Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections.

STUDY OBJECTIVES: To determine whether antipyretic therapy prolongs the course of experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. DESIGN: Retrospective observational study. SETTING: University Center for Vaccine Development. SUBJECTS: Fifty-four volunteers with experimentally induced influenza A, 45 with S. sonnei, and 21 with R. rickettsii infections participated. INTERVENTIONS: Subjects from the six influenza A studies were challenged intranasally. If they met certain criteria, they were offered aspirin or acetaminophen for symptomatic relief. Subjects from the three Shigella studies were challenged with the bacteria and then given trimethoprimsulfamethoxazole. Acetaminophen also could be administered. In the one R. rickettsii trial, subjects were inoculated intradermally and treated with tetracycline. Again, acetaminophen was administered for symptomatic relief. MEASUREMENTS AND MAIN RESULTS: Data, excerpted from subjects' study records, were evaluated using Wilcoxon tests, Spearman's correlation coefficients, and multiple regression analysis. Two-tailed hypotheses with a p value of 0.05 were used for all of the analyses. There was a striking correlation between antipyretic therapy and duration of illness in subjects infected with influenza A and S. sonnei, but not R. rickettsii. CONCLUSIONS: Multivariate analysis suggested that antipyretic therapy prolonged illness in subjects infected with influenza A, but its use was the result of prolonged illness in those infected with S. sonnei. The precise nature of these relationships requires a prospective, randomized, placebo-controlled trial.

Toxicities of drugs used in the management of fever.

Fever is frequently managed outside the purview of medical professionals, and antipyretic therapy, on the whole, is generally considered safe. However, each of the drugs used in the management of fever has significant toxicities. The purpose of this review is to examine the relative safety of such agents with a focus on the nonsteroidal anti-inflammatory drugs and acetaminophen. Toxicity to the gastrointestinal, renal, and hepatic systems are considered; the comparative safety profile of acetaminophen and ibuprofen as antipyretics are highlighted; and specific recommendations to improve the safe use of these therapies are advanced.

Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences.

Various treatments have been used to suppress fever since antiquity. Surprisingly, few studies have been performed to ascertain the physiologic consequences of antipyresis and validate the rationale behind such therapy. More importantly, it has not been established conclusively that the benefits of antipyretic therapy outweigh its risks. The present review considers these issues in light of currently available data and formulates guidelines for antipyretic therapy based on these data.

Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia.

We attempted to determine if an association exists between vancomycin serum concentrations resulting from traditional dosing regimens, and efficacy and toxicity outcomes. We reviewed the medical charts of 273 consecutive patients prescribed 273 courses of vancomycin therapy for documented, gram-positive bacteremia. Of the 273 courses of therapy, 45 and 31 patients met all criteria and were evaluated for toxicity and efficacy, respectively. The duration of fever and abnormal white blood cell counts, length of hospital stay, overall mortality, serum creatinine, and serum vancomycin concentrations were evaluated retrospectively. No association between initial peak or trough levels with mortality was noted. However, patients were more likely to become afebrile within 72 hours if peak and trough concentrations were 20 micrograms/ml or greater and 10 micrograms/ml or greater, respectively (p < 0.01). Patients were also more likely to have their white blood cell count return to normal within 72 hours if trough concentrations were 10 micrograms/ml or above (p < 0.01). No statistically significant correlation between nephrotoxicity and initial serum creatinine, days of hospital stay, or days of vancomycin therapy were found. Serum concentrations of vancomycin, assessed before the development of nephrotoxicity, were significantly higher in patients who became nephrotoxic. Mean (SD) trough concentrations were 23.2 (2.5) micrograms/ml and 10.2 (3.8) micrograms/ml in nephrotoxic and nonnephrotoxic patients, respectively. Our results suggest that the commonly accepted therapeutic range for vancomycin trough concentrations (< 10 micrograms/ml) may be too restrictive in patients receiving vancomycin therapy alone.

The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial.

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

In vitro evaluation of high-level, gentamicin-resistant enterococci isolated from bacteremic patients.

We attempted to characterize the susceptibility of high-level, gentamicin-resistant (HLGR, minimum inhibitory concentration [MIC] > 2000 micrograms/ml) enterococcal blood isolates and evaluated a small subset of these isolates for bactericidal synergy. Thirteen Enterococcus faecalis and three Enterococcus faecium isolates that were HLGR were prospectively collected. Standard broth macrodilution techniques were used to determine the MICs and minimum bactericidal concentrations to a variety of antibiotics. Two isolates were evaluated for synergy by time-kill curve methods using combinations of penicillin and streptomycin, teicoplanin and rifampin, and vancomycin and ciprofloxacin. Teicoplanin was the most active antibiotic tested, with all isolates exhibiting susceptibility to this agent. Four E. faecalis isolates and one E. faecium isolate expressed only low-level resistance to streptomycin (LLSR, MICs 32-64 micrograms/ml). Penicillin and streptomycin produced bactericidal synergy in the LLSR isolate. The other antibiotic combinations did not result in bactericidal synergy in the two isolates tested. For HLGR enterococci that are only LLSR, the combination of penicillin-streptomycin appears to provide adequate bactericidal activity. Teicoplanin may potentially be useful for streptomycin-resistant HLGR isolates.

Prevention of auditory sequelae in pediatric bacterial meningitis: a meta-analysis.

Meta-analysis methods were used to compare the effect of antibiotic regimens and corticosteroids on the development of auditory sequelae after pediatric bacterial meningitis. After a literature search of two major data bases, 11 studies met the criteria and were included in the analysis. Summary odds ratios, with 95% confidence intervals, were calculated that quantified the relative risk of developing auditory sequelae after specific therapies. No significant differences among antibiotics were identified in terms of reducing the risk of meningitis-related hearing impairment. However, corticosteroids significantly reduced the frequency of bilateral, moderate, or greater hearing loss. Patients receiving placebo versus dexamethasone were much more likely to develop auditory dysfunction (odds ratio 3.77; 95% CI 1.77-8.10). The results of this study add quantitative evidence supporting the use of dexamethasone as adjunctive therapy in pediatric bacterial meningitis.

Neutropenia in patients infected with human immunodeficiency virus.

The possible mechanisms of neutropenia associated with both human immunodeficiency virus (HIV) infection and drug treatment in adults are examined, and the current and investigational strategies for managing neutropenia are reviewed. Neutropenia associated with HIV arises from diverse mechanisms, including cellular immune dysfunction, direct effects on progenitor cells, humoral immune dysfunction, and vitamin deficiencies. Drug-induced neutropenia may be related to direct cytotoxic effects, immunologic mediators, and the effects of vitamin depletion on the bone marrow. Bone marrow toxicity in patients receiving zidovudine appears to be more frequent in those patients with advanced disease, low CD4 cell counts, a pretreatment anemia, low serum vitamin B12 levels, and low or low normal serum folic acid levels. Patients with AIDS also are at increased risk for adverse events associated with folate antagonists and sulfonamides compared with other patient populations. Lithium therapy has improved neutrophil counts in patients receiving zidovudine; however, the toxicities associated with use of lithium, combined with the lower dosages of zidovudine now recommended, may obviate its use. The use of colony-stimulating factors appears promising for increasing the number and function of circulating neutrophils. Although concomitant use of interferon alfa and zidovudine may result in a strong synergistic anti-HIV effect, dose-limiting neutropenia has been reported in patients receiving the combination. There are currently no controlled data assessing the effectiveness of intravenous immune globulin in the treatment of HIV-related or drug-related neutropenia. In evaluating neutropenia, the clinician must attempt to discern whether the neutropenia is more likely related to disease state(s) or drug therapies. Potential management strategies include modulation of the disease state, discontinuation or dose reduction of the offending agent, or administration of exogenous immune enhancer.

Absorption and disposition of colloidal drug delivery systems. I. High-performance liquid chromatographic (HPLC) analysis of a cyclosporin emulsion.

The amount of cyclosporin A in an oil-in-water emulsion drug delivery system was determined by HPLC. The direct extraction and analysis of an intact emulsion were compared to the analysis of a cracked emulsion and an olive oil solution of the drug. The intra- and interday variability for the intact emulsion was less than 10% from 35 to 150 micrograms/ml, with recovery of 94%. Comparison of the assay results obtained with the emulsion and the olive oil solution gave a highly correlated regression line with a small intercept and a slope close to unity. Thus, the direct extraction and HPLC analysis of drugs in emulsions may be a viable approach to evaluate drug content.

Effect of renal function on the bioavailability of ciprofloxacin.

The effect of renal function on the bioavailability of ciprofloxacin was studied in 21 subjects with measured creatinine clearances ranging from 0 to 8.99 liters/h per 1.73 m2. Each subject received ciprofloxacin, 200 mg intravenously and 750 mg orally, separated by at least 1 week. Serial (12 to 15) blood samples were obtained over 24 to 48 h. Concentrations in serum were assayed by high-pressure liquid chromatography. Area under the curve was calculated by the trapezoidal rule with extrapolation to infinity. Bioavailability was calculated as the ratio between the dose-normalized area under the curve of oral and intravenous administrations. The overall mean (standard deviation) bioavailability observed was 63.4% (14.6%), similar to that observed in those with normal renal function (69.0% [15.7%]). The mean bioavailability in the subgroup of subjects with renal insufficiency was 59.9% (13.3%). The observed range in bioavailability was 33.9 to 91.4%. Linear regression did not reveal a correlation between creatinine clearance and bioavailability. Renal insufficiency does not appear to affect ciprofloxacin bioavailability.

Infection with the human immunodeficiency virus: epidemiology, pathogenesis, transmission, diagnosis, and manifestations.

The epidemiology, pathogenesis, transmission, and manifestations of infection with the human immunodeficiency virus (HIV) are described, along with the development of diagnostic tests and drugs to combat it. Acquired immunodeficiency syndrome (AIDS) is caused by HIV infection. The syndrome was first reported in 1981, and as of March 31, 1989, nearly 90,000 cases had been reported in the United States alone. Most U.S. adults with AIDS are homosexual or bisexual men; intravenous drug abusers, heterosexuals, hemophiliacs, and blood transfusion recipients account for 17%, 4%, 1%, and 2% of AIDS cases, respectively. HIV is transmitted by sexual, blood, and perinatal routes; infection leads to a profound immunosuppression involving both the cellular and humoral immune systems. The hallmark of AIDS is a quantitative deficiency of T4 lymphocytes bearing CD4+ receptors, to which the virus binds. Monocytes are believed to be the major route of infection into the CNS. There has been rapid progress in the development of sensitive and specific diagnostic tests for HIV infection. The enzyme-linked immunosorbent assay and Western blot test are the most widely used; both are used to detect antibodies to the virus. Two major classes of drugs are under development for use against HIV: antiviral agents and immunomodulatory agents. Thus far only one drug, zidovudine (AZT), has decreased mortality and improved quality of life. Infection with HIV encompasses a broad spectrum of clinical manifestations, from seroconversion to AIDS-related complex to full-blown AIDS. AIDS is a clinical diagnosis based on the presence of recurring opportunistic infections, previously rare cancers, and neurologic manifestations. Because of the many people infected and the long incubation periods, AIDS will continue to be a major issue in health care. Continued education of health-care personnel and the public is needed.

A prospective evaluation of optimal sampling theory in the determination of the steady-state pharmacokinetics of piperacillin in febrile neutropenic cancer patients.

We examined the use of optimal sampling theory in the determination of the pharmacokinetics of piperacillin in febrile, neutropenic cancer patients. Patients were studied prospectively as part of a randomized, double-blind clinical trial of piperacillin and amikacin versus imipenem and placebo. The results from the analysis of 5 optimal samples were compared with those derived from 15 concentration determinations (10 samples, with the 5 optimal samples assayed in duplicate). The use of a standard least-squares estimator as opposed to a bayesian estimator, with normal prior distributions placed on beta and serum clearance, was also examined. Finally, the use of duplicate determinations in improving the precision of parameter estimation was studied. Plasma concentrations obtained at time points determined by optimal sampling theory, when analyzed with a bayesian estimator, produced estimates of pharmacokinetic parameter values that were in good agreement with those derived from the 15-determination set. Duplicate assay did not improve the precision of parameter estimation. Estimation of plasma clearance was quite robust, irrespective of the estimator used, probably because this evaluation was performed at steady state. Optimal sampling theory is a promising technique that can be employed to determine patient-specific estimates of pharmacokinetic parameter values in target populations.

Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate.

Interpretation of the majority of data on the disposition of clindamycin is confounded by the presence of active metabolites, which may interfere with commonly employed bioassays. We undertook a multiple-dose study of the disposition of clindamycin phosphate and clindamycin, given either as 600 mg intravenously every 6 h or 1,200 mg intravenously every 12 h for five and three doses, respectively, in six healthy volunteers. Concentrations in serum and urine were analyzed by a specific gas chromatography assay. Maximum and minimum clindamycin concentrations in serum and the area under the serum concentration-time curve following the first dose were similar to those observed at the steady state. The mean and standard deviation of the maximum, 1-h postdose, and minimum concentrations in serum at steady state for the 600-mg dose given every 6 h were 16.8 +/- 6.0, 7.6 +/- 0.7, and 2.3 +/- 0.9 microgram/ml, whereas for the 1,200-mg dose given every 12 h they were 17.2 +/- 3.5, 9.8 +/- 1.5, and 0.6 +/- 0.3 microgram/ml, respectively. For the 12-h regimen, clindamycin concentrations in serum remained above 2 micrograms/ml for 7 h. The decay of clindamycin phosphate levels in serum was rapid, with virtually 100% of the phosphate eliminated within the first 1.5 h following the dose. Approximately 0.35 and 4.5% of the administered dose were recovered in the urine as clindamycin phosphate and clindamycin, respectively. Further pharmacokinetic evaluation of the 12-hourly dosage regimen should be done before clinical evaluation in infected patients is undertaken.

Relationships between renal function and disposition of oral ciprofloxacin.

