Management of patients with multidrug-resistant tuberculosis.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 µg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 µg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 µg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

Fluoroquinolones for the treatment of tuberculosis in children.

The fluoroquinolones are key components of current multidrug-resistant tuberculosis (MDR-TB) treatment regimens and are being evaluated in shortened treatment regimens as well as in the prevention of drug-resistant TB. The objective of this review was to identify existing evidence for the use of the fluoroquinolones ofloxacin, levofloxacin and moxifloxacin in the treatment of TB in children. Existing data from in vitro, animal and human studies consistently demonstrate the efficacy of the fluoroquinolones against Mycobacterium tuberculosis, with superiority of levofloxacin and moxifloxacin compared to ofloxacin. In vitro and murine studies demonstrated the potential of moxifloxacin to shorten drug-susceptible TB treatment, but in multiple randomized controlled trials shortened fluoroquinolone-containing regimens have not been non-inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration, with newer more potent fluoroquinolones less likely to develop resistance. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-infected children; existing studies show substantially lower serum concentrations in children compared to adults at currently recommended doses, probably due to faster elimination. This has implications for optimizing paediatric treatment and for the development of resistance. Fluoroquinolone use has been restricted in children due to concerns about drug-induced arthropathy. The available data does not demonstrate any serious arthropathy or other severe toxicity in children. Although there is limited paediatric safety data for the prolonged treatment of MDR-TB, extended administration of fluoroquinolones in adults with MDR-TB does not show serious adverse effects and there is no evidence suggesting less tolerability of fluoroquinolones in children. Additional study of moxifloxacin and levofloxacin for TB treatment and prevention in children is an urgent priority.

Rifampicin-monoresistant Mycobacterium tuberculosis disease among children in Cape Town, South Africa.

SETTING: Tygerberg Children's Hospital (TCH) and Brooklyn Chest Hospital (BCH), South Africa. OBJECTIVES: To describe paediatric cases of rifampicin (RMP) monoresistant tuberculosis (RMR-TB) disease. DESIGN: Records of children with culture-confirmed RMR-TB between 1 March 2003 and 28 February 2009 were identified from a prospectively recorded database of drug-resistant TB at TCH and BCH. Mutation analysis was performed on available specimens. RESULTS: Eighteen children with a median age of 6.9 years (range 2 months-12.8 years) were identified. Nine (50%) were human immunodeficiency virus (HIV) infected and four (22%) were HIV-exposed but non-infected. Eleven (61%) had had previous TB treatment or prophylaxis. Nine children (50%) had cavitary disease and five children (22%) had extra-pulmonary disease. Twelve (67%) had adult TB source cases, including five (42%) adults with known RMR-TB. Primary transmission occurred among 11 children (61%) and acquisition of RMR-TB was possible in seven (39%) with prior RMP exposure. Median delay to specific RMR-TB treatment was 70 days (range 23-188). One child died from RMR-TB meningitis. Gene mutations consistent with RMR-TB were confirmed in five available samples. CONCLUSION: RMR-TB disease is increasingly encountered, particularly among HIV-infected and HIV-exposed non-infected children. Delay in commencing appropriate treatment for RMR-TB and high rates of cavitary disease could be a source of RMR-TB transmission.

Pyridoxal-5-phosphate plasma concentrations in children receiving tuberculosis chemotherapy including isoniazid.

AIM: Little is known about pyridoxine nutriture of children treated with isoniazid (INH) regimens. This study documents plasma pyridoxal 5'-phosphate (PLP) concentrations in children, HIV-infected and HIV-uninfected, receiving INH regimens. METHODS: Children from the Western Cape of South Africa hospitalized for tuberculosis (TB) management were studied. Plasma PLP concentrations were determined on enrolment, 1-month after commencing TB treatment, and again after 4-month's treatment. The children received a supplement meeting pyridoxine requirements. RESULTS: Nineteen HIV-infected and 33 HIV-uninfected children received INH (dosage range 4-20 mg/kg) daily. Mean PLP plasma concentrations on enrolment were 8.32 (SD 6.75) ng/mL and 11.28 (SD 3.02) ng/mL in HIV-infected and HIV-uninfected children, respectively (p = 0.11) and after 4-month's treatment 6.75 (SD 2.71) ng/mL and 14.76 (SD 7.96) ng/mL (p < 0.001). On enrolment 9 (50%) HIV-infected and 5 (15%) HIV-uninfected children (p = 0.016) had suboptimal PLP concentrations (<6 ng/mL); after 4-month's treatment 8 (42%) and 2 (6%) (p = 0.004). CONCLUSION: Plasma PLP concentrations in children treated for TB were low on enrolment in HIV-infected and HIV-uninfected children; after 4-month's treatment low values were still common in HIV-infected children. Additional pyridoxine supplementation of malnourished children treated for tuberculosis is advisable, particularly those HIV-infected.

Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis.

BACKGROUND: Ethionamide (ETH) is a structural analogue of isoniazid (INH). Both are pro-drugs requiring activation by separate and common enzyme pathways, which could lead to co- and/or cross-resistance. OBJECTIVE: To characterise paediatric INH-resistant mycobacterial isolates to investigate the presence of ETH resistance and mutations in the katG gene and the inhA promoter region. METHODS: Forty-five INH-resistant and 19 INH-susceptible Mycobacterium tuberculosis control isolates from children from the Western Cape Province, South Africa, were analysed to quantify INH minimal inhibitory concentration, test for ETH resistance and investigate mutations in the katG gene and/or inhA promoter region. RESULTS: Among 45 INH-resistant children, ETH resistance was present in 19 of 39 (49%). An inhA promoter mutation was identified in 15 (33.3%); 12/14 (86%) of these isolates were also ETH-resistant. Of the 21 isolates with a katG mutation, six (29%) were ETH-resistant. No isolate had both katG and inhA promoter mutations. Nine (20%) isolates had neither inhA promoter nor katG mutations. Of 15 isolates with inhA promoter mutation, 14 (93%) displayed low- or intermediate-level INH resistance. Among the 19 INH-susceptible isolates, ETH resistance was present in 1/18 (6%) and none showed inhA or katG gene mutations. CONCLUSION: We found a high level of cross- and co-resistance with ETH among INH-resistant M. tuberculosis isolates from children in this geographic area.

The burden of childhood tuberculosis: a public health perspective.

The burden of childhood tuberculosis (TB) reflects recent transmission within a community and the level of TB control achieved within the adult (maintenance host) population. Children contribute little to the maintenance of the TB epidemic, but they may suffer severe TB-related morbidity and mortality. This review describes the main determinants of the burden of childhood TB within a particular community. Basic infectious disease principles identify the community, and not the individual, as the central entity that sustains an epidemic. The prevalence of TB is determined by the community's exposure to Mycobacterium tuberculosis, and their vulnerability to developing disease following exposure. The main variables that influence both exposure and vulnerability are discussed. Multiple variables are linked to poverty, and it is their cumulative effect, rather than the exact degree of poverty, that seems most important. Diligent contact tracing and the use of preventive chemotherapy will reduce the TB-related suffering of children. The burden of childhood TB, however, is a reflection of our ability to control the epidemic; this remains the ultimate challenge. Current efforts to control the TB epidemic aim to reduce transmission by treating sputum smear-positive adults, while very little emphasis is placed on reducing the vulnerability of high-burden communities. Successful control of the epidemic is the most effective way to reduce the burden of childhood TB, but this will require a holistic approach that acknowledges the importance of sustainable poverty alleviation.

Genome and MIC stability in Mycobacterium tuberculosis and indications for continuation of use of isoniazid in multidrug-resistant tuberculosis.

Mycobacterium tuberculosis strains resistant to two or more of the first line antituberculosis drugs (MDR) are a serious threat to successful tuberculosis control programmes. For this retrospective study, 85 follow-up drug resistant isolates from 23 patients residing in a community with a high incidence of tuberculosis were collected and the level of in-vitro resistance to antibiotics determined quantitatively. PCR-SSCP and sequencing techniques were used to screen for gene mutations associated with resistance in 31 follow-up samples from a smaller group of eight patients. DNA fingerprint analysis was done on sequential isolates to confirm identity. Although treatment had a profound effect on changes in drug resistance patterns, the MIC for a particular agent remained constant in follow-up isolates. DNA fingerprinting and mutational analysis (14 different loci) showed that the genome of MDR strains of M. tuberculosis is relatively stable during the course of therapy. The rpoB gene was the most frequently mutated structural gene involved in drug resistance and a novel C to T mutation upstream of open reading frame (ORF)1 of the inhA operon was detected. No evidence was found of the presence of strain W (New York) in this group of MDR strains. The results stress the importance of confirming individuality of strains for the accurate calculation of frequencies of particular mutations associated with drug resistance, particularly in a high incidence area. Approximately one-half (47.8%) of the patients had isolates resistant to concentrations just above the critical concentration for isoniazid (MICs of 0.2-5 mg/L). Therefore, these patients and their contacts who develop primary drug-resistant tuberculosis may respond to higher dosages of treatment which could have a considerable impact on the cost and the ease of management of resistant tuberculosis.