Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients.

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.

Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% TMIC). To assess the 40% TMIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% TMIC with the free fraction (f 40% TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0-24) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% TMIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis.

Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis.

Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience.

Moxifloxacin (MFX) is a powerful second-line anti-tuberculosis (TB) agent, but the optimal dose has not yet been established and long-term safety data are scarce. We retrospectively reviewed the medical charts of TB patients treated at the Tuberculosis Centre Beatrixoord, University Medical Centre Groningen (Haren, the Netherlands) receiving MFX 400 mg once daily as part of their TB treatment between January 1 2006 and January 1 2009. Safety data and drug-drug interactions were evaluated. Efficacy was predicted based on the area under the concentration-time curve up to 24 h post-dosage (AUC(0-24h))/minimal inhibitory concentration (MIC) ratio. 89 patients were treated with a median dose of 6.9 mg · kg(-1) MFX once daily for a median period of 74 days. Discontinuation of therapy occurred in only three patients due to gastrointestinal side-effects and hypersensitivity. Pharmacokinetic analysis showed an AUC(0-24h)/MIC ratio <100 in eight out of 16 patients. A large variation in protein binding affected the unbound AUC(0-24h) considerably. These data show that MFX treatment was well tolerated in 89 patients receiving a dose of 400 mg once daily for a prolonged period. Considering the variability in (un)bound AUC(0-24h)/MIC ratio, therapeutic drug monitoring is recommended in selected patients (i.e. rifampicin co-medication; MIC ≥ 0.25 mg · L(-1)) to assess optimal therapy.

Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis.

Moxifloxacin cerebrospinal fluid (CSF) penetration was evaluated by obtaining full plasma and CSF time concentration curves for 4 patients with tuberculous meningitis. The geometric mean ratio of the areas under the curve for CSF to plasma were 0.82 (range, 0.70-0.94) at 400 mg once per day and 0.71 (0.58-0.84) at 800 mg once per day.

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.

Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.

Ethambutol-induced optical neuropathy: risk of overdosing in obese subjects.

BACKGROUND: Ethambutol (EMB) is one of the first-line drugs in the treatment against tuberculosis (TB). Side-effects are infrequent, but its main adverse effect, optical neuropathy, has long been recognised. The mechanisms of action and predisposing factors have not yet been fully understood. METHOD: We conducted a retrospective study (1992--2007) in an attempt to find predisposing factors for optical neuropathy. RESULTS: Visual disturbance was reported in 1.3% of the 760 patients treated with EMB; of these, 0.8% were EMB-related. We present the six cases; four were clearly overdosed, but in two obese patients dosage was correctly calculated for total body weight (TBW). CONCLUSION: Analysis of the case histories and previous reports suggest that optical neuropathy may at least partly be caused by EMB overdosing due to daily dosing based on TBW instead of dosing on lean body mass.

Tuberculous peritonitis during infliximab therapy.

Reactivation of tuberculosis is a severe side effect of anti-TNF treatment. Especially extrapulmonary forms of tuberculosis may occur, which are difficult to diagnose. The diagnosis may be obtained by a thorough search for Mycobacterium tuberculosis. We describe two patients who developed tuberculous peritonitis after infliximab therapy that was prescribed for treatment of rheumatoid arthritis. These cases illustrate that tuberculous peritonitis has a nonspecific clinical manifestation and that Mycobacteria can be difficult to find in ascites fluid. For this reason, tuberculostatic therapy has to be started in case of clinical suspicion. Before starting infliximab therapy, the patient must be thoroughly screened for the presence of (latent) tuberculosis.

Indications for percutaneous endoscopic gastrostomy in complex tuberculosis patients.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) is a widely used method for providing long-term administration of tube feeding. Different indications in relation to diseases, impairments and nutritional factors for PEG placement have been mentioned in guidelines. Treatment with PEG has not been described previously for tuberculosis (TB). Our aim was to identify and describe indications and contributing factors for PEG placement in TB patients. METHODS: A retrospective medical record review was conducted of 32 TB patients who required PEG from March 1996 to April 2004. Indications and contributing factors for PEG placement were analysed. RESULTS: PEG placement was based on three different indications. In 18 patients, PEG was used to administer tube feeding, in 4 patients anti-tuberculosis drugs were administered and in 10 patients both tube feeding and antituberculosis drugs were administered. Contributing factors for PEG placement were swallowing disabilities, weakness, anti-tuberculosis drugs and their side effects, pain of neuralgic origin, hiccups and refusal of food and drugs. CONCLUSIONS: In TB, imminent and overt malnutrition, as well as the administration of drugs with a curative aim, are new indications for PEG placement. The use of PEG can overcome various problems in TB treatment and prevent treatment default.

[Underdiagnosis of HIV in patients with tuberculosis]. / Onderdiagnostiek naar hiv bij patiënten met tuberculose.

HIV/AIDS and tuberculosis impose a large infectious burden world wide. The conditions mutually interact, both epidemiologically and biologically. The course and treatment of tuberculosis are importantly complicated by HIV co-infection. A recent study showed that in newly detected tuberculosis patients, HIV sero-testing has been consistently low in the Netherlands. Two random samples of TB cases from the national registry were analysed--1993 and 2003--before and after the introduction of effective therapy for HIV/AIDS became available. There was no significant increase in HIV sero-testing. Guidelines for the treatment of tuberculosis should include routine HIV testing.

