Negative Sputum Cultures Research Articles

P100 Successful eradication of respiratory tract MRSA in cystic fibrosis: a retrospective study

Introduction The prevalence of pulmonary MRSA infection in cystic fibrosis (CF) has been increasing and is associated with accelerated pulmonary function decline and higher mortality rates. Eradication is generally recommended but there is no consensus of the optimal regimen. The current prevalence at our centre is low (3%, n = 20). Method Retrospective review of adult patients with newly acquired MRSA infection (2007–2012) confirmed by ≥1 positive sputum culture. Data were retrieved from clinical records. “New” infection was confirmed by ≥3 consecutive preceding negative MRSA cultures over ≥12 months. Reflective of changing practice towards MRSA eradication at our centre, antibiotic therapy was categorised as either “conventional” (pre-2008) - a single oral agent, or “contemporary” (2008 + ) using dual oral therapy (based on sputum susceptibilities). Our primary outcome was successful MRSA eradication from sputum at 3 months. Results 32 infection episodes (n = 25) were identified. 19 patients had a single episode of infection, 5 had 2 and 1 patient had 3, each separated by an MRSA-free period of ≥12 months. 13 episodes were treated by conventional approaches (n = 13), and 13 by contemporary means (n = 12). Eradication was not attempted for 6 episodes. Eradication at 3 months was confirmed by negative sputum cultures after treatment by conventional or contemporary regimens in 45% and 80% episodes, respectively (p = NS). Combined Rifampicin/Fusidic acid (Rif/Fus) and single agent tetracyclines were the most widely used regimens (treatment duration, median 2 weeks (range 1.4–4)). Rif/Fus was used for 8 infection episodes (n = 8), achieving eradication rates at 3 months of 100% (6/6 patients). Negative MRSA sputum cultures were maintained in 75% (6/8) patients at 6 months and 37.5% (3/8) at 12 months. Tetracyclines were used for 9 infection episodes (n = 9), achieving eradication rates of 42.9% at 3 months (3/7), 33.3% at 6 months (3/9) and 33.3% at 12 months (3/9). Rif/Fus was more likely to achieve eradication at 3 months compared with tetracyclines (p = 0.03), but this did not maintain statistical significance at 6 or 12 months. Conclusion Our findings demonstrate contemporary treatment with an antibiotic combination, particularly Rif/Fus, to be an effective MRSA eradication strategy. This requires validation with a prospective controlled trial.

Comparison of Levofloxacin versus Moxifloxacin for Multidrug-Resistant Tuberculosis

Levofloxacin (LFX) and moxifloxacin (MXF) are the two most frequently recommended fluoroquinolones for treatment of patients with multidrug-resistant tuberculosis (MDR-TB). However, studies comparing the effectiveness of LFX and MXF among patients with MDR-TB are lacking. To compare the effectiveness of LFX and MXF in terms of culture conversion after 3 months of treatment for MDR-TB. In this prospective multicenter randomized open label trial, we randomly assigned 182 patients with MDR-TB (sensitive to LFX and MXF) to receive either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background drug regimen. The primary outcome was the proportion of patients who achieved sputum culture conversion at 3 months of treatment. Secondary outcomes were time to culture conversion and time to smear conversion, with data censored at 3 months, and the proportions of adverse drug reactions. At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27-2.20). Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) in the MXF group (P = 0.75). The choice of LFX or MXF for treatment of patients with MDR-TB may not affect sputum culture conversion at 3 months of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01055145).

Non Invasive Assessment of Lung Disease in Ataxia Telangiectasia by High-Field Magnetic Resonance Imaging

A sensitive imaging technique that assesses ataxia telangiectasia (AT) lung disease without ionizing radiation is highly desirable. We designed a study to evaluate lung changes using magnetic resonance imaging (MRI), and to investigate the relationships among severity and extent of pulmonary abnormalities and clinical, microbiological and functional data in children and young adults with AT. Fifteen AT patients (age, 11.3years; range, 6-31) underwent 3.0-T MRI, spirometry, and deep throat or sputum culture. Images were scored using a modified Helbich score. Although only 8 patients (53%) had recurrent/chronic respiratory symptoms, MRI identified lung abnormalities in all. Bronchiectasis, peribronchial thickening, mucous plugging, and collapse/consolidation were present in 60%, 87%, 67%, and 13% of cases, respectively, with no difference between subjects with or without respiratory symptoms. No difference in changes of specific scores was found between the two groups, but the total MRI score was higher in patients with respiratory symptoms (6.5 versus 5, respectively; p = 0.02). Total or specific MRI scores were not associated with patients' age. Of all scores, only mucous plugging subscore appeared significantly related to FEV1 (r = 0.7, p = 0.04) and FEF25-75% (r = 0.9, p = 0.001). MRI scores from patients with positive (n = 5) or negative (n = 10) sputum culture were not significantly different. MRI is valuable in the assessment of extent and severity of pulmonary changes in children and adults with AT. It represents an helpful tool for the longitudinal evaluation of patients and may be also used as an outcome surrogate to track the effects of medications.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

BackgroundVitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB).MethodsIn a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339.Results200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes.ConclusionNeither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes.Registry ClinicalTrials.gov. Registry number: NCT00677339

Linezolid for multidrug-resistant tuberculosis

In their Comment in The Lancet Infectious Diseases, Kwok-Chiu Chang and colleagues concluded that expansion of access to linezolid for complicated cases of drug-resistant tuberculosis risks the loss of a potentially useful drug and could promote the emergence and spread of drug-resistant tuberculosis in the community. The rationale behind this idea seems to be the scarcity of controlled clinical trials and, in particular, data for optimum linezolid dose. Although we agree that the evidence base is small, our recent systematic review suggests that good outcomes can be achieved with linezolid among patients who would otherwise have very poor outcomes and high mortality. Among 148 patients treated with linezolid, the rate of treatment success (68%) was at least as good as that expected for multidrug-resistant tuberculosis treatment overall (62%). None of the authors of the studies included in that review advocates large-scale and indiscriminate use of linezolid for drugresistant tuberculosis. Conversely, in view of the poor side-eff ect profi le and treatment complexity, linezolid is recommended for patients with few remaining treatment options, treated in well functioning programmes. The risk of emerging drug resistance is relevant, but no more so than for other second-line drugs presently used for drug-resistant tuberculosis. Existing treatment regimens are lengthy, are associated with sub stantial side-eff ects, and result in overall poor outcomes. Unfortunately, controlled trials to defi ne better regimens are scarce. However, failure to scale up treatment access will lead to continued community transmission and worsening of the epidemic. Newer derivatives of linezolid with improved side-eff ect profi les are under development. Meanwhile, linezolid should be available for patients with few treatment options, owing to either extensive drug resistance or previous treatment failure. We have started fi ve patients on strengthened linezolid and clofazimine-containing regimens in Khayelitsha, South Africa, all of whom produced negative sputum cultures within 3 months. Subsequent linezolid withdrawal was necessary in one patient because of severe peripheral neuropathy. Although side-eff ects need to be monitored and managed carefully, the restricting factor in the use of linezolid in our setting, where Pfi zer holds a patent, is cost, rather than scarcity of evidence. In South Africa, linezolid is available in the public sector at a cost of US$1000 per patient per month. Although improved access to linezolid alone will not solve the worldwide drug-resistant tuberculosis crisis, facilitation of access to new and repurposed drugs for drugresistant tuberculosis will contribute to the overall goal of a shorter, more tolerable, and more eff ective treatment regimen than is available at present, and will off er the hope of cure to patients who would otherwise die.

How many sputum culture results do we need to monitor multidrug-resistant-tuberculosis (MDR-TB) patients during treatment?

Discharge of a hospital patient after a single negative sputum culture may save money when treating multidrug-resistant tuberculosis. However, after initial sputum conversion in 336 South Africans, 11.6% and 5.4% reconverted after 1 and 2 months, respectively. These findings endorse the WHO definitions of 2 negative cultures taken ≥ 30 days apart after sputum culture conversion.

Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis

BackgroundLinezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis.MethodsWe enrolled 41 patients who had sputum-culture–positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring.ResultsBy 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed.ConclusionsLinezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)

Isolated Case of Gastrointestinal Histoplasmosis in a Young Male Patient Diagnosed with Acquired Immunodeficiency Syndrome (AIDS) Presenting as Fever of Unknown Origin

Purpose: In this case, we discuss a 23-year-old male from Ecuador recently diagnosed with AIDS (Anti Retroviral [AR] Naive, CD4 count 49, VL 105260 copies/ml) presented with one week of subjective fever and night sweats. Additionally, the patient complained of one to two weeks of productive cough, intermittent abdominal pain and watery non bloody diarrhea. On presentation, patient was febrile to 101.2 F. His physical examination was remarkable only for oral thrush. The patient was placed on contact isolation for possible Tuberculosis (TB) and admitted to Medicine Service for further work up. All initial blood tests, imagining and cultures results were negative. Patient had negative smear and sputum cultures for AFB. Serum Cryptococcal Antigen and Toxoplasmosis antibody were found to be negative. The patient continued to be febrile during his hospital stay and Gallium Scan was done to evaluate for the source of fever. This test showed increased uptake in mid-abdomen specifically in proximal ascending colon. Subsequently, Abdominal Computerized Tomography (CT) scan with contrast demonstrated extensive retroperitoneal and mesenteric adenopathy as well as splenomegaly. Based on this imaging, Surgery performed laproscopic biopsy of the mesenteric lymph node. Pathology of the lymph node showed caseating necrotizing granulomatous inflammation. Gomori-Grocott methenamine Silver (GMS) stain for histoplasmosis and urinary antigen for histoplasmosis were positive. Tissue cultures from surgical biopsy were negative for tuberculosis and malignancy. Patient was discharged with outpatient infectious disease service follow-up. He was started on antiretroviral therapy and itraconazole that resolved his persistent fever without significant complication. Conclusion: Histoplasmosis is usually described as disseminated in the Advanced AIDS population, but this case highlights the fact that, there is subgroup of the patients who would have isolated gastrointestinal histoplasmosis. Histoplasmosis as a localized infection should be part of differential diagnosis in advanced AIDS patients who present with persistent fever of unclear etiology.

Substitution of Rifapentine for Rifampin During Intensive Phase Treatment of Pulmonary Tuberculosis: Study 29 of the Tuberculosis Trials Consortium

Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment. In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase. Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79). The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted. NCT00694629.

Use of a Molecular Diagnostic Test in AFB Smear Positive Tuberculosis Suspects Greatly Reduces Time to Detection of Multidrug Resistant Tuberculosis

BackgroundThe WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings.MethodsThe performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program.ResultsAmong 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistance directly from the sputum specimen in 159 (89.8%) of 177 specimens and MDR-TB in 109 (95.6%) of 114 specimens compared to conventional methods. There was high agreement between the MTBDRplus assay and conventional DST results in detecting MDR-TB (kappa = 0.95, p<0.01). The most prevalent INH resistance mutation was S315T (78%) in the katG codon and the most common rifampicin resistance mutation was S531L (68%) in the rpoB codon. Among 13 specimens from TB suspects with negative sputum cultures, 7 had a positive MTBDRplus assay (3 with MDR-TB). The time to detection of MDR-TB was significantly less using the MTBDRplus assay (4.2 days) compared to the use of standard phenotypic tests (67.3 days with solid media and 21.6 days with broth-based media).ConclusionsCompared to conventional methods, the MTBDRplus assay had high accuracy and significantly reduced time to detection of MDR-TB in an area with high MDR-TB prevalence. The use of rapid molecular diagnostic tests for TB and drug resistance should increase the proportion of patients promptly placed on appropriate therapy.

Manifestations of Tuberculosis in TB-HIV co-infected patients: A retrospective study

Background : Drug resistant Tuberculosis is well documented worldwide and is associated with increasing morbidity and mortality complicating Tuberculosis control with increasing costs of managing the disease. Broad Objective : To describe clinical and laboratory characteristics of multi-drug resistant Tuberculosis (MDR-TB) patients on second line anti-TB drugs at Kibong‟oto hospital in Tanzania. Methodology : A retrospective cohort study for MDR-TB patients in 56 patients on second line anti-TB treatment at Kibong‟oto hospital and cross sectional study in 40 close contacts for MDR-TB residing in Dar-es-Salaam. Information of patients was abstracted from the MDR-TB register book and clinical file clinical notes containing demographics, clinical and radiological information at baseline and after treatment initiation, first line anti-TB drugs use, bacteriology results at baseline and after treatment initiation that were available at Kibong‟oto hospital. A questionnaire was used to record clinical and demographic characteristics of MDR-TB close contacts. Sputum smear collection and chest radiographs were performed on MDR-TB close contacts with respiratory symptoms suggestive of Tuberculosis. Results: Fifty two (92.9%) patients had confirmed MDR-TB and four patients were started on empirically on second line anti-TB drugs following clinical deterioration despite negative cultures. Nine (16.1%) patients were HIV infected. Thirty two (57.2%) patients improved clinically with negative sputum smears and cultures six months after treatment initiation and were discharged home to their nearest centers to continue with intensive phase of treatment. Six (10.7%) patients died, 3 (5.4%) patients defaulted and 15 (26.8%) patients were still on initiation phase of treatment at the hospital. Twenty four (42.9%) patients experienced at least one drug adverse event while on treatment. None of MDR-TB close contact had active Tuberculosis. Conclusion and recommendations : This study shows that MDR-TB patients had a good treatment response following use of second line anti- TB drugs. This data suggests the need of Rapid diagnostic methods such as PCR for early diagnosis and therefore early treatment before clinical worsening or death. Keywords : Multi-drug resistant tuberculosis, contacts, second line anti-TB drugs

An Uncommon Complication of Commonly Used Medication

Purpose: 73-year male was brought to ER with increasing yellowish discoloration of skin for 3 days; right upper quadrant (RUQ) abdominal pain and confusion for 1 day. Past medical history was significant for diabetes mellitus. The patient was in his usual state of health, when he was hospitalized with fever of 101 F, shortness of breath and cough approximately a week ago. After performing the laboratory work and chest x-ray, right lower lobe aspiration pneumonia was diagnosed and treated with intravenous clindamycin. Patient was discharged home on oral clindamycin on 3rd day. Four days post discharge patient started to notice yellowish discoloration of the eyes and face, gradually increasing in intensity over next 2-3 days and ultimately involving the whole body. On further questioning, the patient's family mentioned some RUQ discomfort with nausea, decreased appetite and increased confusion in the last 24 hours. His blood pressure was 98/63 mmHg, pulse 107 bts/min, respiration 22/min with oxygen saturation of 94% on room air and temperature of 99.5 F. On examination he exhibited grade II encephalopathy and profound jaundice. Abdominal exam was significant for tenderness in RUQ. The rest of the examination was unremarkable. Lab: white cell (WBC) of 11.5 Thou/mm3, with 80% neutrophils, liver function test (LFT) showed bilirubin of 6.9 with direct of 3.43 mg/dl, ALT 1076 IU/L, AST 440 IU/L, alkaline phosphatase 203 IU/L, ammonia 55 umol/L and INR was 2.1. His LFT's were normal prior to this visit. Ultrasound of the liver was reported as normal. Patient was admitted to ICU and clindamycin was held because of possible etiology behind the hepatic injury and it was switched to Zosyn® for broader coverage. Patient conditioned worsened and he developed acute respiratory distress syndrome, for which he was intubated. WBC continued to be elevated, in the face of negative sputum and blood culture, perhaps because of initial antibiotic therapy rendering the cultures negative. On 6th day his LFT's were ALT 437 IU/L, AST 205 IU/L, and bilirubin of 3.6 mg/dl. Serum ferritin, cerruloplasmin level, hepatic and antibody panel came back as normal. There was no history of alcohol use, Tylenol® or any other medication use that could be contributed to be the cause of hepatic failure. As patient continued to be mechanical ventilation dependent and failed multiple weaning trials, support was withdrawn according to his wishes. To conclude, our patient developed liver failure after being treated with clindamycin. Disordered LFT's and synthetic function, which improved after removing the offending agent, would support the diagnosis of clindamycin induced liver toxicity.

