Population pharmacokinetics of ethionamide in patients with tuberculosis.

SETTING: Three US referral hospitals. OBJECTIVE: Determine the population pharmacokinetic (PK) parameters of ethionamide (ETA) following multiple oral doses. DESIGN: Fifty-five patients with tuberculosis (TB) participated. Patients received multiple oral doses of ETA as part of their treatment. They also received other anti-tuberculosis medications based upon in vitro susceptibility data. Serum samples were collected over 12 h post-dose, and concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: ETA areas under the concentration-versus-time curve (AUCs) increased linearly with increasing oral doses from 250 to 1000 mg. Compared to the population pattern, delayed absorption was seen at least once in 15% of patients. ETA PK parameter estimates were independent of age, weight, height, gender, and creatinine clearance. TB patients appeared to have larger volumes of distribution (3.22 l/kg) and clearance values (1.88 l/h/kg) compared to previously studied healthy volunteers. This resulted in lower AUC values (3.95 mcg h/ml) in the TB patients. ETA displayed a short elimination half-life (1.94 h). The effect of different dosing strategies on calculated pharmacodynamic parameters was explored. Simulated doses of 250 mg BID to TID failed to achieve serum concentrations above the MIC. CONCLUSION: ETA PK parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption. Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC. Additional research is needed to determine the optimal dosing of ETA.

The role of fluoroquinolones in tuberculosis today.

Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today. The fluoroquinolones are the most recent class of drugs offering hope in the fight against this disease. Ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin are currently the most commonly used agents used against Mycobacterium tuberculosis (TB), with in vitro minimum inhibitory concentrations (MICs) of 0.1 to 4 mcg/ml. Resistance in TB to fluoroquinolones may occur spontaneously or may be acquired, especially when these agents are used inappropriately. Cross-resistance among the fluoroquinolones has been shown in TB. The fluoroquinolones offer a favourable pharmacokinetic profile for the treatment of TB. Most demonstrate excellent oral bioavailability and achieve maximum (peak) serum concentrations well above the MIC. They are also distributed widely, including intracellularly. The fluoroquinolones are cleared renally and/or hepatically, with varying serum half-lives. Fluoroquinolones are most effective when the peak concentration (Cmax) to MIC ratio is maximised. Fluoroquinolones such as ciprofloxacin and ofloxacin have been used in regimens for the prevention of TB, but have been poorly tolerated when used in combination with pyrazinamide. Favourable responses with fluoroquinolones in regimens used in the treatment of clinical TB disease have been seen. They, however, are not to be considered as equal replacements for isoniazid or rifampicin (rifampin) and should be used with at least 2 other antituberculous agents. Therapeutic drug monitoring of fluoroquinolones is beneficial in assuring that maximum Cmax to MIC ratios are being achieved, especially in patients at risk for malabsorption, such as those infected with HIV. Higher, once-daily doses of most fluoroquinolones are becoming more common in treating TB. Fluoroquinolones are generally well tolerated with long term use in treating TB, but rare, serious adverse effects have been reported with general fluoroquinolone use. The most common drug interactions with fluoroquinolones in TB therapy include the malabsorption interactions associated with multivalent cations and cytochrome P450 interactions with ciprofloxacin. An increased risk of central nervous system effects with concomitant cycloserine has been reported and seen clinically. When using fluoroquinolones to treat TB, careful consideration of individual susceptibility patterns, pharmacokinetic and toxicity profiles should be taken. The aid of a TB expert may also be warranted. The exact role of the fluoroquinolones in treating TB remains to be determined.

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.

Ofloxacin population pharmacokinetics in patients with tuberculosis.

SETTING: Two tuberculosis hospitals in the United States. OBJECTIVE: To determine the population pharmacokinetic (PK) parameters of ofloxacin following multiple oral doses. DESIGN: A total of 73 patients with tuberculosis (TB) participated in the study. Subjects received multiple doses of ofloxacin as part of their treatment. They also received concurrent medications based on in vitro susceptibility data. Serum samples were collected over 10 h and assayed by a validated high performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: Ofloxacin concentrations increased linearly with increasing oral doses. Delayed absorption was seen at least once in 29% of patients. Ofloxacin elimination decreased with declining renal function and increasing age. Higher daily doses were well tolerated, and appeared to maximize the peak concentration to minimal inhibitory concentration ratio (Cmax:MIC). CONCLUSION: Ofloxacin PK parameters were comparable to those previously published for other patient populations. Higher daily doses may offer pharmacodynamic advantages for the treatment of TB.

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.

Potential interaction between itraconazole and clarithromycin.

Three patients negative for human immunodeficiency virus infection were admitted for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections. They were treated with different drug combinations, but all regimens included clarithromycin for MAC and itraconazole for aspergillosis. All patients experienced an increase in clarithromycin concentrations and clarithromycin: 14-OH-clarithromycin ratio compared with expected range values. They had no clinical side effects. The time course suggested a possible interaction between clarithromycin and itraconazole, presumably through itraconazole's effects on cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out. The data suggest that, when necessary, these two drugs can be administered together safely. Further investigation is necessary to determine the extent and clinical consequences of coadministration in humans.

Pharmacokinetic evaluation of thiacetazone.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of thiacetazone (TB-1), which is active in vitro against Mycobacterium avium complex (MAC). DESIGN: Open-label phase I study. SETTING: Specialized referral hospital. PATIENTS: Twelve healthy men and women. INTERVENTIONS: Oral TB-1 150 mg/day was administered for 7 days, followed by blood and urine collection over 48 hours. MEASUREMENTS AND MAIN RESULTS: The serum concentration versus time curves of TB-1 showed sustained concentrations, with maximum values of 1.59 +/- 0.47 micrograms/ml, time to maximum 3.30 +/- 1.18 hours, and serum half-life of 15-16 hours. Less than 25% of TB-1 was recovered unchanged in the urine over 48 hours. Rashes occurred in two subjects at the end of the 7-day dosing period and resolved without progression or sequelae. CONCLUSIONS: Based on these data, we initiated a phase II study of TB-I in patients with pulmonary MAC infection who do not have the acquired immunodeficiency syndrome.

Pharmacokinetic evaluation of para-aminosalicylic acid granules.

STUDY OBJECTIVE: To determine the bioavailability and renal elimination of para-aminosalicylic acid (PAS) and its inactive metabolite acetyl-para-aminosalicylic acid (AcPAS) from a new PAS formulation. DESIGN: (a) Single-dose pharmacokinetic study in healthy volunteers; (b) Day-1 and day-8 pharmacokinetic comparison in patients with multidrug-resistant tuberculosis (MDR-TB). SETTING: Referral hospital that specializes in the treatment of mycobacterial infections. PATIENTS: (a) Twelve healthy male and female volunteers recruited by the investigators. Eleven subjects (92%) completed the study; one subject could not maintain venous access and was removed from the study. (b) Six sequential male and female patients receiving multidrug treatment for advanced MDR-TB. All patients completed the study. INTERVENTIONS: (a) Volunteers received a single 4-g dose of enteric-coated PAS granules administered with food. Blood and urine samples were collected over 24 hours after the dose. (b) Patients received 4-g doses of enteric-coated PAS granules every 8 hours for 7 days as part of their treatment regimen. Blood samples were obtained at approximately 2, 4, and 8 hours after the first dose on day 1 and the twenty-second dose on day 8. MEASUREMENTS AND MAIN RESULTS: Concentrations of PAS and AcPAS were determined using high-performance liquid chromatography. The serum concentration-time curves from volunteers and patients showed sustained PAS concentrations, in contrast to immediate-release sodium PAS tablets. In the six patients with tuberculosis, day 8 concentrations were considerably higher than those on day 1, and all were sustained well above the PAS minimal inhibitory concentration for Mycobacterium tuberculosis. CONCLUSIONS: Para-aminosalicylic acid granules produce adequate serum concentrations and appear to be safe.

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.

Tuberculosis and multi-drug resistant tuberculosis in children.

Infection and disease caused by Mycobacterium tuberculosis remain a hugh global problem, and are not well controlled in several areas within the United States. Co-infection with the human immunodeficiency virus (HIV) and immigration from areas with high rates of tuberculosis contribute to the problem in the United States. Organisms resistant to the two main drugs, isoniazid and rifampin, known as multidrug-resistant M. tuberculosis or MDR-TB, present serious therapeutic challenges. Strategies for the management of such cases are presented.

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.

Novel treatment of meningitis caused by multidrug-resistant Mycobacterium tuberculosis with intrathecal levofloxacin and amikacin: case report.

We report the case of a 25-year-old HIV-negative man with disseminated multidrug-resistant tuberculosis (MDRTB), who-on a retreatment regimen-experienced total resolution of TB miliary disease, but progressive TB meningitis. Therefore, intrathecal treatment with amikacin and levofloxacin was instituted, with successful clinical and microbiological results.

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.

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.

Therapeutic drug monitoring in patients with cystic fibrosis and mycobacterial disease.

Cystic fibrosis (CF) patients require higher dosages of many antibiotics. The relapse of tuberculosis in one CF patient, and the repeated growth of Mycobacterium avium-intracellulare in another, despite conventional therapy, raised the question of whether the serum levels of the antimycobacterial drugs were adequate. Antimycobacterial drug serum concentrations were assayed in 10 CF patients with pulmonary mycobacterial disease. Serum levels below the proposed target range were seen 2 h after drug intake in the initial four patients treated: for rifampicin in 2/3, ethambutol in 3/4 and for clarithromycin in 2/3 patients, despite standard dosages. Reassays after dose adjustment and assays in six other patients showed that adequate levels were not achieved 4 h after clarithromycin in 3/5, ethambutol in 1/5, ciproflaxacin in 1/2 and ofloxacin in 2/2 patients. The patient with relapse of tuberculosis and the patient with continuous growth of M. avium-intracellulare improved and became culture negative after dose adjustment. Low drug serum levels is one reason for therapy failure in cystic fibrosis patients with mycobacterial disease. Therapeutic drug monitoring is recommended.

Multidrug-resistant tuberculosis meningitis: clinical problems and concentrations of second-line antituberculous medications.

OBJECTIVE: [corrected] To describe a case of culture-proven multidrug-resistant tuberculous (MDR-TB) meningitis, in which the patient survived long enough for clinicians to adjust antituberculous therapy to second-line therapeutic agents. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: Twenty-one-month-old girl with MDR-TB meningitis. INTERVENTIONS: Initial standard treatment failed. Subsequent treatment with second-line therapeutic agents including ciprofloxacin, cycloserine, ethambutol, ethionamide, and rifabutin were given for approximately two years. Concentrations of these drugs were measured in serum and cerebrospinal fluid in the presence and absence of meningeal inflammation. MAIN OUTCOME MEASURES/RESULTS: The patient survived for approximately two years after initiation of second-line anti-TB therapy. During this treatment, she developed a ventriculo-peritoneal shunt tunnel tract infection secondary to MDR-TB. CONCLUSIONS: All TB meningitis isolates for which the source case antibiotic susceptibility pattern is not known should be cultured and susceptibility tested using rapid broth techniques. Measurement and subsequent adjustment of therapeutic drug concentrations may optimize therapy with second-line anti-TB drugs in TB meningitis. Better pediatric formulations and pharmacokinetic data for second-line and anti-TB therapeutic agents are needed.

Once-daily and twice-daily dosing of p-aminosalicylic acid granules.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.