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.

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.

Etiology of neutropenia in HIV-infected patients.

The causes of neutropenia in HIV-infected patients are described, as is the association of absolute neutrophil count (ANC) and the risk of bacterial infections. In patients with HIV infection, neutropenia can result from the disease or related malignancies, drug therapies, or opportunistic infections. HIV can cause neutropenia by directly or indirectly impairing hematopoiesis. Similarly, microorganisms that cause opportunistic infections, such as cytomegalovirus and Mycobacterium avium complex, can infiltrate the bone marrow and cause myelosuppression. Hematologic toxicities of drug therapy targeted against HIV and opportunistic infections, such as zidovudine, cidofovir, foscarnet, ganciclovir, and trimethoprim/sulfamethoxazole, can further reduce blood cell formation. Several retrospective studies are reviewed that examined the relationship between ANC and the development of bacterial infections in patients infected with HIV. Since neutropenia appears to be associated with increased risk of bacterial infections in HIV-infected patients, approaches to shorten or prevent neutropenia in these patients will likely provide substantial clinical benefit.

Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.

Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible.

Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). DESIGN: Randomized, four-period, crossover phase I study. SUBJECTS: Fourteen healthy men and women volunteers. INTERVENTIONS: Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4+/-10.4 microg/ml, Tmax 1.43+/-1.06 hours, and AUC(0-infinity) 673+/-79.7 microg x hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6+/-9.0 microg/ml, Tmax of 1.43+/-1.23 hours, and AUC(0-infinity) of 628+/-88.4 microg x hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6+/-9.44 pg/ml, Tmax 3.09+/-1.74 hours, and AUC(0-infinity) 687+/-116 microg x hr/ml. CONCLUSIONS: These small changes in Cmax, Tmax, and AUC(0-infinity) can be avoided by giving PZA on an empty stomach whenever possible.

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.

Pneumocystis carinii pneumonia in HIV infected patients: effects of the diseases on glutathione and glutathione disulfide.

Human immunodeficiency virus (HIV) infection is associated with altered levels of glutathione (GSH) in cells and extracellular fluids. GSH is essential for lymphocyte proliferation and inhibits HIV replication. Therefore, determination of GSH and glutathione disulfide (GSSG) levels could be useful as indicators of the progression of the disease. Thyroid hormone levels are altered in acquired immuno-deficiency syndrome (AIDS), such that thyroid hormone might be a useful prognostic indicator of the severity of AIDS. Pneumocystis carinii pneumonia (PCP) is a debilitating disease of the lung that can accompany HIV infection. The effects of pulmonary infections were assessed in AIDS patients on thyroid hormone, GSH, GSSG levels and other parameters. Two groups of AIDS patients were selected, a group with PCP and a control group with other respiratory diseases. GSH was evaluated in plasma, pulmonary lavage fluid, pulmonary biopsy tissue and buccal cells. Levels of GSSG in pulmonary lavage fluid were higher in PCP patients than in controls, which suggests that PCP patients suffer from oxygen radical toxicity in their lungs. PCP patients may have altered plasma GSH utilization such that damaged lung tissue may become less efficient at using plasma GSH. Patients with PCP may have altered CD4 cell functions such that thyroid hormone levels do not correlate with CD4 cell counts. Patients with AIDS and secondary infections of the lung were found to have altered GSH redox states, probably indicative of physiologic adaptation to AIDS.

Serum and blister fluid pharmacokinetics and bactericidal activities of ampicillin-sulbactam, cefotetan, cefoxitin, ceftizoxime, and ticarcillin-clavulanate.

Ampicillin-sulbactam, ticarcillin-clavulanate, cefoxitin, cefotetan, and ceftizoxime are promoted for the treatment of mixed aerobic-anaerobic bacterial infections. Their activities have been compared in vitro but not in vivo. In order to assess the in vivo activities of these agents in serum and interstitial fluid, we administered single, intravenous doses of these antimicrobial agents to healthy subjects. Concentrations of the antimicrobial agents in serum and suction-induced blister fluid and bactericidal activity were measured by high-pressure liquid chromatography and the standard methodology of the National Committee for Clinical Laboratory Standards, respectively. The organisms used for bactericidal activity tests were one isolate each of Staphylococcus aureus, Klebsiella pneumoniae, and Bacteroides fragilis. Pharmacokinetic parameters in serum and blister fluid were similar to those derived in other investigations. Of note were the high and prolonged concentrations of ticarcillin and cefotetan in blister fluid, despite high-level serum protein binding. The bactericidal activities in serum and blister fluid reflected the relative in vitro activities and kinetic dispositions of the various antimicrobial agents except for the bactericidal activity of cefotetan, which was substantially lower in blister fluid than serum, despite a blister fluid:serum area under the concentration-time curve ratio of 1.5. Similarly, the activity of ticarcillin-clavulanate in blister fluid was also substantially less than would have been predicted by the blister fluid:serum ratio of the area under the concentration-time curve of 1.1, possibly because of the low concentrations of clavulanate in blister fluid. The rankings of the in vivo bactericidal activities of the five drugs were as follows: for S. aureus, ampicillin-sulbactam > ticarcillin-clavulanate > ceftizoxime > cefoxitin > cefotetan; for K. pneumoniae, ceftizoxime > cefotetan > ampicillin-sulbactam = ticarcillin-clavulanate > cefoxitin; and for B.fragilis, ticarcillin-clavulanate > cefotetan > ceftizoxime > ampicillin-sulbactam = cefoxitin.

Imipenem pharmacokinetics in patients with burns.

The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem-cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24-hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two-compartment model provided a superior fit to the data compared with a one-compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p greater than 0.05). Combined mean (+/- SD) parameter estimates for the two dosing periods were as follows: VC, 0.11 +/- 0.06 L/kg; Vss, 0.22 +/- 0.06 L/kg; CL, 12.5 +/- 3.6 L/hr/1.73 m2; t1/2 alpha, 0.18 +/- 0.13 hr; t1/2 beta, 1.12 +/- 0.44 hr. Mean clearance in two patients with creatinine clearance values greater than 150 ml/min/1.73 m2 was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values less than 50 ml/min/1.73 m2 was 8.5 L/hr/1.73 m2. No pharmacokinetic parameter was significantly different from previously reported parameters in normal volunteers (p greater than 0.05). Creatinine clearance ranged from 17 to 218 ml/min/1.73 m2. Imipenem clearance was significantly related to creatinine clearance (CL = 63 + 0.059 CLCR; r2 = 0.60, p = 0.001). No significant association was found between total body surface area burns and imipenem clearance (p greater than 0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin pharmacokinetics in critically ill trauma patients.

Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

Imipenem monotherapy versus combination therapy in the management of mixed bacterial infection: a critical appraisal.

There has been a great deal of interest in the use of imipenem monotherapy rather than combinations of antimicrobials for mixed bacterial infections. A review of the published comparative studies of imipenem versus combinations in serious mixed bacterial infections indicated that, overall, imipenem is at least as effective as, and maybe less expensive than, the combinations tested. Several studies suggest that clinical response to imipenem is more rapid than to the comparison regimens; however, other factors may have influenced these values, and the numbers of patients in these reports were small. Imipenem is devoid of the adverse effects associated with aminoglycosides. Other adverse effects, including superinfection and central nervous system toxicity, were similar for imipenem and the comparison regimens. Meta-analysis of the published reports and abstracts revealed that imipenem is as effective as combination regimens for the treatment of serious mixed bacterial infection.

Rapid adjustment of theophylline: a kinetic model.

This study was designed to test the validity and applicability of basic kinetic equations to describe theophylline disposition. The method involves early determination of clearance from a nonsteady-state level, dosage adjustment on the basis of the estimated clearance, and measurement of serum theophylline concentration at a point very near steady state. To test the method, a 32-patient study group was examined. The results were encouraging, with the actual mean level 19-28 hours after dosage adjustment being 13.4 micrograms/ml (SD, 3.1) as compared with a projected level of 13.2 micrograms/ml (SD, 2.9). Although further investigation is necessary, these findings indicate that within the limitations of the population studied this approach is a reliable and rapid method to achieve therapeutic serum theophylline levels while at the same time avoiding toxicity and subtherapeutic responses.