Molecular versus conventional methods: Clinical evaluation of different methods for the diagnosis of tuberculosis in Bangladesh

The diagnosis of tuberculosis (TB) in developing countries, such as Bangladesh, is based mainly on microscopic detection of acid-fast bacilli in smears from clinical specimens. On the other hand, the detection of TB by polymerase chain reaction (PCR) is quite new in Bangladesh. In this study, we compared the molecular method with the conventional diagnosis procedures, where Lowenstein-Jensen medium culture results have been used as the "gold standard." A total of 135 sputum samples were collected from clinically suspected patients with pulmonary TB. A direct smear was made from each sputum specimen and stained by the Ziehl-Neelsen (Z-N) method. The sputum samples were then processed, and the pellet was used for both Z-N (concentration) and auramine O fluorescence staining or resuspended in phosphate buffered saline to inoculate Lowenstein-Jensen medium or processed for PCR detection of Mycobacterium tuberculosis. The direct smear staining yielded 44 (32.6%) sputum samples that were acid-fast positive, which increased after concentration, yielding 60 (44.4%) acid-fast-positive samples. Fluorescence microscopy using auramine O staining further increased the number of positive samples to 67 (49.6%). The biochemical tests showed 75 (55.6%) sputum samples to be culture positive, and the MB/BacT system increased the recovery up to 90 (66.7%) culture positives. On the other hand, PCR yielded 93 (68.9%) positive results, 20 (21.5%) of which were culture-negative sputum specimens. It is suggested that the Z-N direct microscopy on its own is the best method (with high specificity) for confirming the diagnosis of acid-fast bacilli. Although the PCR diagnosis of TB appears to be a rapid and sensitive method, the results should be interpreted with care in the clinical settings.

Clinical Significance of Differentiation of Mycobacterium massiliense from Mycobacterium abscessus

Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.

Predicting results of mycobacterial culture on sputum smear reversion after anti-tuberculous treatment: a case control study

BackgroundLittle is currently known regarding sputum smear reversion (acid-fast smear becomes positive again after negative conversion) during anti-tuberculous treatment. This study aimed to evaluate its occurrence in patients with pulmonary tuberculosis (TB) and identify factors predicting results of mycobacterial culture for smear-reversion of sputum samples.MethodsThe retrospective review was performed in a tertiary referral center and a local teaching hospital in Taiwan. From 2000 to 2007, patients with smear-positive culture-confirmed pulmonary TB experiencing smear reversion after 14 days of anti-tuberculous treatment were identified.ResultsThe 739 patients with smear-positive pulmonary TB had 74 (10%) episodes of sputum smear reversion that grew Mycobacterium tuberculosis in 22 (30%) (Mtb group). The remaining 52 episodes of culture-negative sputum samples were classified as the non-Mtb group. The anti-tuberculous regimen was modified after confirming smear reversion in 15 (20%). Fourteen episodes in the Mtb group and 15 in the non-Mtb group occurred during hospitalization. All were admitted to the negative-pressure rooms at the time of smear reversion. Statistical analysis showed that any TB drug resistance, smear reversion within the first two months of treatment or before culture conversion, and the absence of radiographic improvement before smear reversion were associated with the Mtb group. None of the smear reversion was due to viable M. tuberculosis if none of the four factors were present.ConclusionsSputum smear reversion develops in 10% of patients with smear-positive pulmonary TB, with 30% due to viable M. tuberculosis bacilli. Isolation and regimen modification may not be necessary for all drug-susceptible patients who already have radiographic improvement and develop smear reversion after two months of treatment or after sputum culture conversion.

Use of flexible bronchoscopy for rapid diagnosis of suspected tubercular cases in rural India

Reaching a correct diagnosis is a challenge for physicians treating any of the 30% to 50% of pulmonary tuberculosis patients who have negative sputum cultures or who present with no sputum. Flexible bronchoscopy acquires special importance for these cases for whom empirical anti-tuberculosis therapy is the only option left. In our study we aimed to assess the diagnostic yield of flexible bronchoscopy in patients, suspected to have tuberculosis, whose sputum smears were negative. In our hospital-based cross-sectional study, 42 patients were enrolled by consecutive sampling. Flexible bronchoscopy and selective bronchial washings were done in all patients. Bronchoscopy lavage smears were positive for M. tuberculosis in 10 (23.8%) patients. Fifteen (35.7%) patients had positive culture. Flexible bronchoscopy has an important role in the diagnosis of patients suspected to have tuberculosis, whose sputum smears are negative or who can not produce sputum.

