Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Fever as a predictor of adverse outcomes in COVID-19.

BACKGROUND/INTRODUCTION: There are little data on outcomes of COVID-19 patients with the presence of fever compared to the presence of symptoms. AIM: We examined the associations between symptomology, presence of fever and outcomes of a COVID-19 cohort. DESIGN AND METHODS: Between 23 January and 30 April 2020, 554 COVID-19 patients were admitted to a tertiary hospital in Singapore. They were allocated into four groups based on symptomology and fever-Group 1: asymptomatic and afebrile, Group 2: symptomatic but afebrile, Group 3: febrile but asymptomatic and Group 4: symptomatic and febrile. The primary outcomes were intensive care unit (ICU) admissions and mortality. The composite end-point included ICU admissions, mortality or any COVID-19 related end-organ involvement. RESULTS: There were differences in ferritin (P=0.003), C-reactive protein (CRP) levels (P<0.001) and lymphopenia (P=0.033) across all groups, with the most favourable biochemical profile in Group 1, and the least in Group 4. Symptomatic groups (Groups 2 and 4) had higher ICU admissions (1.9% and 6.0%, respectively, P=0.003) than asymptomatic groups (Groups 1 and 3). Composite end-point was highest in Group 4 (24.0%), followed by Group 3 (8.6%), Group 2 (4.8%) and Group 1 (2.4%) (P<0.001). The presence of fever (OR 4.096, 95% CI 1.737-9.656, P=0.001) was associated with the composite end-point after adjusting for age, pulse rate, comorbidities, lymphocyte, ferritin and CRP. Presence of symptoms was not associated with the composite end-point. DISCUSSION/CONCLUSION: In this COVID-19 cohort, presence of fever was a predictor of adverse outcomes. This has implications on the management of febrile but asymptomatic COVID-19 patients.

Inferring super-spreading from transmission clusters of COVID-19 in Hong Kong, Japan, and Singapore.

Super-spreading events in an outbreak can change the nature of an epidemic. Therefore, it is useful for public health teams to determine whether an ongoing outbreak has any contribution from such events, which may be amenable to interventions. We estimated the basic reproductive number (R0) and the dispersion factor (k) from empirical data on clusters of epidemiologically linked coronavirus disease 2019 (COVID-19) cases in Hong Kong, Japan and Singapore. This allowed us to infer the presence or absence of super-spreading events during the early phase of these outbreaks. The relatively large values of k implied that large cluster sizes, compatible with super-spreading, were unlikely.

The socio-economic impact of multidrug-resistant nosocomial infections: a qualitative study.

The burden of healthcare-associated infections (HCAIs) has traditionally been measured using clinical and economic outcomes. We conducted semi-structured interviews with 18 patients or their caregivers affected by HCAI caused by multidrug-resistant organisms to better understand the human impact of HCAI. Most patients had misconceptions about HCAI and antimicrobial resistance, leading to strong negative feelings towards HCAIs despite positive views of their healthcare providers. Communication issues across power imbalances need to be addressed to help deal with trauma of HCAIs. A holistic approach to HCAIs incorporating patient perspectives will likely help guide policymakers developing solutions to improve patient outcomes.

Extraintestinal Salmonellosis in the Immunocompromised: An Unusual Case of Pyomyositis.

Salmonella infection can cause a wide range of presentations, predominantly gastrointestinal but occasionally with cardiovascular or other extraintestinal manifestations. The diagnosis of extraintestinal salmonellosis requires a high degree of clinical suspicion and should be considered in patients with deep-seated abscesses especially if they are immunocompromised. We present a case of salmonella causing gastroenteritis complicated by an intramuscular abscess of the left leg. With prompt recognition and multidisciplinary management, the patient recovered with no serious sequela.

An in-vitro urinary catheterization model that approximates clinical conditions for evaluation of innovations to prevent catheter-associated urinary tract infections.

