Michael Gardam

Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management

Cases of active tuberculosis have been reported worldwide with the use of therapeutic agents that inhibit tumour necrosis factor (TNF) alpha. TNFalpha has a central role in mycobacterial infection and disease. Accordingly, progression of recently acquired tuberculosis infection or reactivation of remotely acquired infection should be expected with the use of anti-TNF agents. The available in-vitro and epidemiological evidence for the two currently approved agents, infliximab and etanercept, shows that the risk of development of active tuberculosis is greater with infliximab. Tuberculin skin testing (TST) should be undertaken before any significant immunosuppressive therapy including these agents, though the possibility of false-negative reactions in immunocompromised populations must be borne in mind. A positive TST should be followed by medical assessment and chest radiography, as well as by other tests judged appropriate by the physician to identify active disease. Active tuberculosis must be treated appropriately before initiation of treatment with an anti-TNF agent. Treatment of latent tuberculosis can be considered on an individual basis for TST-negative patients receiving anti-TNF agents when significant risk factors for infection are present.

Complete Nucleotide Sequence of a 92-Kilobase Plasmid Harboring the CTX-M-15 Extended-Spectrum Beta-Lactamase Involved in an Outbreak in Long-Term-Care Facilities in Toronto, Canada

ABSTRACT A major outbreak involving an Escherichia coli strain that was resistant to expanded-spectrum cephalosporins occurred in Toronto and surrounding regions in 2000 to 2002. We report the complete sequence of a plasmid, pC15-1a, that was found associated with the outbreak strain. Plasmid pC15-1a is a circular molecule of 92,353 bp consisting of two distinct regions. The first is a 64-kb region that is essentially homologous to the non-R-determinant region of plasmid R100 except for several point mutations, a few small insertions and deletions, and the absence of Tn10. The second is a 28.4-kb multidrug resistance region (MDR) that has replaced the R-determinant region of the R100 progenitor and consists mostly of transposons or partial transposons and five copies of the insertion element IS26. All drug resistance genes found in pC15-1a, including the beta-lactamase genes blaCTX-M-15, blaOXA-1, and blaTEM-1, the tetracycline resistance gene tetA, and aminoglycoside resistance genes aac(6′)-Ib and aac(3)-II, are located in the MDR. The blaCTX-M-15 gene was found downstream of ISEcp1as part of a transposition unit, as determined from the surrounding sequence. Examination of the plasmids from CTX-M-15-harboring strains isolated from hospitals across Canada showed that pC15-1a was found in several strains isolated from a site in western Canada. Comparison of pC15-1a and pCTX15, found in an E. coli strain isolated in India in 1999, revealed that the plasmids had several features in common, including an R100 backbone and several of the resistance genes, including blaCTX-M-15, blaTEM-1, blaOXA-1, tetA, and aac(6′)-Ib.

Spread of a Novel Influenza A (H1N1) Virus via Global Airline Transportation

International air travelers departing from Mexico in March and April 2009 were unknowingly transporting a novel influenza A (H1N1) virus around the world. The purpose of this analysis was to show h...

Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality.

BACKGROUND C. difficile infection (CDI) has become an important and frequent nosocomial infection, often resulting in severe morbidity or death. Severe CDI is more frequently seen among individuals infected with the emerging NAP1/027/BI (NAP1) strain and in the elderly population, but the relative importance of these 2 factors remains unclear. We used a large Canadian database of patients with CDI to explore the interaction between these 2 variables. METHODS The Canada-wide CDI study, performed in 2005 by the Canadian Nosocomial Infection Surveillance Program (CNISP), was used to analyze the role of infecting strain type and patient age on the severity of CDI. A severe outcome was defined as CDI requiring intensive care unit care, colectomy, or causing death (directly or indirectly) within 30 days after diagnosis. RESULTS A total of 1008 patients in the CNISP database had both complete clinical data and infecting strain analysis documented. A total of 311 patients (31%) were infected with the NAP1 strain, 83 (28%) were infected with the NAP2/J strain, and the rest were infected with various other types. The proportion of NAP1 infections correlated with the incidence and the severity of CDI when analyzed by province. Thirty-nine (12.5%) of the infections due to the NAP1 strain resulted in a severe outcome, compared with only 41 (5.9%) of infections due to the other types (P < .001). The patients age was strongly associated with a severe outcome, and patients 60-90 years of age were approximately twice as likely to experience a severe outcome if the infection was due to NAP1, compared with infections due to other types. CONCLUSIONS Our study confirms the strong age association with infection due to the NAP1 strain and severe CDI. In addition, patients 60-90 years of age infected with NAP1 are approximately twice as likely to die or to experience a severe CDI-related outcome, compared with those with non-NAP1 infections. Patients >90 years of age experience high rates of severe CDI, regardless of strain type.

Health Care-Associated Clostridium difficile Infection in Adults Admitted to Acute Care Hospitals in Canada: A Canadian Nosocomial Infection Surveillance Program Study

BACKGROUND Clostridium difficile infection (CDI) is the most frequent cause of health care-associated infectious diarrhea in industrialized countries. The only previous report describing the incidence of health care-associated CDI (HA CDI) in Canada was conducted in 1997 by the Canadian Nosocomial Infection Surveillance Program. We re-examined the incidence of HA CDI with an emphasis on patient outcomes. METHODS A prospective surveillance was conducted from 1 November 2004 through 30 April 2005. Basic demographic data were collected, including age, sex, type of patient ward where the patient was hospitalized on the day HA CDI was identified, and patient comorbidities. Data regarding severe outcome were collected 30 days after the diagnosis of HA CDI; severe outcome was defined as an admission to the intensive care unit because of complications of CDI, colectomy due to CDI, and/or death attributable to CDI. RESULTS A total of 1430 adults with HA CDI were identified in 29 hospitals during the 6-month surveillance period. The overall incidence rate of HA CDI for adult patients admitted to these hospitals was 4.6 cases per 1000 patient admissions and 65 per 100,000 patient-days. At 30 days after onset of HA CDI, 233 patients (16.3%) had died from all causes; 31 deaths (2.2%) were a direct result of CDI, and 51 deaths (3.6%) were indirectly related to CDI, for a total attributable mortality rate of 5.7%. CONCLUSIONS The rates are remarkably similar to those found in our previous study; although we found wide variations in HA CDI among the participating hospitals. However, the attributable mortality increased almost 4-fold (5.7% vs. 1.5%; P<.001).

Outbreak of Multidrug-Resistant Pseudomonas aeruginosa Colonization and Infection Secondary to Imperfect Intensive Care Unit Room Design

BACKGROUND Pseudomonas aeruginosa has been increasingly recognized for its ability to cause significant hospital-associated outbreaks, particularly since the emergence of multidrug-resistant strains. Biofilm formation allows the pathogen to persist in environmental reservoirs. Thus, multiple hospital room design elements, including sink placement and design, can impact nosocomial transmission of P. aeruginosa and other pathogens. METHODS From December 2004 through March 2006, 36 patients exposed to the intensive care unit or transplant units of a tertiary care hospital were infected with a multidrug-resistant strain of P. aeruginosa. All phenotypically similar isolates were examined for genetic relatedness by means of pulsed-field gel electrophoresis. Clinical characteristics of the affected patients were collected, and a detailed epidemiological and environmental investigation of potential sources was carried out. RESULTS Seventeen of the infected patients died within 3 months; for 12 (71%) of these patients, infection with the outbreak organism contributed to or directly caused death. The source of the outbreak was traced to hand hygiene sink drains, where biofilms containing viable organisms were found. Testing by use of a commercial fluorescent marker demonstrated that when the sink was used for handwashing, drain contents splashed at least 1 meter from the sink. Various attempts were made to disinfect the drains, but it was only when the sinks were renovated to prevent splashing onto surrounding areas that the outbreak was terminated. CONCLUSION This report highlights the importance of biofilms and of sink and patient room design in the propagation of an outbreak and suggests some strategies to reduce the risks associated with hospital sinks.

Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial.

Context Isoniazid is hepatotoxic and must be taken for 9 months by patients with latent tuberculosis infection. Contribution In this trial comparing 4 months of rifampin therapy with 9 months of isoniazid therapy, patients who took rifampin had fewer adverse events and were more likely to complete treatment. Caution The investigators did not compare efficacy of the 2 treatments. Implication These safety and adherence data justify a larger trial to compare the efficacy of rifampin and isoniazid for latent tuberculosis infection. The Editors After detection and treatment of active tuberculosis cases, the next priority in tuberculosis control is the diagnosis and treatment of persons with latent tuberculosis infection (LTBI) who are at increased risk for active tuberculosis. Treatment of such individuals can provide individual and public health benefits (14). The current recommended standard therapy in most countries is 9 months of isoniazid therapy (4, 5). The drug has more than 90% efficacy if taken the entire 9 months (6), but completion rates under routine practice conditions are about 50% or less (79). Another important disadvantage of isoniazid therapy is the occurrence of serious adverse events, particularly drug-induced hepatitis (10). Drug-induced hepatitis was not recognized as a complication of isoniazid therapy in early trials involving more than 50000 participants (11), but it was a frequent and potentially severe problem after isoniazid was recommended for tuberculosis prevention in 1970 (12) and was subsequently used more widely (13, 14). This complication makes close monitoring necessary, increasing costs. These problems have stimulated considerable interest in finding shorter and safer regimens for the treatment of LTBI (15). One alternative, 2 months of daily rifampinpyrazinamide, was recommended in 2000 (4) on the basis of evidence from several trials (1618). However, subsequent reports of severe and fatal hepatotoxicity (19, 20) have rendered this regimen unacceptable for most patients. The remaining recommended alternative is 4 months of daily rifampin, but published outcome information is limited and systematic reviews on this regimen have not been done. In the only published trial that compared 3 months of daily rifampin therapy with 6 months of daily isoniazid therapy in 332 patients, efficacy and safety were similar (21). In 2 uncontrolled case series, 6 months of daily rifampin was well tolerated in 49 homeless persons in Boston (22) and in 157 high school students in California (23). Two nonrandomized studies have described better treatment completion and less hepatotoxicity with 4 months of rifampin than with 9 months of isoniazid under program conditions (8, 9). However, rifampin has been reported to cause other problemsnotably drug interactions (24), a flu-like syndrome (24), and rare hematologic problems (immune-mediated thrombocytopenia and anemia) (25). Also, development of drug resistance is a theoretical concern. Given the experience with isoniazid and 2 months of rifampinpyrazinamide, both of which were thought to be safe on the basis of early studies but caused deaths when used more widely, we designed a multicenter, randomized trial to compare the frequency of serious adverse events and treatment completion rates in patients given 4 months of daily rifampin or 9 months of daily isoniazid for LTBI. Methods Setting, Study Sample, and Randomization This open-label trial was conducted at 9 university-affiliated hospitals: 7 in Canada and 1 each in Saudi Arabia and Brazil. We considered patients to be eligible if they were age 18 years or older and had a documented tuberculin skin test that met the criteria for a positive result (5) and if their primary treating physician initially recommended isoniazid for LTBI following national or international guidelines (4, 26, 27). Patients were ineligible if they were contacts of isoniazid- or rifampin-resistant cases (28), were allergic to isoniazid or rifamycins, or were taking concomitant medications that had clinically significant potential drug interactions that could not be easily managed. To ensure a realistic assessment of adverse events, we considered all other adults eligible, regardless of age or additional risk factors for adverse events, as long as their treating physician felt that therapy for LTBI was indicated. A Web-based program verified eligibility and randomly assigned participants (by using a random-number generator), after they signed informed consent, to 4 months of daily rifampin (10 mg per kg of body weight, up to 600 mg/d) or 9 months of daily isoniazid (5 mg/kg, up to 300 mg/d) in blocks of varying size, stratified by center. A team at the University of Sherbrooke, Sherbrooke, Quebec, Canada, prepared the Web-based program and allocation sequence. Study personnel in the different centers enrolled and registered participants, obtained consent, verified assignment, and administered treatment. All study participants signed informed consent before randomization. Institutional review boards in each participating institution approved the study. Processes and Outcomes Patients were followed in routine fashion by their usual treating physician, who made all management decisions, including discontinuation of therapy. By study protocol, all patients had blood tests (complete blood count, liver aminotransferase levels [aspartate aminotransferase and alanine aminotransferase], and bilirubin level) before and after 1 and 2 months of therapy and were seen every month for the first 4 months of therapy and (for those receiving 9 months of isoniazid) at physician discretion every 6 weeks thereafter. Adverse events could be detected at any time throughout the course of therapy. When the treating physician suspected an adverse event and therapy was suspended, investigations, including blood tests, were performed according to study protocol. The treating physician decided whether to discontinue, rechallenge with, or restart the study therapy, although the protocol specified that participants with grade 3 or 4 adverse events (Appendix Table 1) were not to be rechallenged. When all investigations were complete, and if therapy was permanently discontinued in response to the event, the patients clinical course and results of investigations and rechallenge (if any) were made available to a 3-member independent review panel who were blinded to study drug. If therapy was resumed (for example, after resolution of a grade 1 or 2 adverse event) and the event did not recur, the patients information was not reviewed by the panel. Appendix Table 1. Grading System for Adverse Events Used by Independent Panel Each review panel member had substantial experience and expertise in clinical and epidemiologic aspects of tuberculosis, and each independently judged the type and severity of the adverse events and its likely relationship to the study drug. We graded adverse events as recommended by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0 (29) (Appendix Table 1). Liver aminotransferase levels that increased to 5 to 10 or 3 to 10 times the upper limit of normal in the presence of compatible symptoms met criteria for grade 3 hepatotoxicity, whereas those that exceeded 10 times the upper limit of normal met criteria for grade 4 toxicity (30). In the event of disagreement, panel members re-reviewed the information; if disagreement remained, the majority opinion was used. The studys primary outcome was the frequency of grade 3 or 4 adverse events that resulted in study drug discontinuation and were judged by the review panel to be probably related to the drug (Appendix Table 1). The studys secondary outcome was on-time treatment completion, defined as taking more than 80% of doses within a maximum of 150 days for 4 months of rifampin or 301 days (43 weeks) for 9 months of isoniazid. Doses taken were measured with the Medical Event Monitoring System, an electronic device in the pill container cap that recorded the date and time of bottle opening (APREX Corporation, Fremont, California). Other secondary outcomes included grade 1 or 2 adverse events that were judged by the independent panel to be probably study drugrelated and resulted in permanent discontinuation of therapy and changes in liver aminotransferase levels and leukocyte and platelet counts before and 1 and 2 months after beginning treatment. Statistical Analysis We initially calculated a trial sample size by assuming that the frequency of serious adverse events would be significantly higher with rifampin. We calculated that 630 patients per group would provide 90% power (2-sided = 0.05) to detect a difference between frequency of adverse events of 9% and 4% in the rifampin and isoniazid groups, respectively. This estimate also accounted for an anticipated 15% dropout rate during therapy. Because we were unsure about the actual frequency of adverse events with rifampin, we also noted that 630 patients per group provided 80% power to detect a statistically significant difference between rates of adverse events in the 2 groups if the event rates were 2% and 5% in the rifampin and isoniazid groups, respectively, and the dropout rate was 15%. To ensure safety of study participants, we planned 3 interim analyses for when 25%, 50%, and 75% of the planned total sample size had been randomly assigned. The data safety and monitoring board, blinded to the identity of the 2 groups, reviewed the overall rate of serious adverse events in each group. If the rate was significantly higher in 1 group, then the results were unblinded and the data safety and monitoring board made a decision, based on clinical judgment and statistical input, about stopping or continuing the trial. We used an value of 0.01 to account for multiple testing (31). We reported summary baseline liver function test results for each group as the ratio of each patients test result to the upper li

Detecting Latent Tuberculosis Infection in Hemodialysis Patients: A Head-to-Head Comparison of the T-SPOT.TB Test, Tuberculin Skin Test, and an Expert Physician Panel

Current guidelines advocate screening hemodialysis patients for latent tuberculosis infection; however, the tuberculin skin test (TST) is believed to be insensitive in this population. This study compared the diagnostic utility of the TST with that of an IFN-gamma assay (T-SPOT.TB) and the clinical consensus of an expert physician panel. A total of 203 patients with ESRD were evaluated for latent tuberculosis infection with the TST, T-SPOT.TB test, and an expert physician panel. Test results were compared with respect to their association with established tuberculosis risk factors. Tuberculosis infection, as estimated by the tuberculin test, T-SPOT.TB test, and expert physician panel, was detected in 12.8%, 35.5, and 26.1 of patients respectively. Among patients with a history of active tuberculosis and radiographic markers of previous infection, 78.6 and 72.7% had positive T.SPOT.TB results, compared with 21.4 and 18.2% who had positive tuberculin tests. The physician panel unanimously declared infection in these two groups. On multivariate analysis, a positive T-SPOT.TB test was associated with a history of active tuberculosis, radiographic markers of previous infection, and birth in an endemic country, whereas a physician panel diagnosis also was associated with a history of previous tuberculosis contact. The TST is insensitive in hemodialysis patients and is not recommended to be used in isolation to diagnose latent tuberculosis infection. It is suggested that a combination of T-SPOT.TB testing and medical assessment may be the most accurate screening method.

Quantification of the Hawthorne effect in hand hygiene compliance monitoring using an electronic monitoring system: a retrospective cohort study

Background The Hawthorne effect, or behaviour change due to awareness of being observed, is assumed to inflate hand hygiene compliance rates as measured by direct observation but there are limited data to support this. Objective To determine whether the presence of hand hygiene auditors was associated with an increase in hand hygiene events as measured by a real-time location system (RTLS). Methods The RTLS recorded all uses of alcohol-based hand rub and soap for 8 months in two units in an academic acute care hospital. The RTLS also tracked the movement of hospital hand hygiene auditors. Rates of hand hygiene events per dispenser per hour as measured by the RTLS were compared for dispensers within sight of auditors and those not exposed to auditors. Results The hand hygiene event rate in dispensers visible to auditors (3.75/dispenser/h) was significantly higher than in dispensers not visible to the auditors at the same time (1.48; p=0.001) and in the same dispensers during the week prior (1.07; p<0.001). The rate increased significantly when auditors were present compared with 1–5 min prior to the auditors’ arrival (1.50; p=0.009). There were no significant changes inside patient rooms. Conclusions Hand hygiene event rates were approximately threefold higher in hallways within eyesight of an auditor compared with when no auditor was visible and the increase occurred after the auditors’ arrival. This is consistent with the existence of a Hawthorne effect localised to areas where the auditor is visible and calls into question the accuracy of publicly reported hospital hand hygiene compliance rates.

Is Surveillance for Multidrug-Resistant Enterobacteriaceae an Effective Infection Control Strategy in the Absence of an Outbreak?

Multidrug-resistant enterobacteriaceae (MDRE) are an important cause of nosocomial infections. The effectiveness of screening for MDRE in the nonoutbreak setting in an attempt to prevent transmission is unknown. Patients admitted for new organ transplantation were screened for MDRE colonization. Prospective clinical data were collected, and pulsed-field gel electrophoresis and plasmid and integron analysis of isolates were performed. Colonized patients were not isolated except when required by standard precautions. Of the 287 patients, 69 (24%) were colonized, and 6 (9%) of the 69 developed clinical infections. Most colonizing isolates (66/69) were unique. No clinical infections resulted from patient-to-patient transmission. Analysis of clinical isolates from nonstudy patients demonstrated no evidence of transmission leading to clinical disease. The annual cost of a surveillance program was calculated at Canadian