The MOBILISE study: utilisation of ambulatory pumps in the inpatient setting to administer continuous antibiotic infusions-a randomised controlled trial.

In the inpatient setting, antibiotics are generally administered via bedside pumps with multiple daily dosing. Utilisation of a continuous antibiotic infusion (CAI) instead might have patient and nursing satisfaction, workflow efficiencies and infection control benefits. We aimed to study the utilisation of CAI in the inpatient setting for routine antibiotic administration. Patients receiving a peripherally inserted central venous catheter (PICC) for antibiotic administration were screened for the study. The patients were randomised to either (1) standard pump and intermittent antibiotic administration (IAA) or (2) CAI via an ambulatory pump. An accelerometer placed on the ankle was used to assess patient activity. Nursing and patient satisfaction surveys were also carried out. Forty patients met the study criteria for enrolment with 21 patients being enrolled in the CAI arm of the study. One hundred and five days of accelerometer recordings were available for analysis. The geometric mean activity was 45 min/day in the standard arm and 64 min/day in the CAI arm. This represented a 42% (95% CI: -14 to 133%, p = 0.16) difference in activity between the two groups. Nursing staff reported that they spent less time throughout their shift attending the antibiotic line or pump in patients who were in the CAI arm of the study (p < 0.001). In addition, patients in this arm of the study were more likely to recommend this method of administration of antibiotics to a family member (p =0.0001). The MOBILISE study showed nursing and patient satisfaction when CAI were utilised in the inpatient setting. A statistically non-significant difference in mobility was seen. The trial was registered (28/03/2018) with the Australia New Zealand Clinical Trials Registry (ACTRN12618000452291).

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.

Measuring patient-centred long-term outcome following a bloodstream infection: a pilot study.

OBJECTIVES: To evaluate the sequential organ failure assessment (SOFA) and modified SOFA (mSOFA) scoring and a novel performance score based on the Karnofsky score for measuring outcome following a bloodstream infection (BSI). METHOD: This prospective observational cohort study assessed patients with BSI for mortality and functional outcomes with a novel performance score: the functional bloodstream infection score (FBIS). We also tested the SOFA and, given the difficulties with measuring SOFA on ward-based patients, the mSOFA over the first 7 days following a BSI for their association with outcomes. RESULTS: One hundred participants were prospectively recruited. Mortality at 52 weeks following BSI was 21% (21/100). Only 57% of survivors (39/69) were at their baseline functional status at 52 weeks. Stable or improved SOFA/mSOFA over the first 7 days was associated with survival and return to premorbid performance score (risk ratio 3.2, 95%CI 1.3-9.4, p < 0.01). CONCLUSIONS: The acute change in SOFA/mSOFA was associated with 52-week survival and return to premorbid functional performance. The FBIS measurement represents a simple and easy-to-apply measure of functional performance for patients with BSI and was associated with a high response rate (89%) from participants.

Activity of ceftolozane/tazobactam against a collection of Pseudomonas aeruginosa isolates from bloodstream infections in Australia.

Pseudomonas aeruginosa is a common pathogen causing nosocomial infection. In particular, bloodstream infection (BSI) is associated with a high rate of morbidity and mortality. Ceftolozane/tazobactam is a new ß-lactam/ß-lactamase antimicrobial with activity against P. aeruginosa as well as multidrug resistant (MDR) Gram negative Enterobacteriaceae. Ceftolozane/tazobactam has frequently been used in salvage therapy for MDR P. aeruginosa infections. The aim of this study was to determine the activity of ceftolozane/tazobactam against P. aeruginosa isolates from BSIs collected from three clinical microbiology laboratories in Queensland, Australia, with a high proportion of isolates demonstrating ß-lactam resistance. Antimicrobial susceptibility testing was performed by broth microdilution using custom made sensititre plates sourced from ThermoFisher Scientific. In addition to ceftolozane/tazobactam, we also tested piperacillin/tazobactam, ceftazidime, cefepime, meropenem, doripenem, imipenem, aztreonam, ciprofloxacin, levofloxacin, gentamicin, amikacin, tobramycin and colistin. Overall, ceftolozane/tazobactam was the most active agent tested [(MIC50/90 = 1/2 µg/mL, 96% susceptible (S)]. Against 44 isolates with resistance to at least one other ß-lactam agent, 40 were susceptible to ceftolozane/tazobactam. Three ceftolozane/tazobactam resistant isolates were susceptible to colistin, with one of those isolates also susceptible to levofloxacin but not to any other antimicrobials tested. One ceftolozane/tazobactam resistant isolate was susceptible only to meropenem and doripenem but was non-susceptible to imipenem. An association was found between fluoroquinolone resistance and aminoglycoside resistance but not with ß-lactam resistance. In summary, ceftolozane/tazobactam was active against most strains tested, including those resistant to other ß-lactams. Laboratories should consider testing P. aeruginosa against ceftolozane/tazobactam in suspected MDR or extensively drug resistant (XDR) infections.

Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum ß-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E. METHODS: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical-therapy and targeted-therapy cohorts. RESULTS: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. ß-lactam/ß-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy. CONCLUSIONS: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome.

P. aeruginosa blood stream infection isolates: A "full house" of virulence genes in isolates associated with rapid patient death and patient survival.

We have recently characterised the epidemiology of P. aeruginosa blood stream infection (BSI) in a large retrospective multicentre cohort study [1]. Utilising corresponding patient BSI isolates we aimed to characterise the genotypic virulence profile of the P. aeruginosa isolates that were associated with rapid death in the non-neutropenic host. Five P. aeruginosa BSI episodes were identified from a larger cohort of P. aeruginosa BSI episodes previously described by McCarthy et al. [1]. The genotypic profile of another 5 isolates from this cohort in whom the non-neutropenic host had survived one year post the BSI was also analysed for comparison. These isolates underwent Illumina whole genome sequencing, de novo assembly and annotation. A comprehensive suite of virulence genes was collated from the Pseudomonas Genome Database (http://www.pseudomonas.com/) and were searched by BLAST based analysis in assemblies of all BSI isolates [2]. There was extensive conservation of virulence genes across all of the BSI isolates studied. The exoU gene was found in two isolates from patients who died rapidly and in one isolate from a patient that survived one year post BSI. The higA and higB genes were detected in all isolates. The exlA gene was not detected in any of the isolates studied. These findings suggest that to cause a BSI that it is only the virulent P. aeruginosa isolate that succeeds. The virulence gene profile seen was independent of patient outcome. Further phenotypic correlation is required to determine if there is any difference in genotypic expression by the BSI isolates that were associated with rapid death of the host and those BSI isolates associated with host survival at one year.

New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

BACKGROUND: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. AIMS: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms. SOURCES: A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies. CONTENT: Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the ß-lactam/ß-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline. IMPLICATIONS: The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-ß-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.

Draft Genome Sequences of Two Pseudomonas aeruginosa Bloodstream Infection Isolates Associated with Rapid Patient Death.

The morbidity and mortality associated with Pseudomonas aeruginosa bloodstream infections are significant. New strategies are required to treat such infections. We report here the draft genome sequences of two antibiotic-sensitive P. aeruginosa bloodstream infection isolates that were associated with rapid death in nonneutropenic patients.

Pseudomonas aeruginosa blood stream infection isolates from patients with recurrent blood stream infection: Is it the same genotype?

The type identity of strains of Pseudomonas aeruginosa from primary and recurrent blood stream infection (BSI) has not been widely studied. Twenty-eight patients were identified retrospectively from 2008 to 2013 from five different laboratories; available epidemiological, clinical and microbiological data were obtained for each patient. Isolates were genotyped by iPLEX MassARRAY MALDI-TOF MS and rep-PCR. This showed that recurrent P. aeruginosa BSI was more commonly due to the same genotypically related strain as that from the primary episode. Relapse due to a genotypically related strain occurred earlier in time than a relapsing infection from an unrelated strain (median time: 26 vs. 91 days, respectively). Line related infections were the most common source of suspected BSI and almost half of all BSI episodes were associated with neutropenia, possibly indicating translocation of the organism from the patient's gut in this setting. Development of meropenem resistance occurred in two relapse isolates, which may suggest that prior antibiotic therapy for the primary BSI was a driver for the subsequent development of resistance in the recurrent isolate.

Draft Genome Sequence of an IMP-7-Producing Pseudomonas aeruginosa Bloodstream Infection Isolate from Australia.

IMP-7 is one of the two IMP-type carbapenemases that in Pseudomonas aeruginosa are not limited to a geographic area, but it has not been previously reported in the Australian setting. We report here the draft genome sequence of an Australian P. aeruginosa bloodstream infection isolate that contains IMP-7.

Increased risk of death with recurrent Pseudomonas aeruginosa bacteremia.

This study aimed to characterize recurrent Pseudomonas aeruginosa blood stream infection (BSI). Positive blood cultures for P. aeruginosa were identified over a 3-year period from seven tertiary care hospitals. Patients with recurrent BSI were identified. Extensive epidemiological, clinical and outcome data were obtained. BSI recurrence was found to be uncommon with 9% of patients having a first relapse of BSI. Fourteen percent of these patients went on to have a second relapse of BSI. Significant variables associated with recurrence were the presence of a hematological malignancy or receiving recent corticosteroid therapy. Exposure to anti-pseudomonal beta-lactam therapy in the 30days prior to the BSI was more likely in the patient with the recurrent BSI episode. Recurrence was associated with increased mortality when compared to the primary BSI episode. Knowledge of a patient's prior antibiotic therapy may be useful in ensuring effective empirical therapy in the recurrent BSI episode.

Long-term mortality following Pseudomonas aeruginosa bloodstream infection.

BACKGROUND: Pseudomonas aeruginosa bloodstream infections (BSI) are associated with substantial short-term mortality. There is little data on long-term mortality associated with this BSI. AIM: To describe mortality rates up to one year post infection and the significant factors associated with death. METHODS: Positive blood cultures for P. aeruginosa were identified retrospectively from January 2008 to January 2011 at seven tertiary care hospitals. Extensive epidemiological, clinical and outcome data were obtained. FINDINGS: Three hundred and eighty-eight BSI episodes were included in the analysis. The majority of infections were hospital acquired. The most common patient comorbidities were haematological or oncological. Seventy-eight percent of the cohort had a medical device in situ in the preceding seven days. Sixty-one percent of the cohort received adequate empirical therapy. All-cause mortality was 4% at 48 h, 19% at one month and 38% at one year. Forty-eight-hour mortality was associated with non-hospital-acquired infection, pulmonary comorbidity, recent corticosteroid therapy, and a Pitt bacteraemia score >2. Comorbidities became significantly associated with mortality from seven days post infection. Long-term mortality (defined as mortality at one year) was associated with female sex, haematological or oncological comorbidity, a Charlson comorbidity index >2 and recent corticosteroid therapy. CONCLUSION: The exact role of infection, from this highly virulent pathogen, in the cause of death over time needs to be studied further. It is not clear if patients are dying from or with P. aeruginosa BSI.

Community-acquired Pseudomonas aeruginosa bloodstream infection: a classification that should not falsely reassure the clinician.

Pseudomonas aeruginosa bloodstream infection (BSI) is predominantly acquired in the hospital setting. Community-onset infection is less common. Differences in epidemiology, clinical features, microbiological factors and BSI outcomes led to the separation of bacterial community-onset BSI into the categories of healthcare-associated infection (HCAI) and community-acquired infection (CAI). Community-acquired P. aeruginosa BSI epidemiology is not well defined in the literature. In addition, it is also not clear if the same factors separate CAI and HCAI BSI caused by P. aeruginosa alone. A retrospective multicentre cohort study was performed looking at P. aeruginosa BSI from January 2008 to January 2011. Strict definitions for HCAI and CAI were applied. Extensive epidemiological, clinical and outcome data were obtained. Thirty-four CAI episodes and 156 HCAI episodes were analysed. The CAI group could be characterised into seven distinct categories based on comorbidities and clinically suspected source of infection. A pre-morbidly healthy group could not be identified. On multivariate analysis, the presence of a rheumatological or a gastrointestinal comorbidity were significantly associated with CAI. There was no significant difference in length of stay or rates of mortality between HCAI or CAI. The clinician should not be falsely reassured regarding outcome by the diagnosis of a community-acquired P. aeruginosa BSI.

Asymptomatic Clostridium difficile colonization in two Australian tertiary hospitals, 2012-2014: prospective, repeated cross-sectional study.

OBJECTIVES: To investigate the prevalence and risk factors for asymptomatic toxigenic (TCD) and nontoxigenic Clostridium difficile (NTCD) colonization in a broad cross section of the general hospital population over a 3-year period. METHODS: Patients without diarrhoea admitted to two Australian tertiary hospitals were randomly selected through six repeated cross-sectional surveys conducted between 2012 and 2014. Stool specimens were cultured under anaerobic conditions, and C. difficile isolates were tested for the presence of toxin genes and ribotyped. Patients were then grouped into noncolonized, TCD colonized or NTCD colonized for identifying risk factors using multinomial logistic regression models. RESULTS: A total of 1380 asymptomatic patients were enrolled; 76 patients (5.5%) were TCD colonized and 28 (2.0%) were NTCD colonized. There was a decreasing annual trend in TCD colonization, and asymptomatic colonization was more prevalent during the summer than winter months. TCD colonization was associated with gastro-oesophageal reflux disease (relative risk ratio (RRR) = 2.20; 95% confidence interval (CI) 1.17-4.14), higher number of admissions in the previous year (RRR = 1.24; 95% CI 1.10-1.39) and antimicrobial exposure during the current admission (RRR = 2.78; 95% CI 1.23-6.28). NTCD colonization was associated with chronic obstructive pulmonary disease (RRR = 3.88; 95% CI 1.66-9.07) and chronic kidney failure (RRR = 5.78; 95% CI 2.29-14.59). Forty-eight different ribotypes were identified, with 014/020 (n = 23), 018 (n = 10) and 056 (n = 6) being the most commonly isolated. CONCLUSIONS: Risk factors differ between patients with asymptomatic colonization by toxigenic and nontoxigenic strains. Given that morbidity is largely driven by toxigenic strains, this novel finding has important implications for disease control and prevention.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Return to sender: the need to re-address patient antibiotic allergy labels in Australia and New Zealand.