Risk factors of acute hepatic failure during antituberculosis treatment: two cases and literature review.

Hepatotoxicity is a well-known side effect of antituberculosis treatment (ATT). If not recognised in time, drug-induced hepatitis can develop, which may rapidly progress to acute liver failure. We describe two patients with acute hepatic failure caused by ATT, whose pretreatment liver function had been normal. Both patients successfully underwent liver transplantation. Possible risk factors predisposing towards ATT-induced hepatic failure were evaluated, and at least four risk factors were present in these patients. Although available guidelines do not advocate routine monitoring of liver function during ATT unless baseline values are elevated or in the case of pre-existent liver disease, this is nevertheless common practice. Liver function should always be measured in patients who develop symptoms during ATT, and rising liver function parameters should prompt immediate action to prevent the occurrence of liver failure. This report underscores that regular monitoring of liver function parameters and adherence to guidelines is especially important in patients with risk factors for ATT-induced liver disease. An evaluation of chronic viral hepatitis in risk groups before starting ATT could be worthwhile.

[Two pregnant immigrant women with tuberculous peritonitis]. / Twee zwangere buitenlandse vrouwen met peritonitis tuberculosa.

Two primigravid immigrant women aged 20 and 24 years were diagnosed with tuberculous peritonitis. The cases showed a significant delay in diagnosis. This was probably the cause for the premature birth and death of one foetus. The other child was diagnosed with congenital tuberculosis several months after birth and was successfully treated. The women were treated with the usual combination ofisoniazid, rifampicin, ethambutol and pyrazinamide. The unfamiliarity with this clinical picture is a problem in countries with a low incidence of tuberculosis. In both cases the final diagnosis was made by the characteristic image seen during laparoscopy. An early diagnosis and also an early start with tuberculostatic drugs are important for a favourable outcome of pregnancy. Pregnancy and breast-feeding are no contraindications for treatment with tuberculostatic drugs.

[Two patients with tuberculous pleurisy]. / Pleuritis tuberculosa bij 2 patiënten.

Tuberculous pleurisy was diagnosed in two patients, a 21-year-old Somali woman and a 19-year-old Surinam man. The first patient suffered from a paradoxical (immunological) reaction and the other had an infectious reaction. Both patients recovered after treatment with tuberculostatic agents and pleural drainage. The pathophysiology of the paradoxical reaction is still largely unclear. Culture continues to be the gold standard in diagnosing tuberculous pleuritis but, in many cases, bacteriological confirmation is not obtained. The (probable) diagnosis is then often made on the basis of a combination of the patient's history, estimation of the risk, physical examination, radiology and histology, and on the basis of a (trial) treatment with tuberculostatic agents. In the diagnostic process, a PCR on the Mycobacterium tuberculosis complex can be helpful. The routine determination of adenosine deaminase and interferon gamma in patients with tuberculous pleurisy is not useful in low-incidence countries such as The Netherlands. The measurement of the in-vitro T-cell reactivity against M. tuberculosis-specific antigens may be of more value in the future. The pharmacotherapy of tuberculous pleurisy is the same as that of pulmonary tuberculosis. Rinsing the pleural cavity is recommended in the case of an infectious reaction. Drainage of pleural fluid is indicated in the case of a paradoxical reaction if there are mechanical difficulties.

[An outbreak of multiresistant tuberculosis from Eastern Europe in the Netherlands]. / Een uitbraak van multiresistente tuberculose uit Oost-Europa in Nederland.

Infectious multiresistant pulmonary tuberculosis was diagnosed in a 24-year-old woman from an Eastern European country who resided in the Netherlands illegally. Her chest X-ray showed extensive cavitating lesions in both lungs. The patient was infectious for a long time and contact investigation revealed 2 other cases of multiresistant tuberculosis, her boyfriend aged 39 and his father, aged 58 years. Transmission from the index case was confirmed by DNA fingerprinting. Seven contacts had a latent tuberculosis infection. All 3 tuberculosis patients were successfully treated, while a number of the infected contacts received preventive treatment. Multiresistant tuberculosis is on the rise in Eastern Europe. It is a serious disease with a high mortality rate despite treatment and has considerable social implications. This outbreak emphasises the necessity of maintaining an efficient tuberculosis control network in low incidence countries, such as the Netherlands. This is the first time an outbreak of multiresistant tuberculosis of this magnitude is described in the Netherlands.

[Pulmonary infection caused by non-tuberculous mycobacteria in two patients with bronchiectasis]. / Infectie met niet-tuberculeuze mycobacteriën bij 2 patiënten met bronchiëctasieën.

Two patients, a woman aged 67 years and a man aged 80 years, had chronic cough among other respiratory symptoms. In the woman, chest radiograph and CT-scan revealed partial atelectasis of the middle lobe and bronchiectasis. In the man, an interstitial pattern was seen on chest radiograph, and CT scan showed diffuse bronchiectasis. In both the man and the woman, non-tuberculous mycobacteria were identified (Mycobacterium avium complex and Mycobacterium abscessus, respectively). Treatment was successful in both patients. Non-tuberculous mycobacteria can cause considerable pulmonary infection in patients with bronchiectasis.

Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis.

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies.