Jennifer Ho

Pooling sputum specimens is one potential strategy for reducing the cost of using Xpert MTB/RIF, a rapid polymerase chain reaction (PCR)-based test, for the diagnosis of pulmonary tuberculosis. We sought to compare the sensitivity of two alternative method of pooling. Patients referred for assessment for TB, whose initial sputum was Xpert MTB positive, were recruited and their sputum specimens were pooled for analysis with sputum specimens that were Xpert MTB negative. Two alternative pooling strategies were employed: one in which the concentration of sample reagent (buffer) was maintained at 2:1 (standard), in accordance with the manufacturer’s instructions, and another in which the concentration of sample reagent was reduced to 1:1. We tested 101 Xpert MTB positive sputum specimens. Among these, 96% of valid test results (95% confidence interval (CI) 89–99%) were positive using the “standard buffer method”. Using the “reduced buffer pooling” method 94% of valid test results (95% CI 87–98%) were positive. McNemar’s test for the difference in paired proportions did not reach statistical significance (P = 0.56). We have confirmed that pooling of two sputum specimens for testing in a single cartridge is a valid method of reducing the number of cartridges required when using Xpert MTB to detect pulmonary tuberculosis. Two alternative pooling strategies tested here yielded similar results. The present study was conducted within the Active Casefinding in Tuberculosis (ACT3) Trial. The ACT3 Trial had been registered with Australian and New Zealand Clinical Trials Register on 8th April, 2014. The trial registration number is ACTRN12614000372684 . (Retrospectively registered).

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. 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. 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. 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.

Tuberculous meningitis (TBM) comprises a significant proportion of TB cases globally and causes substantial morbidity and mortality, especially in children and HIV‐infected patients. It is a challenging condition to diagnose due to its non‐specific clinical presentation and the limited sensitivity of existing laboratory techniques. Smear microscopy and culture are the most widely available diagnostic tools yet are negative in a significant proportion of TBM cases. Simplified and more affordable nucleic acid amplification tests (NAATs) are increasing in use in resource‐limited settings but have not been optimised for cerebrospinal fluid (CSF) samples. Novel diagnostic methods such as CSF interferon‐gamma release assays and various biomarkers have been developed but require further evaluation to establish their utility as diagnostic tools. There is an urgent need for further research into optimal diagnostic strategies to decrease the morbidity and mortality as a result of delayed or missed diagnosis of TBM. In this review, we discuss current and novel diagnostic tests in TBM and areas where future research should be prioritised.

Introduction The 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. Methods A 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. Results Sixty-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. Conclusions Despite 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.

Multiresistant Gram-negative infections are an increasing problem in hospitals and healthcare facilities worldwide. While much attention has been paid to Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus lately, the importance of Gram-negative nosocomial infections has also been recognized globally. Recent reports have described the spread of carbapenemase-producing Klebsiella pneumoniae across North America. In addition, many strains of Pseudomonas and Acinetobacter in Asia are resistant to all known antibiotics. The global epidemiology of multiresistant Gram-negative pathogens seems to vary by continent. There are very few existing agents which can be used for these pathogens and there are limited options on the horizon. This limited therapeutic armamentarium has been an impetus for novel approaches including combination therapies and increased attention to infection control and prevention efforts. Clinicians need to be aware of the rising problem of resistance in nosocomial and community-acquired Gram-negative pathogens. Novel agents are urgently needed to combat these infections and innovative infection control strategies need to be devised to protect our vulnerable patients.

The enrolment 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. 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. 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. 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.