BACKGROUND: Catheter-associated urinary tract infections (CAUTI) account for approximately 25% of nosocomial infections globally, and often result in increased morbidity and healthcare costs. An additional concern is the presence of microbial biofilms which are major reservoirs of bacteria, especially antibiotic-resistant bacteria, in catheters. Since introduction of the use of closed drainage systems, innovations to combat CAUTI have not led to significant improvements in clinical outcomes. The lack of a robust laboratory platform to test new CAUTI preventive strategies may impede development of novel technologies. AIM: To establish an in-vitro catheterization model (IVCM) for testing of technological innovations to prevent CAUTI. METHODS: The IVCM consists of a continuous supply of urine medium flowing into a receptacle (bladder) where the urine is drained through a urinary catheter connected to an effluent collection vessel (drainage bag). Test organism(s) can be introduced conveniently into the bladder via a rubber septa port. Development of bacteriuria and microbial biofilm on the catheter can be determined subsequently. FINDINGS: With an initial inoculum of Escherichia coli [∼5×105 colony-forming units (cfu)/mL] into the bladder, a 100% silicone catheter and a commercially available silver-hydrogel catheter showed heavy biofilm colonization (∼108 cfu/cm and ∼107 cfu/cm, respectively) with similar bacterial populations in the urine (bacteriuria) (∼108 cfu/mL and ∼107 cfu/mL, respectively) within three days. Interestingly, an antimicrobial peptide (CP11-6A)-coated catheter showed negligible biofilm colonization and no detectable bacteriuria. CONCLUSION: The IVCM is a useful preclinical approach to evaluate new strategies for the prevention of CAUTI.

Outpatient parenteral antibiotic therapy in Singapore.

Outpatient parenteral antibiotic therapy (OPAT) remains in its infancy in Singapore, with the first patients enrolled 4 years ago. Singapore's three largest hospitals, with over 3000 inpatient beds, now have designated and approved OPAT services. This study reviews the demographic, clinical and cost data of all patients enrolled in 2005 to facilitate benchmarking between services in Singapore and abroad and also to identify common needs for further development. In 2005, 225 OPAT enrollments in 208 different patients resulted in 4050 days of OPAT care. Orthopaedic diagnoses constituted 40% of admissions. Vancomycin was the most frequently used antibiotic (34%). The re-admission rate was 8.9%, but complications of OPAT care were only occasionally implicated. An estimated $207,200 was saved by patients despite there being significant financial disincentives to subsidised patients. OPAT is a safe, cost-efficient system that is becoming increasingly accepted in Singapore by patients, clinicians and management. Our three services have evolved independently into very similar practices. There is potential for further innovation, including outreach and carer-delivered dosing. However, major financial disincentives require review.

Practical management of avian influenza in humans.

There has been much alarm about avian influenza and its potential for a global pandemic ever since the current epidemic of avian influenza infections in humans began in 2003. While there have been a number of published reports on the clinical features of avian influenza, there are few guidelines on the practical management of patients with avian influenza. A symposium organised by the Society of Infectious Disease (Singapore), Society of Intensive Care Medicine and the Singapore General Hospital was held in Singapore to gather the views of experts from Turkey, Thailand, Vietnam and Indonesia who collectively had first-hand experience of the management of the majority (more than 100 of 192) of cases of avian influenza worldwide. The experts emphasised the importance of adapting international guidelines to the practicalities of situations on the ground. There was stress on wide screening using clinical criteria primarily, molecular diagnostic techniques (with reference laboratory confirmation) for diagnosis, and rational use of antiviral prophylaxis as well as infection control using at least surgical masks, gowns and gloves. A detailed analysis of data from a pooled database from these and other affected countries is critical to building up the evidence base for practical internationally applicable guidelines.

Use of erythrocyte sedimentation rate and C-reactive protein to predict osteomyelitis recurrence.

