WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

International Society of Cardiovascular Infectious Diseases Guidelines for the Diagnosis, Treatment and Prevention of Disseminated Mycobacterium chimaera Infection Following Cardiac Surgery with Cardiopulmonary Bypass.

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects.

A 13-year molecular epidemiological analysis of tuberculosis in San Francisco.

BACKGROUND: We examined the molecular epidemiology of tuberculosis (TB) in San Francisco during a 13-year period encompassing the peak of TB resurgence and subsequent decline to historic low levels. OBJECTIVE: To compare rates of TB caused either by rapid progression of recent Mycobacterium tuberculosis infection or by reactivation of latent infection. METHODS: All TB cases reported from 1991 to 2003 were included. Genotyping was performed to identify clustered cases. RESULTS: The annual TB case rate decreased significantly from 50.8 to 28.8 cases/100000 persons from 1992 to 1999 (P < 0.0001). After 1999, no significant decrease was observed for the population as a whole or in any subgroup examined. Similarly, the rate of clustered cases decreased significantly from 1992 to 1999 (11.4 to 3.1 cases/100000, P < 0.0001). Although the rate of non-clustered cases also declined significantly (25.6 to 17.6 cases/100,000, P < 0.0001), there was a disproportionate reduction in clustered cases (94.7% vs. 50.8%, P < 0.0001). Neither clustered nor non-clustered cases decreased significantly after 1999. CONCLUSIONS: TB case rates reached a plateau despite ongoing application of control measures implemented in 1993. These data suggest that intensification of measures designed to identify and treat persons with latent TB infection will be necessary to further reduce TB incidence.

Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

OBJECTIVE: To evaluate the early bactericidal activity (EBA) of the new fluoroquinolones levofloxacin, gatifloxacin and moxifloxacin in patients with pulmonary tuberculosis (PTB). DESIGN: Randomized, open-label trial. Forty adults with newly diagnosed smear-positive PTB (10 per arm) were assigned to receive isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. Sputum for quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (EBA 0-2) and last 5 days of monotherapy (extended EBA, EBA 2-7). Laboratory staff were blinded to treatment assignment. RESULTS: The EBA 0-2 of INH (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day) (P = 0.14). Bactericidal activity between days 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison, the EBA 2-7 of the fluoroquinolones was greater than for INH. CONCLUSION: Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA. These drugs warrant further study in the treatment of drug-susceptible TB.

Apparent opposing effects of cyclic AMP and dibutyryl cyclic GMP on the neuronal firing of the blowfly chemo-receptors.

Cyclic AMP and its dibutyryl derivative inhibit neuronal firing of the labellar sugar sensitive receptor of the blowfly when applied in conjunction with the stimulant sucrose. Furthermore, simultaneous application of aminophylline (phosphodieterase inhibitor) and sucrose or in combination with cyclic AMP caused a similar depression of the sugar receptors response. In contrast, dibutyryl cyclic GMP elicited an increase in sugar receptor firing when applied with sucrose to sugar receptor. Either 5'-AMP or 5'-GMP in combination with sucrose had no discernable effect on the sugar receptors response. Different ratio combinations of cyclic AMP and dibutyryl cyyclic GMP showed the striking inhibitory effect of cyclic AMP upon the dibutyryl cyclic GMP elicited increases in receptor firing frequency. Therefore, it is suggested that these two nucleotides may be mediating different but complimentary aspects of sugar receptor function in a push-pull manner.

Problems and solutions for the Stop TB partnership.

Recent international efforts for global control of tuberculosis have resulted in a new movement: the Stop TB partnership. One of the operational goals of this movement is based on WHO-determined targets to detect, by 2005, 70% of new smear-positive cases under DOTS, and to successfully treat 85% of these cases. In a paper in the Bulletin of the World Health Organization, Dye and colleagues present data that show the current case-detection rate to be low (only 27%), and that in many areas treatment-success rates are still below the WHO target level. Dye and colleagues predict, by linear extrapolation of these data, that the WHO target of a 70% case detection rate will be achieved by 2013. Here, we discuss why it is unlikely that the WHO global targets for either case detection or treatment success will be reached by 2013, and we also offer some potential solutions.

The runny nose. Infection of the paranasal sinuses.

Infection of the paranasal sinuses is an important although infrequent complication of the common cold. This article discusses the pathophysiology, etiology, clinical presentation, complications, differential diagnosis, treatment, and prevention of these infections. Proper treatment with the appropriate antibiotic may help in avoiding irreversible mucosal damage, thus decreasing the incidence of chronic sinusitis.

Multiple drug-resistant tuberculosis.

The national and international emergence of drug-resistant M. tuberculosis has complicated both the programmatic control of the tuberculosis epidemic and the clinical management of individual cases. In the United States, the problem of MDR tuberculosis is regionalized and likely stems from multifactorial causes, including the concurrent HIV epidemic. The epidemic is propagated by two distinct entities, PDR and ADR tuberculosis, which result from different inadequacies in tuberculosis control programs. The clinical management of drug-resistant tuberculosis, MDR tuberculosis in particular, is complex, frequently results in adverse outcomes, and often necessitates consultation with a specialist in the field. Two important management principles are to always use at least two agents to which the organism is susceptible and to never add a single drug to a failing regimen. Selection of an appropriate treatment regimen and determination of the duration of therapy depend on the resistance pattern, toxicities of the drugs, and the patient's response to therapy. Measures to ensure patient adherence with therapy are of paramount importance in the setting of drug resistance. Preventive therapy should be considered in the management of close contacts to active cases of MDR tuberculosis, although there is little evidence to support this practice.

The role of molecular epidemiology in contact investigations: a US perspective.

Preventing tuberculosis (TB) transmission through treatment of active cases and contact investigation is the highest priority of TB control programs in the United States. The role of contact investigation is becoming increasingly important as the number of TB cases declines nationally. However, the effectiveness of contact investigation has been difficult to assess because, prior to the availability of molecular genotyping techniques, levels of transmission were crudely measurable. Epidemiological links within and outside the traditional concentric circle approach are limited by the quality of the contact investigation, the skill and knowledge of the investigator and the information provided by the patient. Molecular epidemiology has added a new dimension by enabling the recognition of unsuspected transmission, likely locations of transmission, and quantification of the extent of transmission that is occurring within a given population. In the future, as real-time genotyping becomes more available, the role of molecular epidemiology is likely to expand.

Simultaneous infection with two strains of Mycobacterium tuberculosis identified by restriction fragment length polymorphism analysis.

Simultaneous infection with two different strains of Mycobacterium tuberculosis has been demonstrated using phage typing. We report here the first case of mixed infection identified using IS6110-based genotyping of M. tuberculosis. The patient was diagnosed with pulmonary tuberculosis in February, 1991. The initial isolate of M. tuberculosis had two different genotype patterns (dark 7-band and light 14-band patterns). However, in a repeat isolate obtained several months later, only the 14-band pattern was visible. Exogenous reinfection and laboratory cross-contamination were unlikely because both genotype patterns were unique in the San Francisco database which includes over 1300 isolates of M. tuberculosis. This case demonstrates the importance of identifying mixed infections in the study of the molecular epidemiology of tuberculosis. Mixed infections could be confused with exogenous reinfection or laboratory cross-contamination, and important epidemiologic connections could be missed.

The epidemiology of tuberculosis diagnosed after death in San Francisco, 1986-1995.

SETTING: San Francisco, California. OBJECTIVES: To identify the characteristics of persons in whom tuberculosis was diagnosed after death, and determine whether secondary cases of tuberculosis resulted from them. DESIGN: Retrospective review of all cases of tuberculosis reported in San Francisco from 1986 through 1995, combined with a prospective evaluation of the molecular epidemiology of tuberculosis. RESULTS: Four per cent of the reported 3102 tuberculosis cases were diagnosed after death. The rate of tuberculosis cases diagnosed after death was 1.63 per 100000 population. Age 43 years or older, male sex, white race, and birth in the United States were characteristics independently associated with a diagnosis of tuberculosis after death. During 1993-1995, injecting drug use was also independently associated with a diagnosis of tuberculosis after death (odds ratio 9.24, 95% confidence interval 1.77-39.38). Cases of tuberculosis diagnosed after death do not appear to be significant sources of undetected tuberculosis transmission causing new secondary tuberculosis cases in the community. CONCLUSIONS: Health care providers in San Francisco, and probably other urban areas, should maintain a high index of suspicion for tuberculosis in ageing, white, US-born males, and injecting drug users.

Methods for diagnosing tuberculosis among in-patients in eastern Africa whose sputum smears are negative.

SETTING: Two University hospitals in Eastern African capital cities where large prospective studies had been carried out on hospitalized patients to determine the cause of their respiratory diseases. OBJECTIVE: To identify features that differentiated between tuberculosis (TB) and non-tuberculous respiratory disease (non-TB) in hospitalized patients from Bujumbura, Burundi (n = 111) and Dar es Salaam, Tanzania (n = 71) whose sputum smears were negative on microscopic examination for acid-fast bacilli (AFB). DESIGN: Review of clinical findings, radiologic abnormalities, and laboratory test results from 182 patients, first by univariate and then by multivariate (stepwise logistic regression) analysis to assess the contribution of each factor to the final diagnosis. RESULTS: Of the 182 patients with two or more negative AFB smears, 41 had TB and 141 had non-TB. Stepwise regression analysis revealed four easily ascertained symptoms were associated with TB: 1) cough > 21 days; 2) chest pain > 15 days; 3) absence of expectoration; and 4) absence of shortness of breath. Any two of the four diagnosed TB with 85% sensitivity and 67% specificity; any three of the four with 49% sensitivity and 86% specificity. Multivariate analysis showed that adding lymphadenopathy and hematocrit < 30% improved discrimination. CONCLUSION: This methodological approach provides a means for diagnosing TB among all AFB smear-negative hospitalized patients. In this setting, simple clinical symptoms alone are helpful. Similar studies are needed to develop a system for out-patient TB suspects.

Pyogenic bacterial pneumonia in the acquired immunodeficiency syndrome.

Individuals with human immunodeficiency virus (HIV) infection are more susceptible to bacterial infections because of defects in both cellular and humoral immunity. The most common causes of community-acquired pyogenic bacterial pneumonia in HIV-infected patients are Streptococcus pneumoniae and Haemophilus influenzae. The clinical presentation of HIV-infected patients with pyogenic pneumonia does not seem to differ significantly from that of patients without HIV infection. Response to therapy is generally good, and complications relatively few. Prevention of bacterial pneumonia is very important in the care of HIV-infected persons. The pneumococcal vaccine is currently recommended for all HIV-seropositive individuals, although its efficacy is unknown is this setting. Other forms of prevention require further investigation but may prove to be helpful.

The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review.

SETTING: Tuberculosis (TB) rates are decreasing in many areas, while non-tuberculous mycobacteria (NTM) infection rates are increasing. The relationship between the epidemiology of TB and NTM infections is not well understood. OBJECTIVE: To understand the epidemiologic relationship between TB and NTM disease worldwide. DESIGN: A systematic review of Medline (1946-2014) was conducted to identify studies that reported temporal trends in NTM disease incidence. TB rates for each geographic area included were then retrieved. Linear regression models were fitted to calculate slopes describing changes over time. RESULTS: There were 22 studies reporting trends in rates of NTM disease, representing 16 geographic areas over four continents: 75% of areas had climbing incidence rates, while 12.5% had stable rates and 12.5% had declining rates. Most studies (81%) showed declining TB incidence rates. The proportion of incident mycobacterial disease caused by NTM was shown to be rising in almost every geographic area (94%). CONCLUSION: We found an increase in the proportion of mycobacterial disease caused by NTM in many parts of the world due to a simultaneous reduction in TB and increase in NTM disease. Research into the interaction between mycobacterial infections may help explain this inverse relationship.

Bacterial pneumonia in HIV-infected patients.

Individuals infected with the human immunodeficiency virus (HIV) are more susceptible to bacterial infections because of defects in both cellular and humoral immunity. Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of bacterial pneumonia in HIV-infected patients. However, more unusual bacteria can also cause pneumonia. Response to therapy is generally good for infections caused by pyogenic organisms, and complications are relatively few. Unfortunately, infections caused by Rhodococcus equi and Nocardia species are associated with significant morbidity and mortality. Moreover, the duration of therapy is long, and relapes are common. Prevention of bacterial pneumonia is an important part of the care of HIV-infected patients; the 23 valent pneumococcal vaccine is currently recommended for all HIV-infected patients. The role of other preventative measures remains unknown.

Tuberculosis recurrence in Africa: true relapse or re-infection?

PIP: HIV-seropositive patients respond to rifampicin-containing anti tuberculosis (TB) regimens as well as HIV-seronegative patients. In Nairobi, Kenya, 90% of HIV-positive patients who suffered a recurrence of TB first received a non-rifampicin-containing regimen. The overall unadjusted recurrence rate for HIV-positive patients was 16.7% while it was .5% for HIV-seronegative patients. An earlier, similar study in Zaire also showed a higher recurrence rate in HIV positive patients. A study in the US found a low recurrence rate among HIV-positive patients on rifampicin-containing regimens. A possible explanation for the higher recurrence rates may be that the thiacetazone-containing regimen is not as potent as the rifampicin containing regimen. Another possible explanation may be that no one knows the optimum duration of therapy for HIV-infected patients. 70% of HIV-positive patients in nairobi who suffered a recurrence of TB experienced a cutaneous-hypersensitivity reaction, resulting in a change in therapy and maybe affecting compliance. The researchers of the Nairobi study used DNA fingerprinting to determine whether the patients truly relapsed or were reinfected (cultures were available from only 3 HIV-positive patients). 1 patient was reinfected by a different strain of Mycobacterium tuberculosis. 4 of 17 AIDS patients in New York City were reinfected with a different multidrug resistant strain of M. tuberculosis. Reinfection is more likely to happen in sub-Saharan Africa where TB an HIV are very prevalent. Physicians cannot accurately determine a treatment regimen in HIV-infected patients in an area of high prevalence of TB. Thus, we need to determine reinfection rates in HIV infected patients to plan a response.^ieng

Tropical respiratory medicine. 1. Pulmonary infections in the tropics: impact of HIV infection.

PIP: Infection with Mycobacterium tuberculosis is so common in tropical areas that the World Health Organization (WHO) estimates more than 75% of the 8-10 million new cases of tuberculosis (TB) annually occur therein. Infection with HIV is also common in the tropics; the WHO estimated in 1992 that 9-11 million adults were infected with HIV, mostly in developing countries. This tropical overlap of HIV infection and pulmonary pathogens makes pulmonary infections a common manifestation of HIV infection, especially TB and bacterial pneumonia. Bacterial pneumonia accounts for at least 25% of medical admissions to one of East Africa's largest hospitals and recent cohort and case-control studies have shown increased rates of disease among HIV-infected individuals. Of all the pulmonary infections encountered in the tropics, however, M. tuberculosis is one of the most significant pathogens. Data from sub-Saharan Africa and Haiti have shown that 17-66% of TB cases are seropositive for HIV-1. Moreover, 50% of seropositive patients presenting with pulmonary symptoms have TB. This review, however, focuses upon non-tuberculosis pathogens affecting HIV-infected patients in tropical and developing countries. Pneumococcus, nocardiosis, and melioidosis are discussed under bacterial pneumonia and are followed by cryptococcosis, histoplasmosis, paracoccidioidomycosis, and penicillium marneffei under fungal pneumonia. Other sections explore pneumocystis pneumonia, parasitic pneumonia (strongyloidiasis), pleural effusions, and the evaluation of HIV-infected patients with pulmonary disease.^ieng