BACKGROUND/AIM: Antibiotic allergies are frequently reported and have significant impacts upon appropriate prescribing and clinical outcomes. We surveyed infectious diseases physicians, allergists, clinical immunologists and hospital pharmacists to evaluate antibiotic allergy knowledge and service delivery in Australia and New Zealand. METHODS: An online multi-choice questionnaire was developed and endorsed by representatives of the Australasian Society of Clinical Immunology and Allergy (ASCIA) and the Australasian Society of Infectious Diseases (ASID). The 37-item survey was distributed in April 2015 to members of ASCIA, ASID, the Society of Hospital Pharmacists of Australia and the Royal Australasian College of Physicians. RESULTS: Of 277 respondents, 94% currently use or would utilise antibiotic allergy testing (AAT) and reported seeing up to 10 patients/week labelled as antibiotic-allergic. Forty-two per cent were not aware of or did not have AAT available. Most felt that AAT would aid antibiotic selection, antibiotic appropriateness and antimicrobial stewardship (79, 69 and 61% respectively). Patients with the histories of immediate hypersensitivity were more likely to be referred than those with delayed hypersensitivities (76 vs 41%, P = 0.0001). Lack of specialist physicians (20%) and personal experience (17%) were barriers to service delivery. A multidisciplinary approach was a preferred AAT model (53%). Knowledge gaps were identified, with the majority overestimating rates of penicillin/cephalosporin (78%), penicillin/carbapenem (57%) and penicillin/monobactam (39%) cross-reactivity. CONCLUSIONS: A high burden of antibiotic allergy labelling and demand for AAT is complicated by a relative lack availability or awareness of AAT services in Australia and New Zealand. Antibiotic allergy education and deployment of AAT, accessible to community and hospital-based clinicians, may improve clinical decisions and reduce antibiotic allergy impacts. A collaborative approach involving infectious diseases physicians, pharmacists and allergists/immunologists is required.

Evaluation of a new chromogenic medium, chromID OXA-48, for recovery of carbapenemase-producing Enterobacteriaceae from patients at a university hospital in Turkey.

The purpose of this study was to evaluate a new chromogenic medium, chromID OXA-48, for the isolation of carbapenemase-producing Enterobacteriaceae (CPE) directly from rectal swabs. chromID CARBA and chromID OXA-48 are two chromogenic media that have been commercialized for the isolation of CPE directly from clinical samples. Both media were evaluated alongside a broth enrichment method recommended by the CDC for isolation of CPE, with rectal swabs from 302 unique hospitalized patients at the Hacettepe University Hospital, Ankara, Turkey. A total of 33 patients (11 %) were found to be colonized with CPE using a combination of all methods, and all CPE produced OXA-48 carbapenemase. Klebsiella pneumoniae was by far the most dominant species of CPE and was isolated from 31 patients. Culture on chromID OXA-48 offered the highest sensitivity (75.8 %) for detection of CPE compared with the other two methods (sensitivity for both other methods was 57.6 %) and also offered the highest specificity (99.3 %). However, a combination of methods (either chromID OXA-48 plus CDC method or chromID OXA-48 plus chromID CARBA) was necessary to achieve an acceptable sensitivity (90.9 %). For isolation of CPE, in a setting where OXA-48 carbapenemase is the dominant type of carbapenemase, chromID OXA-48 is a highly useful medium but using a combination of methods is optimal for adequate detection. The combined use of two chromogenic media offered acceptable sensitivity (90.9 %) and the highest specificity (98.5 %) and also allowed for isolation of CPE within 18-20 h.

Legionellosis and biologic therapies.

BACKGROUND: Biologic therapies are widely used in inflammatory diseases, and they are associated to an increased infection risk, especially to granulomatous and intracellular infections such as Legionella. RESULTS: A review of the literature revealed 105 cases of Legionella pneumonia in patients taking biologic therapies. Sixty-four patients (65.3%) were treated with infliximab, 23 (23.5%) with adalimumab, 5 (5%) with etanercept and 3 (3%) with rituximab. Seventy-one per cent of the patients were treated for rheumatologic diseases and 16% for inflammatory bowel diseases. The majority of the patients received one or more concomitant immunosuppressive drugs, especially steroids (43%). Overall mortality was 19%. Legionella pneumonia might complicate therapy with biologic therapies, especially in patients being treated with infliximab or adalimumab given concomitantly with other immunosuppressive medications during their first 6 months of treatment. CONCLUSION: Physicians should be aware of this potentially severe association. Early recognition and treatment would likely result in reduced morbidity and mortality.