

A 69-year-old man developed meningitis due to Bacteroides fragilis and Streptococcus MG-intermedius, which progressed during chloramphenicol and nafcillin therapy to the extent that he seemed near death, with frank pus covering the spinal cord at surgery. Treatment with intravenous metronidazole and penicillin G was curative. After multiple trauma, a 20-year-old man developed meningitis due to Escherichia coli and B fragilis. He failed to respond to chloramphenicol alone, but responded to combined treatment with chloramphenicol and metronidazole. The right frontal sinus and epidural space abscesses were drained and a right frontal lobe abscess was excised. Metronidazole may be a uniquely effective agent for treatment of meningitis due to susceptible strains of Bacteroides fragilis.

Cefoxitin therapy for surgical patients.

Cefoxitin was administered to 25 patients on a general surgical service. In 16 of these patients, a bacteriologic diagnosis was made: four patients had peritonitis, one had ascending cholangitis, seven had cellulitis, and four had abscess. The dosage of cefoxitin varied from 4 to 8 g per day and was generally well tolerated, although there were three cases of phlebitis and one superinfection. There was no evidence of renal, liver, or bone marrow toxicity. All isolates of Bacteroides (eight), Escherichia coli (six), and Staphylococcus aureus (five) were sensitive to cefoxitin. Two of three strains of Pseudomonas aeruginosa were resistant. All patients recovered with cefoxitin and corrective surgery. The results indicate that cefoxitin has the potential of replacing combination therapy in some surgical patients.

Perioperative antibiotic prophylaxis is cesarean section.

The effect of an 8-hour, 3-dose perioperative regimen of cefazolin or placebo was evaluated in 97 patients. Postoperative morbidity occurred in 13 patients (27.1%) in the cefazolin group and in 17 patients (34.7%) who received placebo. The clinical sites of infection were similar in both groups except that wound infections (2) and sepsis (2) were found only in patients receiving placebo. Aerobic organisms diminished and anaerobes increased in patients who received antibiotics. Aerobic isolates were essentially unchanged and fewer anaerobes were recovered from patients given placebo. Antibiotic levels observed at cesarean section were in the therapeutic range. The only risk factor which correlated with morbidity was the presence of ruptured membranes. This short course, single drug regimen did not significantly reduce morbidity although it was bacteriologically effective.

Bacterial flora of patients with prematurely ruptured membranes.

Twenty consecutive patients with premature rupture of the membranes were studied to determine the vaginal, endocervical, and neonatal bacteriologic flora. Patients who had membranes ruptured for more than 12 hours had more anaerobic species isolated from vaginal plus endocervical or endocervical cultures alone than did those patients with membranes ruptured for less than 12 hours. Overall, aerobic organisms were more frequently isolated than anaerobic organisms, but the majority of cultures were of a mixed flora. Streptococci, corynebacteria, and Bacteroides organisms were the most frequently isolated organisms from all sites cultured. Lactobacilli were isolated in only 45% of endocervical and vaginal cultures, and Enterobacteriaceae were infrequently encountered. This study indicates that there is a change toward a preponderance of anaerobic species in the birth canal when membranes are ruptured for more than 12 hours, and that this change is detectable before delivery.