The relationships between creatinine clearance (CLCR) and the pharmacokinetics of oral ciprofloxacin were characterized. On the basis of these data, a dosage adjustment strategy, which incorporates the severity of infection and the size and renal function of the patient, was developed. An adaptive (feedback) control algorithm is proposed. A total of 32 subjects (8 normal, 8 anuric, and 16 with CLCR between 0.53 and 4.3 liters/h per 1.73 m2) were given a single 750-mg tablet of ciprofloxacin by mouth. Serial serum and urine samples were collected, assayed by high-pressure liquid chromatography, and comodeled. The population relationship between total apparent ciprofloxacin clearance (CL/f) and CLCR, both measured in liters per hour per 1.73 m2, was CL/f = 2.83 x CLCR + 21.8 (r = 0.69; P less than 0.001). The mean terminal half-life was not significantly related to CLCR but was much more variable in subjects with CLCR less than 3 liters/h per 1.73 m2 (F = 4.8; P less than 0.005). We conclude that patients with CLCR less than 1.2 liters/h per 1.73 m2 should receive two-thirds of the normal daily dose and that the dose interval should not be lengthened.

The pharmacokinetics of metronidazole and its metabolites in critically ill patients.

We evaluated the disposition of metronidazole and its two major metabolites in 14 critically ill patients with liver and renal dysfunction. Patients received 500 mg of metronidazole iv for periods of 2-13 days and were studied either during therapy or after their final dose. The metronidazole half-life ranged between 4.95 and 42.4 h. Patients with obstructive liver disease exhibited the longest half-lives (9.15-42.4 h) and lowest clearances (0.281-1.17 ml/min/kg). The presence of obstructive liver disease or renal impairment appeared to prolong the elimination of the hydroxymetabolite. We conclude that the pharmacokinetics of metronidazole and its metabolites are significantly affected in critically ill patients with liver and renal dysfunction.

Current concepts in clinical therapeutics: immunologic treatment of human immunodeficiency virus infections.

An overview of the immune system is presented, and the pathogenesis, transmission, diagnostic tests, diagnosis, immunotherapy, and vaccine development for human immunodeficiency virus (HIV) are reviewed. More than 42,000 cases of acquired immunodeficiency syndrome (AIDS) have now been reported in the United States, and an additional 250,000 cases are expected by 1991. The immunopathogenesis of HIV infection involves both cellular and humoral components of the immune system, with a characteristic depletion of helper T lymphocytes, impaired delayed hypersensitivity, and polyclonal B-cell activation. Monocytes and macrophages are also infected, and these cells provide a transport mechanism into the central nervous system. HIV is transmitted primarily by sexual, blood, and perinatal mechanisms. Enzyme-linked immunosorbent and Western blot assays are used in diagnostic tests, and diagnosis of AIDS is based on the presence of secondary infection or tumor at least moderately indicative of cellular immune deficiency in the absence of predisposing factors. Three approaches are being tested for treating HIV infection: immunomodulators, vaccines, and antiviral agents. Immunomodulators--including interferons, interleukin-2, immune reconstitution with bone-marrow transplantation and lymphocyte transfusions, transfer factor, granulocyte-macrophage colony-stimulating factor, inosine pranobex (isoprinosine), and naltrexone--are being tested with no great successes. Various approaches to vaccine development, including genetically engineered subunit proteins, synthetic peptides, and infectious recombinant viruses, are being considered. Primary immune responses do result from at least one vaccine. Future studies will evaluate combination approaches to therapy. HIV infections confront the health-care system with a serious challenge. It is too early to assess the effectiveness of the various therapeutic strategies for immune deficiencies caused by HIV.

Steady-state pharmacokinetics of imipenem in febrile neutropenic cancer patients.

We ascertained the pharmacokinetics of imipenem in febrile granulocytopenic cancer patients. The values observed were both different from and significantly more variable than those observed in normal volunteers. Free drug concentrations exceeded the MIC for 90% of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains for greater than 6 h. The MIC for 90% of Pseudomonas aeruginosa strains was exceeded for 4 h. Because imipenem induces a 2-h postantibiotic effect in P. aeruginosa, it is promising as single-agent empiric therapy in this setting.

Effect of dose size on bioavailability of ciprofloxacin.

We evaluated the bioavailability of ciprofloxacin at two dose sizes in eight healthy volunteers. Each volunteer was given 200 mg of ciprofloxacin both orally and intravenously in a randomized crossover fashion and 750 mg orally. Bioavailability at the two doses was similar: 69 and 69.1% for the 200- and 750-mg doses, respectively. However, the bioavailability observed with the 750-mg dose was significantly more variable than that observed with the 200-mg dose. Between 375 and 700 mg of ciprofloxacin reached the systemic circulation after administration of the 750-mg dose, with no evidence of adverse reactions.