The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis

Patients in whom acid-fast bacilli smear-positive pulmonary tuberculosis was newly diagnosed were randomized to receive 400 mg moxifloxacin, 300 mg isonaizid, or 600 mg rifampin daily for 5 days. Sixteen-hour overnight sputa collections were made for the 2 days before and for 5 days of monotherapy. Bactericidal activity was estimated by the time taken to kill 50% of viable bacilli (vt(50)) and the fall in sputum viable count during the first 2 days designated as the early bactericidal activity (EBA). The mean vt(50) of moxifloxacin was 0.88 days (95% confidence interval [Cl], 0.43-1.33 days) and the mean EBA was 0.53 (95% CI 0.28-0.79). For the isoniazid group, the mean vt(50) was 0.46 days (95% Cl, 0.31-0.61 days) and the mean EBA was 0.77 (95% Cl, 0.54-1.00). For rifampin, the mean vt(50) was 0.71 days (95% Cl, 0.48-0.95 days) and the mean EBA was 0.28 (95% Cl, 0.15-0.41). Using the EBA method, isoniazid was significantly more active than rifampin (p < 0.01) but not moxifloxacin. Using the vt(50) method, isoniazid was more active than both rifampin and moxifloxacin (p = 0.03). Moxifloxacin has an activity similar to rifampin in human subjects with pulmonary tuberculosis, suggesting that it should undergo further assessment as part of a short course regimen for the treatment of drug-susceptible tuberculosis

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses

Pseudomonas aeruginosa bacteremia in patients undergoing liver transplantation: An emerging problem

In our institution, Pseudomonas aeruginosa bacteremia appeared to occur with increasing frequency in patients undergoing liver transplantation. We thus conducted a prospective study to define risk factors and outcome in these patients. Over a 19-month period 6% of liver transplants were followed by Pseudomonas bacteremia. The mean age was 46 years (range, 24 to 67 years). The interval between transplantation and onset of bacteremia was 3 to 372 days (mean, 80). The incidence of Pseudomonas bacteremia in liver transplants was three times that of other transplants (heart, lung, kidney). Ninety one percent of infections were nosocomial. Polymicrobial bacteremia occurred in 30% of episodes. The portal of entry was respiratory in 30%, abdominal in 35%, and biliary in 13%. Four patients had recurrent Pseudomonas bacteremia: liver abscess (1), biliary obstruction (2), subhepatic abscess (1). Survival at 14 days was 70%. Survival rates were significantly lower for patients with hypotension, on mechanical ventilators, and increasing severity of illness (p < 0.05). Survival was higher when bacteremia occurred within the first 30 days after transplantation compared to after 30 days. A large number (43.4%) of Pseudomonas bacteremias occurred after transplant surgery or biliary tract manipulation, while the patient was receiving a prophylactic regimen of cefotaxime and ampicillin. P. aeruginosa is an important pathogen in the liver transplant recipient; prevention may be possible for a subgroup of patients with the use of prophylactic antibiotics with activity against P. aeruginosa

Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.

BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV

Aspergillosis of the CNS in a pediatric liver transplant recipient: Case report and review

A 2-month-old infant who had undergone orthotopic liver transplantation at the age of 2 weeks for carbamoyl phosphate synthetase deficiency developed infection of the CNS due to Aspergillus fumigatus. The patient was successfully treated with administration of a combination of antifungal agents (including intraventricular amphotericin B), drainage of the parietal lobe abscess, and cessation of immunosuppression. An intraventricular catheter was used both to obtain ventricular fluid for microbiologic testing and to deliver amphotericin B during nearly 4 months of treatment. We review literature on aspergillosis in solid-organ transplant recipients, especially those in whom the disease involves the CNS, and discuss in particular clinical presentation, diagnosis, treatment, and outcome

Antimicrobial effects of folk medicinal plants from the North of Iran against Mycobacterium tuberculosis

Background: Medicinal plants have been used traditionally in Golestan province (north of Iran), against Mycobacterium tuberculosis or the clinical signs of tuberculosis (TB). Objectives: This study aimed to define the inhibitory effects of ethanolic extracts of six of these medicinal plants against Mycobacterium tuberculosis. Materials and Methods: Peganum harmala (seed extract), Punica granatum (peel extract), Digitalis sp. (leaf extract), fruit extract of Citrus lemon, Rosa canina and Berberis vulgaris were extracted in ethanol and their activity against M. tuberculosis isolates were determined by the agar diffusion method. The zone of inhibition (at 200 to 1.6 mg/mL) was measured and the results were compared with isoniazid and rifampin as standard positive controls. Also the concentration of vitamin C of each the extracts was evaluated. Results: The ethanolic extract of Peganum harmala seed and Punica granatum peel exhibited potential activity against all M. tuberculosis isolates with mean inhibitory zone of 18.7 and 18.8 mm, at 200 mg/mL concentration. The mean inhibitory zone around isoniazid and rifampinwere 19.2 and 18.8 mm. Ethanolic extract of Citrus lemon showed moderate inhibitory activity only against sensitive (non MDR; non multi drug resistant) strains of M. tuberculosis, and Digitalis sp. showed inhibitory effects on five isolates. Ascorbic acid content was 43.3 mg/dL in Punica granatum and Digitalis sp. and only 9.1 mg/dL in ethanolic extract of Peganum harmala. Conclusions: The highest content of vitamin C was observed in the extract of Punica granatum, which was observed to be highly active against Mycobacterium tuberculosis, while the P. harmala must have contained other phytochemical constituents that contributed to the anti-tuberculosis effects of this plant. Our findings showed that ethanolic extracts of P. granatum and P. harmala had anti-TB effects comparable to isoniazid and rifampin and can be good candidates for novel and safe natural products against tuberculosis. © 2015, Pediatric Infections Research Center

Recurrent Cutaneous Tuberculosis in an Immunocompetent 7-Year-Old Male

Cutaneous tuberculosis (TB) makes up a small proportion of the 10.4 million cases around the world. Although it is more commonly found in the developing world, cutaneous TB is rarely reported in the developed countries. It is fairly challenging to diagnose without histological examination. In this report, we present an immunocompetent 7-year-old male with a complex medical history diagnosed with cutaneous Mycobacterium tuberculosis after multiple ventriculoperitoneal shunt (VPS) revisions. This case of cutaneous TB in an immunocompetent patient is remarkable in its uncharacteristic presentation with no obvious source of TB infected contacts or travel history

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli