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Biomedical subjects

W J Burman

Publications and source records attributed to W J Burman.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Absorption↗
PubMed2002

Lack of toxicity from concomitant directly observed disulfiram and isoniazid-containing therapy for active tuberculosis.

We retrospectively evaluated the use of disulfiram among alcoholic patients being treated for active tuberculosis. There were 13 alcoholics treated with disulfiram, 105 alcoholics not on disulfiram, and 249 non-alcoholics. Rates of toxicity were higher among alcoholics than among non-alcoholics (58% vs. 32%), but there was no difference between alcoholics taking and those not taking disulfiram (61% vs. 57%). There were no neurological side effects in the disulfiram group. Disulfiram appeared to be safe when added to intermittent, directly observed isoniazid-containing tuberculosis treatment, and was useful in managing complications of alcohol abuse. However, the small number of patients on disulfiram limits the strength of this negative finding.

Alcohol Deterrents↗
PubMed2001

Breaking the camel's back: multicenter clinical trials and local institutional review boards.

Clinical research has undergone remarkable and beneficial expansion in the past 25 years, but with this growth has come an unprecedented increase in workload for the human subjects protection system. Recently, a major change in federal oversight of local institutional review boards (IRBs) became evident. Although it was not announced publicly, in 1998 and 1999 federal regulatory actions against local IRBs increased threefold. Particularly notable was the marked increase in regulatory actions taken against the IRBs of academic medical centers (1 in 1997 compared with 14 in 1999). Ironically, this apparent federal crackdown began at the same time that two federal review panels called for major changes in the regulations governing local IRBs. A key factor in the current crisis in the function of local IRBs is the ascendance of multicenter clinical trials as the dominant form of clinical research. Local IRBs were not designed to handle the initial evaluation and ongoing review required by the rapidly increasing number of multicenter clinical trials. Furthermore, local IRB review of the thousands of safety reports from multicenter clinical trials monopolizes resources without promoting patient safety. Instead of rigid enforcement of outmoded regulations that do not contribute to patient safety, the responsibilities of the local IRB in the oversight of multicenter clinical trials must be systematically evaluated.

Academic Medical Centers↗
PubMed2001

Population pharmacokinetics of intravenous and intramuscular streptomycin in patients with tuberculosis.

STUDY OBJECTIVES: To determine population pharmacokinetic parameters of streptomycin after administration of multiple intramuscular and intravenous doses. DESIGN: Prospective, unblinded clinical study. SETTING: Two medical centers in Denver, Colorado. PATIENTS: Thirty patients with tuberculosis. INTERVENTION: Patients received multiple doses of streptomycin as part of their tuberculosis treatment. They received concurrent drugs based on in vitro susceptibility data. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected over a 10-hour period and assayed by validated high-performance liquid chromatography Concentration-time data were analyzed using population methods. Streptomycin concentrations increased linearly with increasing intravenous doses. The intramuscular doses did not produce as linear a relationship, presumably because of variability in rates of and, potentially, completeness of absorption. Streptomycin elimination decreased with declining renal function. Higher, intermittent doses were well tolerated and appeared to maximize the peak concentration:minimal inhibitory concentration ratio. CONCLUSION: Overall, pharmacokinetic parameters of streptomycin were comparable with those previously published for streptomycin and other aminoglycosides. Higher, intermittent doses maximize pharmacodynamic parameter estimates and might have advantages for treatment of tuberculosis.

Adult↗
PubMed2001

Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials.

The rifamycin antibacterials, rifampicin (rifampin), rifabutin and rifapentine, are uniquely potent in the treatment of patients with tuberculosis and chronic staphylococcal infections. Absorption is variably affected by food; the maximal concentration of rifampicin is decreased by food, whereas rifapentine absorption is increased in the presence of food. The rifamycins are well-known inducers of enzyme systems involved in the metabolism of many drugs, most notably those metabolised by cytochrome P450 (CYP) 3A. The relative potency of the rifamycins as CYP3A inducers is rifampin > rifapentine > rifabutin; rifabutin is also a CYP3A substrate. The antituberculosis activity of rifampicin is decreased by a modest dose reduction from 600 to 450mg. This somewhat surprising finding may be due to the binding of rifampicin to serum proteins, limiting free, active concentrations of the drug. However, increasing the administration interval (after the first 2 to 8 weeks of therapy) has little effect on the sterilising activity of rifampicin, suggesting that relatively brief exposures to a critical concentration of rifampicin are sufficient to kill intermittently metabolising mycobacterial populations. The high protein binding of rifapentine (97%) may explain the suboptimal efficacy of the currently recommended dose of this drug. The toxicity of rifampicin is related to dose and administration interval, with increasing rates of presumed hypersensitivity with higher doses combined with administration frequency of once weekly or less. Rifabutin toxicity is related to dose and concomitant use of CYP3A inhibitors. The rifamycins illustrate the complexity of predicting the pharmacodynamics of treatment of an intracellular pathogen with the capacity for dormancy.

Anti-Bacterial Agents↗
PubMed2001

The effect of changes in laboratory practices on the rate of false-positive cultures for Mycobacterium tuberculosis.

CONTEXT: False-positive cultures for Mycobacterium tuberculosis have been found in nearly all DNA fingerprinting studies, but the effectiveness of interventions to reduce cross-contamination has not been evaluated. OBJECTIVE: To evaluate whether changes in laboratory policies and procedures reduced the rate of false-positive cultures. DESIGN: Retrospective study of isolates with matching DNA fingerprints. SETTING: A mycobacteriology laboratory serving an urban tuberculosis control program and public hospital system. PATIENTS: All M tuberculosis isolates processed from July 1994 to December 1999. METHODS: Isolates were fingerprinted using IS6110; pTBN12 was used to fingerprint isolates having fewer than 6 copies of IS6110. We further evaluated all patients having only one positive culture whose DNA fingerprint matched that of another isolate processed in the laboratory within 42 days. INTERVENTIONS: We changed laboratory policy to reduce the number of smear-positive specimens processed and changed laboratory procedures to minimize the risk of cross-contamination during batch processing. MAIN OUTCOME MEASURE: The rate of false-positive cultures. RESULTS: Of 13 940 specimens processed during the study period, 630 (4.5%) from 184 patients and 48 laboratory proficiency specimens grew M tuberculosis. There were no cases (0/184) of probable or definite cross-contamination, compared with the 4% rate (8/199) identified in our previous study (P =.008). We also fingerprinted a convenience sample of isolates from other laboratories in Denver; 13.6% (3/22) of these were false-positive, a rate similar to the 11.9% rate (5/42) identified for other laboratories in our previous study (P =.84). CONCLUSIONS: Laboratory cross-contamination decreased significantly after relatively simple, inexpensive changes in laboratory policies and practices. Cross-contamination continued to occur in other laboratories in Denver.

Colorado↗
PubMed2000

Review of false-positive cultures for Mycobacterium tuberculosis and recommendations for avoiding unnecessary treatment.

We reviewed reports of false-positive cultures for Mycobacterium tuberculosis and here propose guidelines for detecting and managing patients with possible false-positive cultures. Mechanisms of false-positive cultures included contamination of clinical devices, clerical errors, and laboratory cross-contamination. False-positive cultures were identified in 13 (93%) of the 14 studies that evaluated > or = 100 patients; the median false-positive rate was 3.1% (interquartile range, 2.2%-10.5%). Of the 236 patients with false-positive cultures reported in sufficient detail, 158 (67%) were treated, some of whom had toxicity from therapy, as well as unnecessary hospitalizations, tests, and contact investigations. Having a single positive culture was a sensitive but nonspecific criterion for detecting false-positive cultures. False-positive cultures for M. tuberculosis are not rare but are infrequently recognized by laboratory and clinical personnel. Laboratories and tuberculosis control programs should develop procedures to identify patients having only 1 positive culture. Such patients should be further evaluated for the possibility of a false-positive culture.

Culture Media↗
PubMed2000

Epidemiology of Pneumocystis carinii pneumonia in an era of effective prophylaxis: the relative contribution of non-adherence and drug failure.

