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C A Peloquin

Publications and source records attributed to C A Peloquin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Using therapeutic drug monitoring to dose the antimycobacterial drugs.

The available data suggest that selected patients with tuberculosis and MAC fail to respond to therapy because they malabsorb their medications. In particular, patients with AIDS and known gastrointestinal diseases have problems absorbing these drugs. In addition, because MDR-TB and MAC are so difficult to treat, TDM with the antimycobacterial drugs offers the clinician a chance to ensure that the patient achieves serum concentrations above the MIC of the pathogen. TDM has become the standard of practice at the National Jewish Center for Immunology and Respiratory Medicine. By combining specific and sensitive assays, carefully collected samples, and clinical expertise, we are able to control and optimize antimycobacterial drug therapy. We continue to refine our approach with ongoing pharmacokinetic and pharmacodynamic research, including the development of population pharmacokinetic models. We hope that these efforts will provide insight into the nature of current therapeutic problems. We also hope they will help us improve the clinical outcomes of our patients.

AIDS-Related Opportunistic Infections↗
PubMed1997

Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide.

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.

Absorption↗
PubMed1997

Early bactericidal activity of isoniazid in pulmonary tuberculosis. Optimization of methodology. The DATRI 008 Study Group.

Early bactericidal activity (EBA) of antituberculosis drugs is the rate of decrease in the concentration of tubercle bacilli sputum during the initial days of therapy. The study reported here was designed to optimize the methodology for obtaining precise EBA measurements. The study compared the results with two versus five treatment days; overnight sputum collections with early morning collections; and quantitative smears for acid-fast bacilli (AFB) with quantitative cultures. Isoniazid (INH) was used as a model drug. Among 28 smear-positive patients enrolled in the study in five cities in the United States, 16 were evaluable (INH-susceptible tuberculosis [TB] and adequate sputum collections). The mean baseline bacterial load was 6.69 log10 cfu/ml (SE = 0.24). Quantitative culture of 10- or 12-h sputum collections obtained on two baseline days and treatment Day 5 was the optimal method for EBA measurement. The mean 5-d EBA was 0.21 log10 cfu/ml/d (SE = 0.03; p < 0.001) and the EBA appeared to be constant during the first five treatment days. On the basis of these data, multiarm studies of investigational drugs will require 25 evaluable subjects per arm to detect (80% power and two-tailed alpha of 0.05) an EBA at least 50% as large as the EBA of INH. In countries with a low incidence of TB, the usefulness of this methodology for rapidly assessing new antituberculosis agents may be limited by the relatively large number of subjects required to compare EBA values across treatment arms.

Adult↗
PubMed1997

Mycobacterium avium complex infection. Pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes.

Mycobacterium avium complex (MAC) is an infrequent pulmonary pathogen in immunocompetent hosts. In patients with AIDS, MAC causes disseminated infection (DMAC) in up to 50% of those with CD4+ counts less than 100 cells/mm3. A significant portion of the total body burden of MAC is found inside macrophages, and the distribution of organisms has implications for drug therapy. Clarithromycin, azithromycin, and rifabutin all appear to enter these cells well; rifampicin (rifampin), ethambutol, ciprofloxacin, and other agents also appear to enter these cells. MAC susceptibility is probably best tested using the radiometric method (BACTEC). Susceptibility break-points have been proposed for the various anti-MAC agents; however, solid clinical correlations have been achieved only for clarithromycin. Further research is required to establish break-points for the other agents. Based on current data, azithromycin and clarithromycin appear to be key drugs in the treatment of MAC, while rifabutin has been used more often than rifampicin in studies involving patients with AIDS. Among the drugs traditionally used for M. tuberculosis (TB), ethambutol, rifampicin and streptomycin are perhaps the most useful for MAC. Amikacin and clofazimine may also be useful. The limited data available on AIDS patients with MAC, plus additional data from AIDS patients with TB, suggest that malabsorption of the oral antimycobacterial drugs is common. Some drugs (rifampicin and ethambutol) appear to be particularly affected. Because most of the studies of DMAC have not evaluated the pharmacokinetics of the drugs, questions of drug efficacy cannot be separated from questions of biovailability. This significant oversight in study design should be eliminated from future investigations. Patient-specific susceptibility data combined with therapeutic drug monitoring and dosage individualisation is one way to identify problems with drug therapy and to overcome them. Because many of the drugs used in patients with AIDS affect the metabolism of concurrently used drugs, therapeutic drug monitoring is a valuable asset for untangling multiple drug interactions. Since drug therapy is the only aspect of a mycobacterial infection within our control, the better we control the drug therapy, the better our patients should do.

