Jennifer Ho

Safe and successful treatment of intravenous drug users with a peripherally inserted central catheter in an outpatient parenteral antibiotic treatment service

BACKGROUND The enrollment of intravenous drug users (IVDUs) into an outpatient parenteral antibiotic treatment (OPAT) service using a peripherally inserted central catheter (PICC) is controversial and often avoided. The National University Hospital in Singapore has a policy of permitting OPAT-based treatment of IVDU patients with appropriate medical indications. We report on our experiences. METHODS A prospective observational study was conducted on IVDU patients requiring parenteral antibiotics via an OPAT service from January 2005 to December 2009. Clinically appropriate patients were screened using pre-defined criteria and enrolled into our service, where standardized measures were enforced to prevent and detect PICC abuse and optimize treatment. Outcomes measured included mortality, completion of therapy, PICC abuse, and readmission for infective or treatment-related complications during OPAT and a 30 day follow-up period. RESULTS Twenty-nine IVDU patients received treatment in our OPAT service (total 675 patient-days). The median duration of therapy was 18 days (range 1-85). Infective endocarditis was the primary diagnosis in 42% of cases. Two patients (7%) had recrudescent infection after absconding during their inpatient stay. These two patients subsequently completed treatment in OPAT. There were no deaths or cases of PICC abuse. Five patients (17%) during OPAT and one patient (3%) during the 30-day follow-up period required readmission for infective or treatment-related complications. CONCLUSIONS Appropriately selected, counselled and monitored patients with a history of being an IVDU can be treated safely and successfully via OPAT centres. It is likely that some will respond better to treatment in an outpatient setting.

Detection of influenza A and B with the Alere™ i Influenza A & B: a novel isothermal nucleic acid amplification assay

Rapid influenza diagnostic tests (RIDTs) have an important role in clinical decision‐making; however, the performances of currently available assays vary widely.

Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment

OBJECTIVES The clinical significance of the emergence of Mycobacterium tuberculosis (MTB) isolates that contain rpoB mutations (genotypic resistance), but are phenotypically susceptible to rifampicin (RIF G(R) P(S)), remains uncertain. The aim of this study was to determine the prevalence of MTB cases that demonstrate this discordant rifampicin resistance pattern and to establish whether these patients have poorer treatment outcomes with rifampicin-based regimens. METHODS rpoB sequencing was performed on all MTB isolates demonstrating phenotypic resistance to one or more first-line antituberculosis agents (excluding rifampicin). Rifampicin MICs were determined for rpoB mutation-positive isolates and clinical case notes were reviewed to identify treatment outcomes in these patients. RESULTS Of the 214 phenotypically drug (excluding rifampicin)-resistant isolates tested, 5 contained rpoB mutations (4 isoniazid resistant and 1 pyrazinamide resistant). These isolates demonstrated elevated rifampicin MICs (low-level resistance), despite testing susceptible using phenotypic broth-based methods. One patient experienced a relapse of tuberculosis (TB) 2 years after completion of a rifampicin-containing regimen. These findings are consistent with a recent study that reported treatment failure with rifampicin-based regimens in patients with isoniazid-resistant MTB and genotypic rifampicin resistance. CONCLUSIONS While MTB RIF G(R) P(S) strains remain relatively uncommon, they can be associated with low-level rifampicin resistance and poorer treatment outcomes with rifampicin-based regimens. This recently recognized form of multidrug-resistant TB should be adequately detected and managed.

The impact of sputum quality on tuberculosis diagnosis: a systematic review.

OBJECTIVE To perform a systematic review to evaluate the impact of sputum quality on the yield of tuberculosis (TB) diagnostic tests. METHODS We searched PubMed, EMBASE, LILACS and the Cochrane Database to identify studies that addressed 1) the impact of sputum quality on the proportion of sputum samples with Mycobacterium tuberculosis detected using smear, culture or polymerase chain reaction (PCR); and 2) the impact of pre-sputum collection interventions on sputum quality and M. tuberculosis detection. RESULTS Ten studies met the eligibility criteria for review inclusion. Five studies assessed macroscopic and/or microscopic sputum quality characteristics and M. tuberculosis detection. The other five studies assessed the impact of pre-sputum collection interventions on sputum quality and M. tuberculosis detection. No studies assessed the impact of sputum quality on PCR-based diagnostic tests. CONCLUSION Definitive conclusions about the utility of sputum quality assessments are limited by the paucity of, and heterogeneity within, the available data. Given the potential for sputum quality assessments to enhance diagnostic yield and prevent wasteful laboratory testing, further research into this field is urgently needed.

