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A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases–Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

In this randomized clinical trial in patients presenting to U.S. emergency departments with an acute uncomplicated cutaneous abscess, drainage plus trimethoprim–sulfamethoxazole therapy for a week was associated with modest clinical benefits as compared with drainage alone. Between 1993 and 2005, annual emergency department visits for skin and soft-tissue infections in the United States increased from 1.2 million to 3.4 million, primarily because of an increased incidence of abscesses. 1 , 2 During this period, community-associated methicillin-resistant Staphylococcus aureus (MRSA) emerged as the most common cause of purulent skin and soft-tissue infections in many parts of the world. 3 Trimethoprim–sulfamethoxazole, which has retained in vitro activity against community-associated MRSA, is among the most commonly prescribed antibiotics to treat these infections. 4 The primary treatment of a cutaneous abscess is drainage. 5 Whether adjunctive antibiotics lead to improved outcomes in patients with uncomplicated . . .

New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-positive pathogens. We aimed to assess the efficacy and safety of intravenous to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections. ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centres in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a minimum lesion area of 75 cm2 and were suspected or documented to be associated with a Gram-positive pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive intravenous once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geographic region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clinical response (≥20% reduction in lesion area at 48–72 h compared with baseline), with a non-inferiority margin of −10%. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01421511. 666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clinical response (difference 2·6%, 95% CI −3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group. Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings. Cubist Pharmaceuticals.

Background Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. Methods In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. Results Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference  − 1.1%; 95% CI  − 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. Conclusions Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. Trial registration ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Background. High rates of resistance to trimethoprim-sulfamethoxazole (TMP-SMX) among uropathogenic Escherichia coli are recognized, and concerns exist about emerging fluoroquinolone resistance. Methods. Adults presenting to 11 US emergency departments with (1) flank pain and/or costovertebral tenderness, (2) temperature >38°C, and (3) a presumptive diagnosis of pyelonephritis were enrolled; patients for whom 1 uropathogen grew on culture were analyzed. Epidemiologic and clinical data were collected at the time of care. The prevalence of E. coli in vitro antibiotic resistance and risk factors associated with TMP-SMX–resistant E. coli infection were determined. Results. Among 403 women with uncomplicated pyelonephritis caused by E. coli, the mean site rate of E. coli resistance to TMP-SMX was 24% (range, 13%–45%). Mean site rates of E. coli resistance to ciprofloxacin and levofloxacin were 1% and 3%, respectively. Only TMP-SMX exposure within 2 days before presentation and Hispanic ethnicity were associated with E. coli resistance to TMP-SMX (compared with resistance rates of ∼20% among women lacking these risk factors); antibiotic exposure within 3–60 days before presentation, health care setting exposure within 30 days before presentation, history of urinary tract infections, and age >55 years were not associated with E. coli resistance to TMP-SMX. Among 207 patients with complicated pyelonephritis, mean site rates of E. coli resistance to ciprofloxacin and levofloxacin were 5% and 6%, respectively. Conclusions. These results suggest that the prevalence of TMP-SMX–resistant infection among patients with uncomplicated pyelonephritis is ⩾20% in many areas of the United States, and risk stratification cannot identify patients at low risk of infection. Rates of fluoroquinolone-resistant E. coli infection appear to be low among patients with uncomplicated pyelonephritis but higher among those with complicated infections. Fluoroquinolones should remain to be the preferred empirical treatment for women with uncomplicated pyelonephritis.

