Matthew P. Cheng

Is a Lumbar Puncture Necessary When Evaluating Febrile Infants (30 to 90 Days of Age) With an Abnormal Urinalysis

Objectives: Guidelines for the management of febrile infants aged 30 to 90 days presenting to the emergency department (ED) suggest that a lumbar puncture (LP) should be performed routinely if a positive urinalysis is found during initial investigations. The aim of our study was to assess the necessity of routine LPs in infants aged 30 to 90 days presenting to the ED for a fever without source but are found to have a positive urine analysis. Methods: We retrospectively reviewed the records of all infants aged 30 to 90 days, presenting to the Montreal Childrens Hospital ED from October 2001 to August 2005 who underwent an LP for bacterial culture, in addition to urinalysis and blood and urine cultures. Descriptive statistics and their corresponding confidence intervals were used. Results: Overall, 392 infants were identified using the microbiology laboratory database. Fifty-seven patients had an abnormal urinalysis. Of these, 1 infant (71 days old) had an Escherichia coli urinary tract infection, bacteremia, and meningitis. This patient, however, was not well on history, and the peripheral white blood cell count was low at 2.9 × 109/L. Thus, the negative predictive value of an abnormal urinalysis for meningitis was 98.2%. Conclusions: Routine LPs are not required in infants (30-90 days) presenting to the ED with a fever and a positive urinalysis if they are considered at low risk for serious bacterial infection based on clinical and laboratory criteria. However, we recommend that judicious clinical judgment be used; in doubt, an LP should be performed before empiric antibiotic therapy is begun.

Voriconazole inhibition of vitamin A metabolism: are adverse events increased in cystic fibrosis patients?

As Voriconazole is being used more frequently in cystic fibrosis (CF) patients, we aimed to describe the adverse events associated with voriconazole treatment in this population.

Visual Hallucinations Associated with High Posaconazole Concentrations in Serum

Posaconazole is a triazole used for the prevention and treatment of fungal infections. Unlike other mold-active azoles, posaconazole is generally well tolerated. Dose-dependent toxicity was not identified during the registration trials of the intravenous and tablet formulations, and levels in serum as high as 3.35 g/ml were observed (1, 2). We present herein the first case of visual hallucinations and neurological disturbances associated with extremely high levels of posaconazole in a patient undergoing treatment for chronic pulmonary aspergillosis (CPA). The patient is a 37-kg, 69-year-old female known to have chronic obstructive pulmonary disease. She was diagnosed with CPA in March 2014 and was treated with itraconazole at 200 mg per os (p.o.) twice a day (BID) for 11 months. In May 2015, voriconazole at 200 mg p.o. BID was initiated for treatment of a clinical and radiological relapse of her disease. After 1 week of voriconazole therapy, she presented to our hospital with acute complaints of disturbing visual hallucinations, including menacing miniature people. A medication review revealed no known drug-drug interactions associated with hallucinations. Voriconazole levels were not measured, but a diagnosis of voriconazoleassociated visual toxicity was made, her therapy was changed to posaconazole in oral suspension (200 mg p.o. four times a day [QID]), and her visual hallucinations resolved over 10 days. One month later, the posaconazole suspension was changed to the tablet formulation at 300 mg p.o. daily for improved tolerability. Five days later, she developed an acute recurrence of similar visual hallucinations, altered mental status, and symptoms of parkinsonism. A posaconazole trough level was 10.10 g/ml, which is, to our knowledge, the highest reported level of this agent in serum. Posaconazole tablets were discontinued, and her symptoms resolved with decreasing levels of posaconazole in serum (Table 1). Posaconazole suspension at 200 mg p.o. BID was initiated without symptom recurrence. Visual and neurological disturbances are well-described adverse effects associated with voriconazole (3, 4). Although the exact mechanism remains unclear, it has been suggested that voriconazole-mediated inhibition of CYP46A1 leads to reduced 24S-hydroxycholesterol levels in retinal and neural cells, disrupting cholesterol homeostasis and membrane function (5). Alternatively, data from mouse models suggest that visual disturbances may result from voriconazole-mediated inhibition of transient receptor potential cation subunit M (TRPM1 and TRPM3) channels within retinal and neural cells (6). Posaconazole also binds CYP46A1 and may therefore also inhibit these pathways (7, 8). Moreover, phospholipidosis due to membrane accumulation of posaconazole has been reported (9). Although central nervous system (CNS) toxicity has not previously been reported with posaconazole, this observation may reflect the low levels achieved with the oral suspension combined with its low CNS penetration (7, 10). However, newer formulations result in significantly higher posaconazole concentrations in serum (11), particularly in patients with low body mass (12). Use of posaconazole tablets can result in serum concentrations above the range that has been well