Reassessment of the positive predictive value and specificity of Xpert MTB/RIF: a diagnostic accuracy study in the context of community-wide screening for tuberculosis

BACKGROUND Community-wide screening for tuberculosis with Xpert MTB/RIF as a primary screening tool overcomes some of the limitations of conventional screening. However, concerns exist about the low positive predictive value of this test in screening settings. We did a cross-sectional assessment of this diagnostic test to directly estimate the actual positive predictive value of Xpert MTB/RIF when used in the setting of community-wide screening for tuberculosis, and to draw an inference about the specificity of the test for tuberculosis detection. METHODS Field staff visited households in 60 randomly selected villages in Ca Mau province, Vietnam. We included people aged 15 years or older who provided written informed consent and were able to produce 0·5 mL or more of sputum, irrespective of reported symptoms. Participants were tested with Xpert MTB/RIF, then those with positive results had two further sputum samples tested for smear microscopy and culture, and underwent chest radiography at the provincial TB Health Center. The positive predictive value of Xpert MTB/RIF was compared against two reference standards for tuberculosis diagnosis-a positive sputum culture for Mycobacterium tuberculosis, and a positive sputum culture or a chest radiograph consistent with active pulmonary tuberculosis. We then calculated the specificity of Xpert MTB/RIF for tuberculosis detection on the basis of these positive predictive values and disease prevalence in this setting. FINDINGS 43 435 adults consented to screening with Xpert MTB/RIF. Sputum samples of 0·5 mL or greater were collected from 23 202 participants, producing 22 673 valid results. 169 participants had positive Xpert MTB/RIF results (0·39% of those screened and 0·75% of those with valid sputum results). The positive predictive value of Xpert MTB/RIF was 61·0% (95% CI 52·8-68·7) when compared against a positive sputum culture and 83·9% (76·8-89·2) when compared against a positive sputum culture or chest radiograph consistent with active tuberculosis. On the basis of these positive predictive values, the specificity of Xpert MTB/RIF was determined to be between 99·78% (95% CI 99·71-99·84) and 99·93% (99·88-99·96). INTERPRETATION The positive predictive value and specificity of Xpert MTB/RIF in the context of community-wide screening for tuberculosis is substantially higher than that predicted in previous studies. Our findings support the potential role of Xpert MTB/RIF as a primary screening tool to detect prevalent cases of tuberculosis in the community. FUNDING Australian National Health and Medical Research Council.

Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis

Abstract Objective To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches. Methods We searched ClinicalTrials.gov, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization’s portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses. Findings Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes. The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01–1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38–1.13), for death RR: 1.01 (95% CI: 0.67–1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48–2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models. Conclusion Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

Fluoroquinolone resistance in non-multidrug-resistant tuberculosis— a surveillance study in New South Wales, Australia, and a review of global resistance rates

BACKGROUND Fluoroquinolones (FQs) are used for drug-susceptible tuberculosis (TB) in patients unable to tolerate first-line agents. Current trials are also investigating these drugs in empiric first-line TB therapy, to improve outcomes and allow for shortened treatment regimens. Widespread FQ use in the community has resulted in FQ resistance in many microorganisms, including Mycobacterium tuberculosis. Despite this, FQ drug susceptibility testing (DST) is rarely performed in non-multidrug-resistant TB (non-MDR-TB). METHODS We conducted a 1-year surveillance study of FQ resistance on all MTB isolates from New South Wales (NSW), Australia. In addition, we performed a literature review of previous studies assessing FQ resistance in non-MDR-TB to summarize the global extent of this resistance pattern. RESULTS Two (0.6%) out of 357 MTB isolates from NSW were found to be FQ-resistant. One isolate was an MDR strain (11% of all MDR-TB). The other was isoniazid-monoresistant (0.3% of all non-MDR-TB). Eleven studies from 10 countries had performed FQ resistance surveillance on non-MDR-TB. In the majority of these studies, FQ resistance was found to be low (mean 1%; 95% confidence interval 0.2-2%). CONCLUSIONS FQ resistance in non-MDR-TB is uncommon in NSW, Australia. The existing global evidence suggests that FQ resistance remains largely confined to MDR-TB strains. In the majority of TB endemic regions, however, FQ resistance in non-MDR-TB has not been assessed. Knowledge of the prevalence of FQ resistance in MTB is essential to guide the rational use of these drugs, including their feasibility as first-line agents.

The role of macroscopic sputum quality assessments to optimise sputum testing for tuberculosis.