AIDS-Related Opportunistic Infections↗
PubMed1997

The role of advanced generation macrolides in the prophylaxis and treatment of Mycobacterium avium complex (MAC) infections.

Since the start of the acquired immunodeficiency syndrome (AIDS) epidemic, the role of Mycobacterium avium complex (MAC) as an opportunistic pathogen in advanced AIDS patients has become more and more clear. Once identified in an advanced AIDS patient it is possible to find evidence that the MAC organism and infection is not only present in the pulmonary tree, but has also disseminated to a wide variety of body organs. Treatment of MAC or disseminated MAC (DMAC) infections has historically been very difficult due to the inherent resistance of the MAC pathogen to most standard antimycobacterial agents. This has resulted in the development of new agents for the prevention of DMAC infection as well as combinations of both new and standard agents for its treatment. Three drugs are currently approved for single-agent DMAC prophylaxis, including rifabutin, azithromycin and clarithromycin. Combinations of agents for DMAC treatment are highly variable in content but most experts agree that all combinations should contain one of the advanced generation macrolides (azithromycin or clarithromycin). Both of these agents have favourable intracellular pharmacokinetics and pharmacodynamics which maximise their effects against this mostly intracellular pathogen. Due to the paucity of comparative data, no one macrolide can be recommended over the other. However, the expected increase in compliance, lower weekly and annual costs, and lack of any drug interactions may make azithromycin a preferable choice, but this should be decided on a case-by-case basis.

Anti-Bacterial Agents↗
PubMed1996

Low antituberculosis drug concentrations in patients with AIDS.

OBJECTIVE: To determine the frequency and magnitude of below normal apparent peak serum concentrations for antituberculosis drugs in patients with AIDS and CD4 cell counts less than 200 cells/mm3. We also explored the data for potential relationships between response variables and patient characteristics. DESIGN: Prospective study of consecutive patients seen in tuberculosis clinics. SETTING: Five urban tuberculosis clinics in four major metropolitan areas. PARTICIPANTS: Twenty-six patients diagnosed with HIV infection and receiving treatment for active tuberculosis were eligible. MAIN OUTCOME MEASURES: After 2 weeks or more of therapy, blood was collected 2 hours after observed doses of the antituberculosis drugs. Serum samples were frozen, shipped to National Jewish Center in Denver, and analyzed by HPLC or GC. Serum concentrations were compared with the proposed normal ranges. Data were analyzed to determine correlations between antituberculosis drug serum concentrations and patient characteristics. RESULTS: Low-2-hour serum concentrations were common for antituberculosis drugs, particularly rifampin and ethambutol. Absorption of isoniazid was generally high. Potential drug-drug interactions were found between rifampin and fluconazole (fluconazole appears to increase rifampin concentrations) and between pyrazinamide and zidovudine (zidovudine may lower pyrazinamide concentrations). Patients receiving pyrazinamide had lower rifampin concentrations than those not receiving pyrazinamide. CONCLUSIONS: Low antituberculosis drug serum concentrations occur frequently during the treatment of tuberculosis in patients with AIDS. Additional research is required for patients with drug-resistant tuberculosis, and to clarify the nature of the potential drug-drug interactions.

Adult↗
PubMed1996

Therapeutic drug monitoring of the antimycobacterial drugs.

Because MDR tuberculosis and MAC are difficult to treat, TDM with the antimycobacterial drugs has become the standard of practice at NJC. By combining specific and sensitive assays, carefully collected samples, and clinical expertise, we are able to control and optimize antimycobacterial drug therapy. We continue to refine our approach with ongoing pharmacokinetic and pharmacodynamic research. Although such an array of services is not typical of most nonspecialized institutions, it is possible to follow the techniques described and to access our assay services. Furthermore, the elements of a good TDM service described can be applied to the TDM for any other disease state.

Antibiotics, Antitubercular↗
PubMed1995

Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema.

We describe a patient with drug-resistant chronic tuberculous empyema in whom substantial differences between achievable pleural fluid and serum drug concentrations were displayed. The ratio of maximum concentration in pleural fluid to serum was especially low for rifampin (4%) but was also low for streptomycin (34%) and ofloxacin (48%). Subtherapeutic drug concentrations in the pleural fluid may have contributed to acquisition of drug resistance in this case.

Aged↗
PubMed1995

Long-term safety of ofloxacin and ciprofloxacin in the treatment of mycobacterial infections.