Microbial Biofilms in Pulmonary and Critical Care Diseases

Microbial biofilms can colonize medical devices and human tissues, and their role in microbial pathogenesis is now well established. Not only are biofilms ubiquitous in natural and human-made environments, but they are also estimated to be associated with approximately two-thirds of nosocomial infections. This multicellular aggregated form of microbial growth confers a remarkable resistance to killing by antimicrobials and host defenses, leading biofilms to cause a wide range of subacute or chronic infections that are difficult to eradicate. We have gained tremendous knowledge on the molecular, genetic, microbiological, and biophysical processes involved in biofilm formation. These insights now shape our understanding, diagnosis, and management of many infectious diseases and direct the development of novel antimicrobial therapies that target biofilms. Bacterial and fungal biofilms play an important role in a range of diseases in pulmonary and critical care medicine, most importantly catheter-associated infections, ventilator-associated pneumonia, chronic Pseudomonas aeruginosa infections in cystic fibrosis lung disease, and Aspergillus fumigatus pulmonary infections.

Risk of Active Tuberculosis in Patients with Cancer: A Systematic Review and Meta-Analysis.

Background Cancer is a known risk factor for developing active tuberculosis (TB). We determined the incidence and relative risk of active TB in cancer patients compared to the general population. Methods Electronic databases were searched up to December 2015: Medline, Medline InProcess, EMBASE, PubMed, the Cochrane Database of Systematic Reviews, Cancerlit, and Web of Science. Studies of pathologically confirmed cancer patients were included if active TB was identified concurrently or after the diagnosis. Cumulative incidence rate/100,000 population (CIR) of new cases of TB occurring in cancer patients and comparative incidence rate ratios (IRR) to the general population from the same country of origin were estimated. A random effect meta-analysis was conducted on the CIR and IRR. Results A total of 23 studies reporting 593 TB cases occurring in 324,041 cancer patients between 1950 and 2011 were identified. In a meta-analysis of 6 studies conducted in the US in 317,243 cancer patients (98% of all patients) the CIR of active TB decreased by 3 fold and 6.5 fold in hematologic and solid cancers respectively before and after 1980. After 1980 the CIR of active TB was highest in hematologic (219/100,000 population, IRR=26), head and neck (143; 16), lung cancers (83; 9) and was lowest in breast and other solid cancers (38; 4). Conclusions Individuals living in the US with hematologic, head and neck, and lung cancers had a 9-fold higher rate of developing active TB compared to those without cancer and would benefit from targeted latent TB screening and therapy.

Using MRSA Screening Tests To Predict Methicillin Resistance in Staphylococcus aureus Bacteremia.

ABSTRACT Bloodstream infections with Staphylococcus aureus are clinically significant and are often treated with empirical methicillin resistance (MRSA, methicillin-resistant S. aureus) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in S. aureus bacteremia and could help determine the requirement for empirical vancomycin therapy. We reviewed consecutive S. aureus bacteremias over a 5-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-day criterion), as tested within 30 days but accounting for any prior positive results (ever-positive criterion), or as tested in known-positive patients, with patients with unknown MRSA status being labeled negative (known-positive criterion). There were 409 S. aureus bacteremias: 302 (73.8%) methicillin-susceptible S. aureus (MSSA) and 107 (26.2%) MRSA bacteremias. In the 167 patients with MSSA bacteremias, 7.2% had a positive MRSA test within 30 days. Of 107 patients with MRSA bacteremia, 68 were tested within 30 days (54 positive; 79.8%), and another 21 (19.6%) were previously positive. The 30-day criterion provided negative predictive values (NPV) exceeding 90% and 95% if the prevalence of MRSA in S. aureus bacteremia was less than 33.4% and 19.2%, respectively. The same NPVs were predicted at MRSA proportions below 39.7% and 23.8%, respectively, for the ever-positive criterion and 34.4% and 19.9%, respectively, for the known-positive criterion. In MRSA-colonized patients, positive predictive values exceeded 50% at low prevalence. MRSA screening could help avoid empirical vancomycin therapy and its complications in stable patients and settings with low-to-moderate proportions of MRSA bacteremia.

Management of Severe Malaria in the Intensive Care Unit

Severe malaria is a medical emergency requiring early intervention to prevent death. This article highlights key aspects of the management of severe malaria syndromes in the intensive care unit, with a focus on individual case management of imported malaria. Key differences in the presentation, management, and outcomes of severe malaria by endemicity and by age group are emphasized. In all groups with severe malaria, intravenous artesunate is the antimalarial agent of choice. This article discusses specific antimalarial therapies, optimal supportive management strategies, differences from strategies for bacterial sepsis, and trials of adjunctive therapy for severe malaria in humans.

Post-vaccination myositis and myocarditis in a previously healthy male

BackgroundThe immunological literature has been redefining clinical phenomena as hypotheses emerge regarding causal links between triggers, immunologic manifestations, and their specific inflammatory cascades. Of late, autoimmune manifestations that appear to be caused by an external adjuvant have been grouped into a complex syndrome referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syndrome may present with diverse clinical problems, which may include neurocognitive impairment, inflammatory musculoskeletal changes, and constitutional symptoms. There is evidence in the literature linking vaccines to different auto-immune manifestations. Vaccines have not traditionally been reported to trigger ASIA, although reports are emerging linking the human papilloma virus and hepatitis B vaccines to it.Case presentationWe report the first suspected case of ASIA in a previously healthy patient who received the Fluad seasonal influenza vaccine, which contains the MF59 adjuvant. He presented to hospital with profound weakness and was diagnosed with severe rhabdomyolysis. He also had elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis. His infectious and rheumatologic work-ups were negative. He responded well to conservative management and did not require immune suppressive therapy.ConclusionGiven the benefits of the influenza vaccine, and the low incidence of clinically significant complications, we encourage ongoing seasonal influenza immunization. However, ongoing surveillance is required to evaluate the occurrence of rare adverse events, including ASIA.

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non–Small Cell Lung Cancer

Introduction: Despite widespread administration of programmed death receptor 1 (PD‐1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials. Methods: Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD‐1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first‐line setting). Results: Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a programmed death ligand‐1 tumor proportion score ≥50%, three partial responses were observed. All patients received antiretroviral therapy while on anti–PD‐1 treatment. None of the patients experienced grade 3 or 4 immune‐related adverse events or immune reconstitution inflammatory syndrome, and none required PD‐1 inhibitor dose interruption or discontinuation due to toxicity. Conclusions: Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV.

Tuberculosis in HIV-infected persons in British Columbia during the HAART era.

OBJECTIVE: Prior to the introduction of highly active antiretroviral therapy (HAART), active tuberculosis (TB) was a major contributor to HIV-related morbidity and mortality in Canada and other low-incidence regions. We performed this study to examine TB incidence, clinical manifestations and screening uptake in HIV-infected TB patients during the era of HAART therapy.METHODS: We performed a retrospective study on all HIV-infected TB patients in British Columbia over a 10-year period (2003–2012). Demographic and clinical characteristics were extracted along with screening and treatment outcomes. Trends in provincial TB incidence, HIV testing and HAART prevalence were also examined.RESULTS: In total, 2,839 TB cases were identified in BC during this period, including 129 HIV-infected TB patients. Surprisingly, only 64 HIV-infected TB patients (50%) had a documented screening tuberculin skin test (TST) prior to TB diagnosis. Of the 39 HIV-infected TB patients with prior TST positivity, 38 (97.4%) had not completed a course of isoniazid preventive therapy. TB incidence decreased significantly in the HIV-infected population of BC over the study period, from 1.9 to 0.5 TB cases per 1,000 HIV-infected individuals (p<0.001).CONCLUSION: The incidence of HIV-TB decreased significantly over the past decade despite suboptimal latent TB infection screening and prevention practices. This decrease in TB incidence is likely attributable to the increased uptake of HAART. Consideration should be given to intensifying prevention efforts to accelerate TB elimination in HIV-infected populations in low-incidence regions.RésuméOBJECTIF : Avant l’avènement de la thérapie antirétrovirale hautement active (TAHA), la tuberculose progressive était l’un des principaux facteurs de morbidité et de mortalité liées au VIH au Canada et dans d’autres régions à faible incidence. Notre étude visait à examiner l’incidence de la tuberculose, ses manifestations cliniques et le recours au dépistage chez les patients tuberculeux infectés par le VIH à l’ère de la TAHA.MÉTHODE : Nous avons mené une étude rétrospective de tous les patients tuberculeux infectés par le VIH en Colombie-Britannique sur une période de 10 ans (2003–2012). Nous avons extrait leurs caractéristiques démographiques et cliniques, ainsi que les données sur le dépistage et les effets du traitement. Nous avons aussi examiné les tendances de l’incidence de la tuberculose, du dépistage du VIH et de la prévalence de la TAHA dans la province.RÉSULTATS : En tout, 2 839 cas de tuberculose ont été signalés en C.-B. au cours de la période, dont 129 patients tuberculeux infectés par le VIH. Étonnamment, seuls 64 patients tuberculeux infectés par le VIH (50 %) avaient subi un test cutané à la tuberculine (TCT) consigné en dossier avant leur diagnostic de tuberculose. Sur les 39 patients tuberculeux infectés par le VIH ayant eu un TCT positif au préalable, 38 (97,4 %) n’avaient pas suivi un traitement préventif complet à l’isoniazide. L’incidence de la tuberculose a considérablement diminué dans la population infectée par le VIH en C.-B. au cours de la période de l’étude, passant de 1,9 à 0,5 cas de tuberculose pour 1 000 personnes infectées par le VIH (p<0,001).CONCLUSION : L’incidence de la comorbidité VIH-tuberculose a considérablement diminué au cours de la dernière décennie malgré les pratiques sous-optimales de prévention et de dépistage de la tuberculose latente. Cette incidence réduite de la tuberculose est probablement imputable au recours accru à la TAHA. Il faudrait envisager d’intensifier les efforts de prévention afin d’accélérer l’élimination de la tuberculose au sein des populations infectées par le VIH dans les régions à faible incidence.