Background. The cause of cellulitis is unclear. Streptococcus pyogenes, and to a lesser extent, Staphylococcus aureus, are presumed pathogens. Methods. We conducted a study of adults with acute cellulitis without drainage presenting to a US emergency department research network. Skin biopsy specimens were taken from the infected site and a comparable uninfected site on the opposite side of the body. Microbiology was evaluated using quantitative polymerase chain reaction (PCR), pyrosequencing, and standard culture techniques. To determine the cause, the prevalence and quantity of bacterial species at the infected and uninfected sites were compared. Results. Among 50 subjects with biopsy specimens from infected and uninfected sites, culture rarely identified a bacterium. Among 49 subjects with paired specimens from infected and uninfected sites tested with PCR, methicillin-susceptible S. aureus was identified in 20 (41%) and 17 (34%), respectively. Pyrosequencing identified abundant atypical bacteria in addition to streptococci and staphylococci. Among 49 subjects with paired specimens tested by pyrosequencing, S. aureus was identified from 11 (22%) and 15 (31%) and streptococci from 15 (31%) and 20 (41%) of the specimens, respectively. Methicillin-resistant S. aureus was not found by culture or PCR, and S. pyogenes was not identified by any technique. Conclusions. The bacterial cause of cellulitis cannot be determined by comparing the prevalence and quantity of pathogens from infected and uninfected skin biopsy specimens using current molecular techniques. Methicillin-susceptible S. aureus was detected but not methicillin-resistant S. aureus or S. pyogenes from cellulitis tissue specimens. For now, optimal treatment will need to be guided by clinical trials. Noninfectious causes should also be explored.

Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5–7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5–10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0–2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4–96.6%; moxifloxacin 90.3–96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1–89.7%; moxifloxacin 74.2–97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens.

Background Complicated skin and soft tissue infections (cSSTIs) occur frequently, but limited data do not allow any consensus on an optimal treatment strategy. We designed this prospective, multicenter, observational study to to explore the current epidemiology, treatment, and resulting clinical outcomes of cSSTIs to help develop strategies to potentially improve outcomes. Methods From June 2008 to December 2009 we enrolled a pre-specified number of adults treated in 56 U.S. hospitals with intravenous antibiotic(s) for any of the following cSSTIs: diabetic foot infection (DFI); surgical site infection (SSI); deep soft tissue abscess (DSTA); or, cellulitis. Investigators treated all patients per their usual practice during the study and collected data on a standardized form. Results We enrolled 1,033 patients (DFI 27%; SSI 32%; DSTA 14%; cellulitis 27%; mean age 54 years; 54% male), of which 74% had healthcare-associated risk factors. At presentation, 89% of patients received initial empiric therapy with intravenous antibiotics; ~20% of these patients had this empiric regimen changed or discontinued based on culture and sensitivity results. Vancomycin was the most frequently used initial intravenous antibiotic, ordered in 61% of cases. During their stay 44% of patients underwent a surgical procedure related to the study infection, usually incision and drainage or debridement. The mean length of stay was 7.1 days, ranging from 5.8 (DSTA) to 8.1 (SSI). Conclusion Our findings from this large prospective observational study that characterized patients with cSSTIs from diverse US inpatient populations provide useful information on the current epidemiology, clinical management practices and outcomes of this common infection. Keypoints This large prospective observational study that characterized patients with cSSTIs from diverse US inpatient populations provides useful information on the current epidemiology clinical management practices and outcomes of this common infection.

BACKGROUNDNovel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics.METHODSIn this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14.RESULTSClinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference = -21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone.CONCLUSIONThis study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs.TRIAL REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.

Community-acquired pneumonia (CAP) is a major health problem in the United States and is associated with substantial morbidity, mortality, and health care costs. Patients with CAP commonly present to emergency departments where physicians must make critical decisions regarding diagnosis and management of pneumonia in a timely fashion, with emphasis on efficient and cost-effective diagnostic choices, consideration of emerging antimicrobial resistance, timely initiation of antibiotics, and appropriate site-of-care decisions. In light of the burden that pneumonia places on health care systems and the emergency department in particular, this article reviews significant developments in the management of CAP in the United States 5 years since the publication of the 2007 Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of CAP in adults, focusing on recent studies and recommendations for managing CAP, the primary bacterial pathogens responsible for CAP, and trends in resistance, new diagnostic technologies, and newer antimicrobials approved for the treatment of CAP. These new data and additional guidelines pertaining to the treatment of CAP further our knowledge and understanding of this challenging infection. Furthermore, appreciation of the availability of new diagnostic testing and therapeutic options will help meet the demand for improved management of CAP.