Michael E. Murphy

Moxifloxacin for tuberculosis

We believe Helen Cox and colleagues’ proposal to restrict moxifl oxacin use to multidrug-resistant tuberculosis is based on fl awed logic. In a clinical trial of the present fi rst-line regimen for drug-susceptible tuberculosis, cure rates were greater than 95% and no new regimen is likely to improve on this rate. However, reducing treatment duration with moxifl oxacincontaining regimens would lead to a decreased risk of default and consequent drug resistance. Moxifl oxacin-containing regimens render sputum cultures sterile more rapidly than standard therapy, and so reduce onward transmission. A resultant decline in incident cases has been estimated by modelling studies. Cox and colleagues suggest that reserving moxifl oxacin for use in drugresistant tuberculosis will decrease future drug resistance. Restriction might be feasible in government programmes but is unrealistic in private practice, which is a common setting for tuberculosis treatment in countries with a high tuberculosis burden, including India. Furthermore, that all drugs in this class can be restricted is unlikely because of their widespread use and low cost. Those drugs with poorer anti-tuberculosis activity are more likely to select for resistance—for example, exposure to subinhibitory ciprofl oxacin concentrations increased mycobacterial mutation rates by up to 200 times compared with the rates without the antibiotic. Cross-resistance among fl uoroquinolones is common. Therefore, restriction of one drug in the class would not achieve a useful result. Cox and colleagues note that treatment-shortening trials are underway, and we advocate that patients with uncomplicated susceptible disease should not be treated with moxifl oxacin until results of these trials are known. In cases of drug resistance or poor tolerance, fl uoroquinolones should be used only in settings where susceptibility results are available to prevent the risk of increasing resistance.

Recurrent Microvirgula aerodenitrificans Bacteremia

ABSTRACT Microvirgula aerodenitrificans is a denitrifying Gram-negative organism first described by Patureau et al. in 1998 (D. Patureau et al., Int. J. Syst. Bacteriol. 48:775–782, 1998). The organism has been isolated globally but has never been described as causative of clinical infection. We describe the first human case of bacteremia attributed to M. aerodenitrificans in an infant with Pompes disease.

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

BackgroundDrug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment.MethodsPatients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements.ResultsA total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14–56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008).ConclusionsOur results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.

Toxicity associated with tuberculosis chemotherapy in the REMoxTB study

BackgroundThe incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin.MethodsAll grade 3 & 4 adverse events (AEs) and their relationship to treatment for patients who had taken at least one dose of therapy in the REMoxTB clinical trial were recorded. Univariable logistic regression was used to test the relationship of baseline characteristics to the incidence of grade 3 & 4 AEs and significant characteristics (p < 0.10) were incorporated into a multivariable model. The timing of AEs during therapy was analysed in standard therapy and the experimental arms. Logistic regression was used to investigate the relationship between AEs (total and related-only) and microbiological cure on treatment.ResultsIn the standard therapy arm 57 (8.9%) of 639 patients experienced ≥1 related AEs with 80 of the total 113 related events (70.8%) occurring in the intensive phase of treatment. Both four-month experimental arms (“isoniazid arm” with moxifloxacin substituted for ethambutol & “ethambutol arm” with moxifloxacin substituted for isoniazid) had a lower total of related grade 3 & 4 AEs than standard therapy (63 & 65 vs 113 AEs). Female gender (adjOR 1.97, 95% CI 0.91–1.83) and HIV-positive status (adjOR 3.33, 95% CI 1.55–7.14) were significantly associated with experiencing ≥1 related AE (p < 0.05) on standard therapy. The most common adverse events on standard therapy related to hepatobiliary, musculoskeletal and metabolic disorders. Patients who experienced ≥1 related AE were more likely to fail treatment or relapse (adjOR 3.11, 95% CI 1.59–6.10, p < 0.001).ConclusionsMost AEs considered related to standard therapy occurred in the intensive phase of treatment with female patients and HIV-positive patients demonstrating a significantly higher risk of AEs during treatment. Almost a tenth of standard therapy patients had a significant side effect, whereas both experimental arms recorded a lower incidence of toxicity. That patients with one or more AE are more likely to fail treatment suggests that treatment outcomes could be improved by identifying such patients through targeted monitoring.