OBJECTIVE: To determine the relative contribution of patient non-adherence, provider failure to prescribe prophylaxis, and drug failure to the continued occurrence of Pneumocystis carinii pneumonia (PCP), and to determine correlates of non-adherence. DESIGN: Retrospective case-control study. METHODS: Patients with confirmed or presumptive PCP from May 1995 to September 1997 who had at least 6 months of prior HIV care (cases) were compared to controls matched for initial CD4 cell count and date of initial HIV care. RESULTS: The incidence of PCP declined by 85% in the 28 months of the study. Of the 118 cases of PCP identified, 59 (50%) were in HIV care for > 6 months prior to PCP diagnosis. In a multivariate logistic regression model, risk factors for PCP among patients in HIV care were patient non-adherence [odds ratio (OR), 12.4; 95% confidence interval (CI), 6.4-23.5], use of prophylaxis other than trimethoprim-sulfamethoxazole (OR, 27.0; 95% CI, 13.8-52.9), and absence of antiretroviral use (OR, 7.5; 95% CI, 4.5-12.5). Provider non-adherence occurred in one out of 59 cases (2%), and five out of 106 controls (5%). Of the patients who developed PCP on prophylaxis, 18 cases (30%) appeared due to drug failure; there were no cases of apparent drug failure among patients on trimethoprim-sulfamethoxazole. In multivariate analysis, non-adherence was more common among patients of non-white race, those with a history of injecting drug use, and those with active substance abuse or psychiatric illness. CONCLUSIONS: Patient non-adherence was the most common reason for the occurrence of PCP among patients in HIV care; provider non-adherence was uncommon. Drug failure occurred only among patients on prophylaxis other than trimethoprim-sulfamethoxazole.

AIDS-Related Opportunistic Infections↗
PubMed2000

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2000

Comparison testing of current (PPD-S1) and proposed (PPD-S2) reference tuberculin standards.

Since 1951, the tuberculin PPD-S1 has been used to standardize commercial PPD reagents and perform special tuberculin surveys. PPD-S1 is now in short supply and a new standard (PPD-S2) has been manufactured. To determine if PPD-S2 is equivalent and can replace PPD-S1, we conducted a double-blind clinical trial. Between May 14 and October 28, 1997, 69 subjects with a history of culture-proven tuberculosis (TB patients) and 1,189 subjects with a very low risk for TB infection were enrolled, received four skin tests (with PPD-S1, PPD-S2, and one each of the commercially available PPDs), and had reactions measured by two trained observers. Among the TB patients, we found statistically indistinguishable immunogenicity (mean reaction size +/- standard deviation): 15.6 +/- 6.6 mm for PPD-S1 and 14.8 +/- 5.6 mm for PPD-S2. Among low-risk subjects, the tests had equally high specificities (PPD-S1, 98.7% and PPD-S2, 98. 5%), using a 10-mm cutoff. The number of discordant (negative versus positive) interpretations for PPD-S2, assuming that low-risk subjects who had a >/= 10 mm reaction to PPD-S1 were truly infected, was low (0.5%) and indistinguishable from the rate of discordant interpretations of the same test when read by two different observers (0.8%). The study results indicate that PPD-S2 is qualified to be used as the new U.S. reference standard for PPD tuberculin.

Adult↗
PubMed1998

Long-term outcomes of treatment of Mycobacterium avium complex bacteremia using a clarithromycin-containing regimen.

OBJECTIVES: To describe the long-term outcomes of treatment of AIDS-related Mycobacterium avium complex (MAC) bacteremia using a standard clarithromycin-based regimen. DESIGN: Retrospective study of patients with MAC bacteremia diagnosed between April 1992 and April 1995. SETTING: An urban AIDS clinic SUBJECTS: One hundred seventy-six consecutive patients with MAC bacteremia. INTERVENTIONS: Clarithromycin 500 mg twice daily, ethambutol 800 or 1200 mg daily, and clofazimine 100 mg daily. MAIN OUTCOME MEASURES: Late treatment failure (defined as a positive blood culture more than 90 days after starting treatment), clarithromycin susceptibility of initial and treatment-failure isolates, DNA fingerprinting of isolates from treatment failures. RESULTS: Two out of 176 (1.1%) baseline isolates were resistant to clarithromycin. One hundred and fifty-one patients were treated for MAC bacteremia, 144 (95%) with the standard regimen. Of the 117 patients who survived > 90 days after starting therapy, 25 (21%) met the criteria for late treatment failure. Of the 22 treatment-failure isolates available for susceptibility testing, 19 (86%) were resistant to clarithromycin. Therefore, 13% of patients treated using the standard regimen (19 out of 144) had treatment failure associated with the emergence of clarithromycin resistance. Using logistic regression, non-compliance was associated with treatment failure (P = 0.02). Fourteen out of the 17 (82%) evaluable paired isolates had identical DNA fingerprint patterns, whereas three pairs showed that a different strain of MAC was present at the time of treatment failure. CONCLUSIONS: Initial resistance to clarithromycin was rare during this period. However, late treatment failure associated with the emergence of clarithromycin resistance was relatively common during long-term follow-up. Most late treatment failures represented emergence of clarithromycin resistance in the initial strain.

AIDS-Related Opportunistic Infections↗