SETTING Community-wide active case finding for tuberculosis (TB) using Xpert® MTB/RIF as the primary screening tool, Ca Mau Province, Viet Nam. OBJECTIVES To determine whether macroscopic sputum quality characteristics (sputum colour and volume) can be used to predict Xpert MTB-negative sputum and hence exclude sputum samples from testing. DESIGN Field staff conducted household visits to approximately 51,200 adults in 58 villages randomly selected from throughout the province. Sputum samples from all screened participants who were able to produce ⩾1 ml sputum underwent macroscopic sputum assessment and were tested with Xpert. RESULTS Of the 21,624 sputum samples tested, 159 (0.74%) were Xpert MTB-positive; 93% of the samples were 1-2 ml and nearly all were mucoid (93%) or mucopurulent (5.7%). One salivary sample was Xpert MTB-positive (2.0% of all salivary samples). The lowest positive predictive value for any sputum volume or colour characteristic was 0.66%. This was not substantially different from the overall prevalence of positive sputum Xpert MTB (0.74%). CONCLUSION Sputum colour and volume cannot be used to predict the presence or absence of M. tuberculosis in sputum detected using Xpert. These sputum quality parameters cannot therefore be used to exclude sputum samples from testing for TB.

International Approaches to Treating Intravenous Drug Users in Outpatient Parenteral Antibiotic Services

IntroductionThe use of outpatient parenteral antibiotic therapy (OPAT) in intravenous drug–using (IVDU) patients remains controversial. It is currently unknown what the approaches and outcomes are of treating IVDU patients in OPAT services from around the world. We conducted an international survey to gain a better understanding of this issue. MethodsA survey was conducted using an online survey program from May to October 2010 to OPAT centers from around the world. This survey addressed a range of issues including the following: the approach of health institutions on the treatment of IVDU patients requiring prolonged parenteral antibiotics, the outcomes of IVDU patients treated with OPAT, and the providers’ concerns and views on this form of therapy. The results were collated as a whole and also divided into geographical groups to compare responses internationally. ResultsSixty-four OPAT centers from Australia, New Zealand, Asia, North America, United Kingdom, and Europe participated in this survey. Most of the responding centers (84.4%) stated they treat patients with a history of IVDU, and a significant proportion (44.2%) use peripherally inserted central catheters. Despite some concerns, most responders (84%) believe that the use of OPAT in IVDU patients is beneficial and outweighs the risks with little interregional variation in this approach and opinion. ConclusionsDespite some limitations to survey distribution, we feel that these findings are important and unique. They show that, around the world, OPAT centers are treating IVDU patients with acceptable outcomes. Moreover, this form of therapy is increasingly regarded as a beneficial and a preferred treatment option in this significant group of patients.

Predicting tuberculosis without knowing test specificity: Authors' reply

Authors’ reply We thank O Kaya Koksalan and colleagues for their cor respondence about our study, which assessed the performance of Xpert MTB/RIF in the context of community-wide screening for tuberculosis. We acknowledge that the concern regarding our approach to estimating sensitivity and specifi city is a valid one. However, in the present study, we have not sought to estimate the sensitivity of Xpert. What we have done, on a large scale, is to directly assess the positive predictive value of the Xpert test in the screening context. Positive predictive value is estimated only in people with positive test results; in this case the 169 people with a positive Xpert result. We have used a range of plausible criteria for establishing which of these people with a positive Xpert result were true positives and which were false positives. One of these criteria is the presence of a positive culture for Mycobacterium tuberculosis. An alternative criterion is the presence of an abnormal chest radiograph consistent with a radiological diagnosis of tuberculosis. We have acknowledged that this was not investigated in a blinded way and could overestimate the number of true positives. Nevertheless, we think it is reasonable to assume that the true positive rate lies somewhere between these two estimates (61–84%). We then made a range of plausible assumptions about the sensitivity of Xpert, using data from a Cochrane review of 22 studies and almost 9000 individuals, and the prevalence of tuberculosis in the population, using data from the present study and from a previous prevalence survey. With these data, we have reverse-calculated what the specifi city must have been to result in the observed positive predictive value. In our original Article, table 3 shows that, under a wide range of plausible assumptions, the specifi city must have been at least 99·57% and was probably higher than this. Although this is a novel approach, we stand by its validity. The reference standards used included a gold standard microbiological reference, and a composite reference that also included chest radiography. A study by Theron and others done on 480 individuals suspected of having tuberculosis in South Africa, also suggested that a composite reference standard could be more appropriate to assess the diagnostic accuracy of molecular tests for tuberculosis, especially in settings where mycobacteria culture facilities can be overburdened and under-resourced. Because of the many Xpert tests used in this study, we were able to estimate the positive predictive value and specificity of this test with more precision than previous studies combined. Both the positive predictive value and specificity of Xpert for M tuberculosis detection were substantially greater than previous estimates. Taken together with previous data on the sensitivity of the test, our data suggest that the accuracy of Xpert is adequate to support its role as a primary screening tool for detecting patients with tuberculosis in the context of community-wide screening in a moderate to high prevalence setting.