Antibiotic Treatment of Mycobacterium abscessus Lung Disease

The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established.To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease.Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization.Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P = 0.007). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days.Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved.

Comment on: Daily 300 mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis

Sir, Koh et al. reported the use of 300 mg of linezolid daily for the treatment of intractable drug-resistant tuberculosis. While it is certainly beneficial to reduce the dosage of linezolid and minimize undesirable adverse drug reactions, there are a number of concomitant concerns. Although the proportion of reported patients with consecutive negative sputum culture taken at least 4 weeks apart appeared high (92%), the actual cure rate would be likely to be much lower, as suggested by a previous report. Even if there were cures, it might be difficult to attribute them to treatment with 300 mg of linezolid daily. Important confounders included accompanying drugs used, alongside their dosages and scheduling (especially for moxifloxacin/levofloxacin), as well as recourse to surgical resection. Furthermore, the peak serum levels of linezolid did not appear to correlate well with the reported outcomes. While linezolid can achieve a good concentration in epithelial lining fluid in human volunteers, this might not be so in the presence of sequestered pulmonary tuberculosis with sizeable thick-walled cavities. Resistance to linezolid among Mycobacterium tuberculosis isolates is emerging in various parts of the world. It is indeed a pressing issue to delineate the optimal dosage and scheduling of linezolid in the treatment of ‘difficult’ drug-resistant tuberculosis, through balancing efficacy, suppression of drug resistance, tolerance and toxicity of the oxazolidinone. It would be very important to follow-up on the susceptibility of the M. tuberculosis isolates harboured by those patients reported by Koh et al. who failed to achieve cure after antituberculosis chemotherapy.

Pulmonary nontuberculous mycobacterial infections: Antibiotic treatment and associated costs

Recent studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease. In the absence of prevalence and cost data, the public health burden of pulmonary NTM disease is difficult to assess. The goal of this study was to assess costs associated with NTM disease treatment and to identify risk factors associated with increased costs. Records from subjects with pulmonary NTM disease enrolled in a natural history protocol were abstracted for presenting symptoms, comorbidities, microbiology, and treatment histories. Antibiotic frequency, duration, adverse reaction, and costs were noted, the total antibiotic burden and cost were calculated, and risk factors associated with high costs were analyzed. From Jan 2004 to Dec 2005, 33 subjects were enrolled; 27 met disease criteria and had sufficient data to assess antibiotic use. Mycobacterium avium complex was present in 89% and Mycobacterium abscessus was present in 21% of subjects. Subjects received a median of 5 (1-10) antibiotics. Adverse effects were common seen in up to 50% with common antibiotics and up to 100% with uncommonly used antibiotics. Median burden of treatment was 2638 (84-7689) drug-days and the median total cost per patient was $19,876 ($398-70,917). Subjects with high treatment costs had an adjusted 9.5 fold (95% CI 1.5-97.2) likelihood of having M. abscessus and a 4.2 fold (95% CI 0.6-59.3) increased likelihood of having more extensive disease. Pulmonary NTM represent an underappreciated disease burden in the US population, with an associated treatment cost comparable to that for other chronic diseases of infectious origin such as HIV/AIDS.

Substitution of Moxifloxacin for Isoniazid during Intensive Phase Treatment of Pulmonary Tuberculosis

Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited. Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB. Adults with sputum smear-positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol. All doses were directly observed. Sputum was collected for culture every 2 weeks. The primary outcome was negative sputum culture at completion of 8 weeks of treatment. Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%) were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites. Negative cultures at Week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the moxifloxacin arm (P = 0.37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of Week-8 culture negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the moxifloxacin group versus 22/205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, 0.81, 2.25). Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity.