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Staphylococcus epidermidis is a conspicuous member of the human microbiome, widely present on healthy skin. Here we show that S. epidermidis has also evolved to become a formidable nosocomial pathogen. Using genomics, we reveal that three multidrug-resistant, hospital-adapted lineages of S. epidermidis (two ST2 and one ST23) have emerged in recent decades and spread globally. These lineages are resistant to rifampicin through acquisition of specific rpoB mutations that have become fixed in the populations. Analysis of isolates from 96 institutions in 24 countries identified dual D471E and I527M RpoB substitutions to be the most common cause of rifampicin resistance in S. epidermidis , accounting for 86.6% of mutations. Furthermore, we reveal that the D471E and I527M combination occurs almost exclusively in isolates from the ST2 and ST23 lineages. By breaching lineage-specific DNA methylation restriction modification barriers and then performing site-specific mutagenesis, we show that these rpoB mutations not only confer rifampicin resistance, but also reduce susceptibility to the last-line glycopeptide antibiotics, vancomycin and teicoplanin. Our study has uncovered the previously unrecognized international spread of a near pan-drug-resistant opportunistic pathogen, identifiable by a rifampicin-resistant phenotype. It is possible that hospital practices, such as antibiotic monotherapy utilizing rifampicin-impregnated medical devices, have driven the evolution of this organism, once trivialized as a contaminant, towards potentially incurable infections. Genomic analysis uncovers global prevalence of three multidrug-resistant Staphylococcus epidermidis lineages encoding rifampicin resistance and reduced susceptibility to glycopeptide antibiotics.

Background. We identified 12 patients with Clostridium difficile infection between July 2011 and March 2012 from whom an unusual C. difficile strain was isolated. This strain had a single-nucleotide deletion of the tcdC gene at position 117 and binary toxin genes, which are characteristic of the hypervirulent ribotype (RT) 027 strain. Methods. A retrospective cohort study of 12 patients infected with C. difficile RT244 and 24 patients infected with non-RT244/non-RT027 strains matched for place of diagnosis and time of collection of specimen was performed. We performed whole-genome sequencing to understand the relationship of the RT244 strain to other C. difficile strains and further understand its virulence potential. Results. Clostridium difficile RT244 was associated with more severe disease and a higher mortality rate. Phylogenomic analysis using core genome single-nucleotide polymorphisms showed that RT244 is in the same genetic clade (clade 2) as RT027 but is distinct from all RT027 strains. The pathogenicity locus of the RT244 strain encodes a variant toxin B, and this was confirmed by demonstration of Clostridium sordellii–like cytopathic effect on Vero cells. Toxin B production in culture supernatants was lower than that seen with a RT027 strain. Conclusions. Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains.

Background. Longer-term morbidity and outcomes of Cryptococcus gattii infection are not described. We analyzed clinical, microbiological, and outcome data in Australian patients followed for 12 months, to identify prognostic determinants. Methods. Culture-confirmed C. gattii cases from 2000 to 2007 were retrospectively evaluated. Clinical, microbiological, radiological, and outcome data were recorded at diagnosis and at 6 weeks, 6 months, and 12 months. Clinical and laboratory variables associated with mortality and with death and/or neurological sequelae were determined. Results. Annual C. gattii infection incidence was 0.61 per 10 6 population. Sixty-two of 86 (72%) patients had no immunocompromise; 6 of 24 immunocompromised hosts had idiopathic CD4 lymphopenia, and 1 had human immunodeficiency virus/AIDS. Clinical and microbiological characteristics of infection were similar in immunocompromised and healthy hosts. Isolated lung, combined lung and central nervous system (CNS), and CNS only disease was reported in 12%, 51% and 34% of the cases, respectively. Complications in CNS disease included raised intracranial pressure (42%), hydrocephalus (30%), neurological deficits (27%; 6% developed during therapy) and immune reconstitutionlike syndrome (11%). Geometric mean serum cryptococcal antigen (CRAG) titers in CNS disease were 563.9 (vs 149.3 in isolated lung infection). Patient immunocompromise was associated with increased mortality risk. An initial cerebrospinal fluid CRAG titer of ≥256 predicted death and/or neurological sequelae (P = .05). Conclusions. Neurological C. gattii disease predominates in the Australian endemic setting. Lumbar puncture and cerebral imaging, especially if serum CRAG titers are ≥512, are essential. Long-term follow up is required to detect late neurological complications. Immune system evaluation is important because host immunocompromise is associated with reduced survival.

Although infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility (SA-RVS) have been reported from a number of countries, including Australia, the optimal therapy is unknown. We reviewed the clinical features, therapy, and outcome of 25 patients with serious infections due to SA-RVS in Australia and New Zealand. Eight patients had endocarditis, 9 had bacteremia associated with deep-seated infection, 6 had osteomyelitis or septic arthritis, and 2 had empyema. All patients had received vancomycin before the isolation of SA-RVS, and glycopeptide treatment had failed for 19 patients (76%). Twenty-one patients subsequently received active treatment, which was effective for 16 patients (76%). Eighteen patients received linezolid, which was effective in 14 (78%), including 4 patients with endocarditis. Twelve patients received a combination of rifampicin and fusidic acid. Surgical intervention was required for 15 patients (60%). Antibiotic therapy, especially linezolid with or without rifampicin and fusidic acid, in conjunction with surgical debulking is effective therapy for the majority of patients with serious infections (including endocarditis) caused by SA-RVS.

Background. Existing severity assessment tools, such as the pneumonia severity index (PSI) and CURB-65 (tool based on confusion, urea level, respiratory rate, blood pressure, and age <65 years), predict 30-day mortality in community-acquired pneumonia (CAP) and have limited ability to predict which patients will require intensive respiratory or vasopressor support (IRVS). Methods. The Australian CAP Study (ACAPS) was a prospective study of 882 episodes in which each patient had a detailed assessment of severity features, etiology, and treatment outcomes. Multivariate logistic regression was performed to identify features at initial assessment that were associated with receipt of IRVS. These results were converted into a simple points-based severity tool that was validated in 5 external databases, totaling 7464 patients. Results. In ACAPS, 10.3% of patients received IRVS, and the 30-day mortality rate was 5.7%. The features statistically significantly associated with receipt of IRVS were low systolic blood pressure (2 points), multilobar chest radiography involvement (1 point), low albumin level (1 point), high respiratory rate (1 point), tachycardia (1 point), confusion (1 point), poor oxygenation (2 points), and low arterial pH (2 points): SMART-COP. A SMART-COP score of <3 points identified 92% of patients who received IRVS, including 84% of patients who did not need immediate admission to the intensive care unit. Accuracy was also high in the 5 validation databases. Sensitivities of PSI and CURB-65 for identifying the need for IRVS were 74% and 39%, respectively. Conclusions. SMART-COP is a simple, practical clinical tool for accurately predicting the need for IRVS that is likely to assist clinicians in determining CAP severity.

Immune checkpoint inhibitor (ICI) use has been associated with numerous autoimmune side effects, known as immune related adverse events (irAEs). Cutaneous irAEs are common and affect up to 50% of patients treated with ICIs. There have been an increasing number of cases reported in the literature regarding ICI-induced subacute cutaneous lupus erythematosus (SCLE). ICI-induced SCLE is important to recognize as it can result in a delayed and/or prolonged skin reaction despite treatment discontinuation. We describe a patient with gastro-esophageal adenocarcinoma who developed SCLE following one cycle of nivolumab treatment. A 75-year-old man presented to our clinic with a new photo-distributed rash composed of oval scaly pink papules and plaques involving his chest and arms. Despite treatment with topical corticosteroids, he presented to the emergency department 1 week later with worsening rash. Skin biopsy showed vacuolar interface pattern, along with superficial perivascular lymphocytic infiltrate, consistent with a drug eruption. The clinicopathological presentation was consistent with ICI-induced SCLE. Nivolumab treatment was discontinued due to the severity of the rash. The rash remitted with systemic corticosteroids, high potency topical steroids, and hydroxychloroquine. Unfortunately, the patient developed intraperitoneal metastatic disease, and was enrolled in hospice care. In this paper, we highlight the importance of early identification and treatment of this irAE. A review of the literature, including a discussion on the management of ICI-induced SCLE is also provided.

Background. Available data on the etiology of community-acquired pneumonia (CAP) in Australia are very limited. Local treatment guidelines promote the use of combination therapy with agents such as penicillin or amoxycillin combined with either doxycycline or a macrolide. Methods. The Australian CAP Study (ACAPS) was a prospective, multicenter study of 885 episodes of CAP in which all patients underwent detailed assessment for bacterial and viral pathogens (cultures, urinary antigen testing, serological methods, and polymerase chain reaction). Antibiotic agents and relevant clinical outcomes were recorded. Results. The etiology was identified in 404 (45.6%) of 885 episodes, with the most frequent causes being Streptococcus pneumoniae (14%), Mycoplasma pneumoniae (9%), and respiratory viruses (15%; influenza, picornavirus, respiratory syncytial virus, parainfluenza virus, and adenovirus). Antibiotic-resistant pathogens were rare: only 5.4% of patients had an infection for which therapy with penicillin plus doxycycline would potentially fail. Concordance with local antibiotic recommendations was high (82.4%), with the most commonly prescribed regimens being a penicillin plus either doxycycline or a macrolide (55.8%) or ceftriaxone plus either doxycycline or a macrolide (36.8%). The 30-day mortality rate was 5.6% (50 of 885 episodes), and mechanical ventilation or vasopressor support were required in 94 episodes (10.6%). Outcomes were not compromised by receipt of narrower-spectrum β-lactams, and they did not differ on the basis of whether a pathogen was identified. Conclusions. The vast majority of patients with CAP can be treated successfully with narrow-spectrum β-lactam treatment, such as penicillin combined with doxycycline or a macrolide. Greater use of such therapy could potentially reduce the emergence of antibiotic resistance among common bacterial pathogens.

To the Editor: In their Perspective article (April 8 issue), 1 Alvarez-Arango et al. highlight the important potential gender- and race-related bias associated with the term “Red Man Syndrome.” However, Rothenberg did not use this name in the initial description, 2 as suggested. “Red Man’s Syndrome” was introduced by Garrelts and Peterie, and “Red-neck Syndrome” was proposed in the Journal in 1985 (since the reaction can be confined to the neck and head). 3 The original 1959 report and the 1985 report both described cases in women, and the syndrome occurs with approximately equal frequency in men and women. 4-6 “Red person syndrome” was . . .

Background. We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. Methods. Patient data from culture-confirmed cases (2000–2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. Results. Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2–12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. Conclusions. Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.