PURPOSE: To determine the association between both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and osteomyelitis recurrence. METHODS: Records of 81 males and 27 females aged 10 to 87 (median, 54) years who underwent antibiotic/ surgical treatment for primary (n=68) or recurrent (n=40) osteomyelitis that was related (n=26) or unrelated (n=82) to a prosthesis were reviewed. Of the 40 cases of osteomyelitis recurrence followed up for a median of 23.4 (range, 0.6-74.0) months, 7 and 33 were related and unrelated to a prosthesis, respectively. The cutoff points of lowest ESR and CRP for osteomyelitis recurrence were calculated. Risk factors for osteomyelitis recurrence were determined. RESULTS: Osteomyelitis recurrence was associated with diabetes mellitus, ischaemic heart disease, non-healing wound, infection in the lower limb, and infection with methicillin-resistant Staphylococcus aureus. The cutoff points of CRP ≥5 mg/l and ESR ≥20 mm/h were used for osteomyelitis recurrence. Risk factors for osteomyelitis recurrence were ESR ≥20 mm/h, infection with methicillin-resistant S aureus, and infection in the lower limb. CONCLUSION: ESR was more sensitive, specific, and independently associated with osteomyelitis recurrence and should be used to guide the duration of antibiotic treatment.

Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis.

The influenza virus infects millions of people each year and can result in severe complications. Understanding virus recognition and host responses to influenza infection will enable future development of more effective anti-viral therapies. Previous research has revealed diverse yet important roles for the annexin family of proteins in modulating the course of influenza A virus (IAV) infection. However, the role of Annexin-A1 (ANXA1) in IAV infection has not been addressed. Here, we show that ANXA1 deficient mice exhibit a survival advantage, and lower viral titers after infection. This was accompanied with enhanced inflammatory cell infiltration during IAV infection. ANXA1 expression is increased during influenza infection clinically, in vivo and in vitro. The presence of ANXA1 enhances viral replication, influences virus binding, and enhances endosomal trafficking of the virus to the nucleus. ANXA1 colocalizes with early and late endosomes near the nucleus, and enhances nuclear accumulation of viral nucleoprotein. In addition, ANXA1 enhances IAV-mediated apoptosis. Overall, our study demonstrates that ANXA1 plays an important role in influenza virus replication and propagation through various mechanisms and that we predict that the regulation of ANXA1 expression during IAV infection may be a viral strategy to enhance its infectivity.

Paraneoplastic progressive supranuclear palsy syndrome in a patient with B-cell lymphoma.

An important component in the diagnosis of atypical parkinsonian disorders is the exclusion of secondary causes. Paraneoplastic causes of parkinsonism are extremely rare. We describe a case which presented initially as probable progressive supranuclear palsy (PSP) but on follow-up displayed a rapidly progressive course, unexplained fever, peripheral neuropathy and an abnormal CSF. We highlight the difficulties faced in formulating a diagnosis for this unusual case prior to the discovery of an occult B-cell lymphoma, and discuss its relevance in the exclusion criteria for PSP. A paraneoplastic cause should be considered if disease progression is unusually rapid.

The relationship between pyuria and infection in patients with indwelling urinary catheters: a prospective study of 761 patients.

BACKGROUND: Pyuria is universally considered as essential for identifying urinary tract infections in noncatheterized patients. The utility of pyuria in the catheterized patient, to identify catheter-associated urinary tract infection (CAUTI), has not been adequately defined. METHODS: We prospectively studied 761 newly catheterized patients in a university hospital; 82 (10.8%) developed nosocomial CAUTI (> 10(3) colony-forming units per milliliter). While catheterized, each patient was seen daily, a quantitative urine culture was obtained, and the urine white blood cell concentration was measured quantitatively using a hemocytometer. RESULTS: The mean urine leukocyte count in patients with CAUTI was significantly higher than in patients without infections (71 vs 4 per microliter; P= .006). Pyuria was most strongly associated with CAUTI caused by gram-negative bacilli (white blood cell count, 121 vs 4 per microliter; P = .03); infection with coagulase-negative staphylococci and enterococci (white blood cell count, 39 vs 4 per microliter; P = .25) or yeasts (white blood cell count, 25 vs 4 per microliter; P = .15) produced much less pyuria. Pyuria with a white blood cell count greater than 10 per microliter (>5 per high-power field in a conventional urinalysis) had a specificity of 90% for predicting CAUTI with greater than 10(5) colony-forming units per milliliter but a sensitivity of only 37%. CONCLUSIONS: In patients with short-term indwelling urinary catheters, pyuria is less strongly correlated with CAUTI than in noncatheterized patients with urinary tract infection. The strongest association is with CAUTI caused by gram-negative bacilli; the association is far weaker for infections caused by gram-positive cocci or yeasts. Most patients with CAUTI are asymptomatic and do not have associated fever. Pyuria should not be used as the sole criterion to obtain a urine culture in a patient with a catheter.

Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients.

BACKGROUND: Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection, accounting for more than 1 million cases each year in US hospitals and nursing homes. OBJECTIVE: To define the clinical features of CAUTI. SETTING AND PATIENTS: A university hospital; 1,497 newly catheterized patients. DESIGN: Every day that the catheter was in place, a quantitative urine culture and urine leukocyte count were obtained, and the patient was queried by a research worker regarding symptoms. To more precisely define the role of CAUTI in patients' symptoms, a subset of 1,034 patients, 89 of whom developed CAUTI with more than 10(3) colony-forming units per milliliter, who did not have another potentially confounding site of infection besides the urinary tract, was analyzed. OUTCOME MEASURES: Presence of fever, symptoms commonly associated with community-acquired urinary tract infection, and peripheral leukocytosis. RESULTS: There were 235 new cases of nosocomial CAUTI during the study period. More than 90% of the infected patients were asymptomatic; only 123 infections (52%) were detected by patients' physicians using the hospital laboratory. In the subset analysis, there were no significant differences between patients with and without CAUTI in signs or symptoms commonly associated with urinary tract infection-fever, dysuria, urgency, or flank pain-or in leukocytosis. Only 1 of the 235 episodes of CAUTI that were prospectively studied was unequivocally associated with secondary bloodstream infection. CONCLUSIONS: Whereas CAUTIs are a major reservoir of antibiotic-resistant organisms in the hospital, they are rarely symptomatic and infrequently cause bloodstream infection. Symptoms referable to the urinary tract, fever, or peripheral leukocytosis have little predictive value for the diagnosis of CAUTI.

Selection of medical students in Singapore: a historical perspective.

The selection of medical students in Singapore has been a contentious issue for more than 140 years. Initially, students were selected for Madras Medical College, the traditional source for medical officers in early Singapore, by a combination of an examination as well as an observed preceptorship at the General Hospital. With the establishment of the medical school in Singapore in 1905, the selection criteria have been progressively refined over the years. These have included a baseline academic threshold, linguistic competence and performance at an interview. In the past, other criteria such as gender and political suitability were important but at the present, only hepatitis B virologic status is a limiting factor for otherwise qualified applicants. Singapore's Ministry of Health reports an attrition rate of 10% from our medical school. This poses a challenge as there are far more qualified applicants for medical school in Singapore than there are places. This is a worldwide problem and locally, attempts are being made to further refine the admission process to ensure that the community as a whole is best served by the future doctors we select.

Tuberculosis post-liver transplantation: a rare but complicated disease.

INTRODUCTION: Tuberculosis is a rare but serious complication after transplantation. We report a case and discuss its presentation and management. CLINICAL PICTURE: A 60-year-old Indonesian male presented initially with fever, acute confusion and rapidly progressive right upper lobe pneumonia 3.5 months post-liver transplant, and was diagnosed with pulmonary tuberculosis by positive sputum smear for acid-fast bacilli and tuberculosis culture. TREATMENT/OUTCOME: Standard anti-tuberculosis therapy was administered but was complicated by interaction with cyclosporine and drug-induced cholestasis. CONCLUSION: A high level of suspicion, prompt antituberculosis treatment and close follow-up are essential in management of post-transplant tuberculosis.

A prospective study of pathogenesis of catheter-associated urinary tract infections.

OBJECTIVE: To determine the pathogenesis of catheter-associated urinary tract infection (CAUTI) and the relative importance of each of the possible mechanisms of entry of infecting microorganisms to the catheterized urinary tract. MATERIAL AND METHODS: We conducted a prospective study of 1,497 newly catheterized patients. Paired quantitative urine cultures were obtained daily, from the catheter specimen port and from the collection bag, using a technique that could detect 1 colony-forming unit/mL. We assumed that with extraluminal infections, caused by microorganisms ascending from the perineum in the mucous film contiguous to the external surface of the catheter, the organisms would be detected first in bladder urine or in far higher concentrations in urine from the specimen port than from the collection bag. With intraluminal CAUTIs, caused by microorganisms gaining access to the catheter lumen because of failure of closed drainage or contamination of collection bag urine, the organisms would be detected first or in far larger numbers in a collection bag specimen. RESULTS: The probable mechanism of infection could be determined for 173 of 250 organisms (69.2 %) identified in 235 new-onset CAUTIs. Among these 173 cases, 115 (66%) were extraluminally acquired, and 58 (34%) were derived from intraluminal contaminants. For these determinable cases, CAUTIs caused by gram-positive cocci (enterococci and staphylococci) and yeasts were far more likely to be extraluminally acquired (extraluminal:intraluminal, 2.9) than were gram-negative bacilli, which caused CAUTIs by both routes equally (extraluminal: intraluminal, 1.2; P = 0.007). Surprisingly, no significant differences were noted in pathogenetic mechanisms between men and women. CONCLUSION: We conclude that, in both men and women, CAUTIs occur by both extraluminal and intraluminal portals of entry but derive preponderantly from organisms that gain access extraluminally. Strategies for prevention of CAUTIs must focus on new technologies to prevent access of organisms by all possible routes.

Diagnosis of nipah virus encephalitis by electron microscopy of cerebrospinal fluid.

BACKGROUND: between 1998 and 1999, an outbreak of potentially fatal viral encephalitis erupted among pig farm workers in West Malaysia, and later spread to Singapore where abattoir workers were afflicted. Although Japanese encephalitis virus was initially suspected, the predominant aetiologic agent was subsequently confirmed to be Nipah virus, a novel paramyxovirus related to but distinct from Hendra virus. OBJECTIVE: to describe a case of Nipah virus encephalitis in a pig farm worker from Malaysia. STUDY DESIGN: the clinical, laboratory and radiological findings of this patient were scrutinized. Special emphasis was placed on the electron microscopic analysis of the cerebrospinal fluid (CSF) specimen from this patient. RESULTS: the neurological deficits indicative of cerebellar involvement were supported by the magnetic resonance imaging that showed prominent cerebellar and brainstem lesions. CSF examination provided further evidence of viral encephalitis. Complement fixation and/or RT-PCR assays were negative for Japanese encephalitis, herpes simplex, measles and mumps viruses. ELISA for detecting IgM and IgG antibodies against Hendra viral antigens were equivocal for the CSF specimen, and tested initially negative for the first serum sample but subsequently positive for the repeat serum sample. Transmission electron microscopy of negatively-stained preparations of CSF revealed enveloped virus-like structures fringed with surface projections as well as nucleocapsids with distinctive helical and herringbone patterns, features consistent with those of other paramyxoviruses, including Hendra virus. CONCLUSION: this case report reiterates the relevant and feasible role of diagnostic electron microscopy for identifying and/or classifying novel or emerging viral pathogens for which sufficiently specific and sensitive tests are lacking.

Widespread resistance to new antimicrobials in a university hospital before clinical use.

The activity of cefpirome, cefepime and piperacillin/tazobactam previously unused in the hospital was evaluated in parallel with five broad-spectrum antibiotics (ceftazidime, ceftriaxone, imipenem, ciprofloxacin and amikacin) currently being used to treat serious infections in the National University Hospital, Singapore. Two hundred and two clinically significant, organisms consecutively isolated during 1998 were included in the study. In vitro efficacy of cefepime, cefpirome and piperacillin/tazobactam was not superior to imipenem, ciprofloxacin and amikacin which are currently used. More than 40% of Enterbacteriaceae were found to be ESBL producers. The incidence of nosocomial organisms resistant to drugs used in serious infections had increased since 1995. Imipenem-resistance occurred in 34.4% of Acinetobacter spp. and 19.2% Pseudomonas aeruginosa. No single agent appeared to be suitable for empirical monotherapy of serious sepsis.