Ofloxacin and ciprofloxacin are potentially useful agents for treating mycobacterial infections. We retrospectively reviewed 7 years' experience with these agents in 103 patients. Ofloxacin was used primarily to treat tuberculosis (TB), dosed to achieve 2-hour postdose serum concentrations of 8-12 micrograms/ml. Ciprofloxacin was used primarily to treat Mycobacterium avium complex (MAC) infection, dosed to achieve 2-hour post-dose serum concentrations of 4-6 micrograms/ml. Despite differences in patient characteristics, underlying disease, and concurrent medications, ofloxacin and ciprofloxacin were associated with a similar spectrum and incidence of adverse reactions. Both drugs were generally well tolerated. Adverse effects led to an ofloxacin dosage change in 1 patient (3%) and discontinuation of ofloxacin in 2 patients (6%). Adverse effects led to a ciprofloxacin dosage change in 2 patients (3%) and discontinuation of ciprofloxacin in 5 patients (7%). Ofloxacin and ciprofloxacin appear to be tolerated as well as or better than other "second-line" antimycobacterial drugs.

Antitubercular Agents↗
PubMed1995

Recent advances: antiinfectives.

OBJECTIVE: To update readers on the significant changes in infectious diseases pharmacotherapy. DATA SOURCES: An Index Medicus and Iowa Drug Information Service search (1993-1994) of English-language literature pertaining to the selected topic areas was performed. Additional information from abstracts presented at scientific meetings were identified by the authors. STUDY SELECTION AND DATA EXTRACTION: All identified studies were screened and those judged relevant to the update were evaluated. DATA SYNTHESIS: New or clinically significant data since 1992 that related to peptic ulcer disease, microbial resistance (e.g., Enterococcus spp., Streptococcus pneumoniae, Mycobacterium tuberculosis, Candida albicans), immunomodulators, and AIDS were evaluated and compared with previous data. CONCLUSIONS: There have been several exciting and significant changes in infectious diseases pharmacotherapy evident from this review.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Infection caused by Mycobacterium tuberculosis.

OBJECTIVE: To update readers on the clinical management of infections caused by Mycobacterium tuberculosis, to provide a general description of the organism, culture and susceptibility testing, and clinical manifestations of the disease, and to provide several aspects of the treatment of the disease, including historical perspective, current approaches, and research opportunities for the future. DATA SOURCES: The current medical literature, including abstracts presented at recent international meetings, is reviewed. References were identified through MEDLINE, MEDLARS II, Current Contents, and published meeting abstracts. STUDY SELECTION: Data regarding the epidemiology, clinical manifestations, culture and susceptibility testing, and treatment of tuberculosis are cited. Specific attention has been focused on the clinical management of patients with noncontagious infection and potentially contagious active disease (TB) caused by M. tuberculosis. DATA EXTRACTION: Information contributing to the discussion of the topics selected by the authors is reviewed. Data supporting and disputing specific conclusions are presented. DATA SYNTHESIS: The incidence of TB is increasing in the US, despite the fact that available technologies are capable of controlling the vast majority of existing cases. Fueling the fire is the problem of coinfection with HIV and M. tuberculosis. Very few drugs are available for the treatment of TB, and few of these approach the potency of isoniazid and rifampin. Preventive therapy of patients exposed to multiple-drug-resistant M. tuberculosis (MDR-TB) is controversial and of unknown efficacy. Treatment of active disease caused by MDR-TB requires up to four times longer, is associated with increased toxicity, and is far less successful than the treatment of drug-susceptible TB. Strategies for the management of such cases are presented. The rising incidence of TB in the US reflects a breakdown in the healthcare systems responsible for controlling the disease, which reflects the past budgetary reductions. Although TB control is one of the most cost-effective public health strategies, funding has been cut repeatedly despite the fact that TB was never eliminated. This has helped to produce the current crisis, including the spread of MDR-TB in many urban areas. The elimination of TB will now take decades longer, cost hundreds of millions of dollars more, and result in vastly higher morbidity and mortality rates than would have occurred with timely, adequate measures. CONCLUSIONS: Tremendous effort and far more funding will be required to eliminate TB in the US. The selection of drug therapy must be based on the susceptibility data for each isolate. Multiple-drug therapy must be continued for 6 to > or = 24 months, and patient adherence to prescribed regimens must be verified in all cases of TB. Significant antimycobacterial drug malabsorption has been documented in AIDS patients with TB, and may result in treatment failure. New agents are needed to improve the clinical outcome in patients with MDR-TB.

Adult↗