Early Clinical Response Rates Research Articles

Pooled microbiological findings and efficacy outcomes by pathogen in adults with community-acquired bacterial pneumonia from the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 phase 3 trials of lefamulin versus moxifloxacin

Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. In LEAP 1, adults (PORT risk class III‒V) received intravenous (IV) lefamulin 150 mg every 12 h (q12h) for 5‒7 days or moxifloxacin 400 mg every 24 h (q24h) for 7 days, with optional IV-to-oral switch. In LEAP 2, adults (PORT II‒IV) received oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Primary outcomes were early clinical response (ECR) at 96 ± 24 h after treatment start and investigator assessment of clinical response (IACR) 5‒10 days after the last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen testing, serology and/or real-time PCR). Baseline CABP pathogens were detected in 709/1289 patients (55.0%; microbiological intention-to-treat population). The most frequently identified pathogens were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. Lefamulin is a valuable IV and oral monotherapy option for empirical and directed CABP treatment in adults.

A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP).

BackgroundThe clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin’s shape and charge profile uniquely impact its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin with moxifloxacin for the treatment of CABP.MethodsA randomized, double-blind, comparator-controlled, multicenter, global phase 3 study compared the efficacy and safety of delafloxacin 300 mg twice daily or moxifloxacin 400 mg once daily in adults with CABP. The primary end point was early clinical response (ECR), defined as improvement at 96 (±24) hours after the first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed.ResultsIn the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events that were considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group.ConclusionsIntravenous/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for Gram-positive, Gram-negative, and atypical pathogens.ClinicalTrials.gov IdentifierNCT03534622.

2233. Efficacy and Symptom Resolution by Visit in Adults With Community-Acquired Bacterial Pneumonia (CABP) Treated With Lefamulin (LEF) or Moxifloxacin (MOX): Pooled Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results

BackgroundEfficacy and safety of LEF were shown in 2 noninferiority trials (LEAP 1/2) vs. MOX in adults with CABP. We assessed the efficacy of LEF by visit based on a pooled analyses of LEAP 1/2 data.MethodsIn LEAP 1, PORT III–V patients (patients) received LEF 150 mg IV q12h for 5–7 days or MOX 400 mg IV q24h for 7 days, with optional IV-to-oral switch (600 mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600 mg q12h for 5 days or oral MOX 400 mg q24h for 7 days. Criteria for defining the FDA primary endpoint of early clinical response (ECR) at 96 ± 24 hours after first dose were applied to each visit through late follow-up (LFU; days 27–34) in the intent-to-treat (ITT; all randomized patients) population. Investigator assessment of clinical response (IACR) was examined at end of treatment (EOT; within 2 days after last dose), test-of-cure (TOC; 5–10 days after last dose; EMA primary endpoint), and LFU in the modified ITT (mITT; received ≥1 dose of study drug) and clinically evaluable (CE; met predefined evaluability criteria) populations. Results are presented by visit for pooled LEAP 1/2 data.Results1289 ITT patients were randomized (LEF, n = 646; MOX, n = 643). Most patients in both groups achieved ECR at Day 3, with further increases through Day 7 and sustained efficacy through LFU (Fig 1). In mITT patients, IACR success rates at EOT/TOC/LFU were 87.1/85.0/83.2% with LEF and 88.1/87.1/86.1% with MOX; results were consistent in CE patients. The proportions of ITT patients with resolution of all baseline signs/symptoms of CABP increased similarly by visit in both treatment groups (Fig 2). Most patients did not achieve complete sign/symptom resolution until TOC, with fever generally being the first and cough the last to resolve. There was no apparent relationship between ECR and age, gender, renal status, SIRS, PORT, prior antibiotic use, baseline pathogens, typical/atypical pathogens, or mono/polymicrobial pathogens. The high percentage of patients at LFU with baseline symptom resolution suggests that symptom resolution was sustained.ConclusionIn this pooled analysis, efficacy results were similar by visit in the LEF and MOX groups, with high ECR rates maintained through LFU. LEF will provide a potential new effective systemic monotherapy alternative to fluoroquinolones for the empiric treatment of CABP. Disclosures All authors: No reported disclosures.

Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia

New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.

Tedizolid Versus Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis.

This meta-analysis aims to assess the efficacy and safety of tedizolid, compared to linezolid, in the treatment of acute bacterial skin and skin structure infection (ABSSSI). PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid Medline and Embase databases were accessed until 18 July 2019. Only randomized controlled trials (RCTs) comparing the efficacy of tedizolid with linezolid for adult patients with ABSSSIs were included. The outcomes included the clinical response, microbiological response, and risk of adverse events (AEs). A total of four RCTs involving 2056 adult patients with ABSSSI were enrolled. The early clinical response rate was 79.6% and 80.5% for patients receiving tedizolid and linezolid, respectively. The pooled analysis showed that tedizolid had a non-inferior early clinical response rate to linezolid (odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.77–1.19, I2 = 0%). The early response rate was similar between tedizolid and linezolid among patients with cellulitis/erysipelas (75.1% vs. 77.1%; OR = 0.90, 95% CI = 0.64–1.27, I2 = 25%), major cutaneous abscess (85.1% vs. 86.8%; OR = 0.93, 95% CI = 0.42–2.03, I2 = 37%) and wound infection (85.9% vs. 82.6%; OR = 1.29, 95% CI = 0.66–2.51, I2 = 45%). For methicillin-resistant Staphylococcus aureus patients, tedizolid had a favorable microbiological response rate of 95.2% which was comparable to linezolid (94%) (OR = 1.19, 95% CI = 0.49–2.90, I2 = 0%). In addition to the similar risk of treatment-emergent AEs (a serious event, the discontinuation of the study drug due to AEs and mortality between tedizolid and linezolid), tedizolid was associated with a lower risk of nausea, vomiting and abnormal neutrophil count than linezolid. In conclusion, once-daily tedizolid (200 mg for six days) compared to linezolid (600 mg twice-daily for 10 days) was non-inferior in efficacy in the treatment of ABSSSI. Besides, tedizolid was generally as well tolerated as linezolid, and had a lower incidence of gastrointestinal AEs and bone marrow suppression than linezolid.

Tedizolid phosphate for the treatment of acute bacterial skin and skin-structure infections: an evidence-based review of its place in therapy.

IntroductionTedizolid phosphate is an oxazolidinone approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) and active against methicillin-resistant Staphylococcus aureus.AimsThe objective of this article was to review the evidence for the efficacy and safety of tedizolid phosphate for the treatment of ABSSSI.Evidence reviewApproval of tedizolid phosphate for the treatment of ABSSSI was based on the results of two phase III randomized controlled trials, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing 6-day once-daily tedizolid vs 10-day twice-daily linezolid. In ESTABLISH-1, noninferiority was met with early clinical response rates of 79.5% and 79.4% in tedizolid and linezolid groups, respectively (difference 0.1%, 95% CI –6.1% to 6.2%, with a 10% noninferiority margin). In ESTABLISH-2, noninferiority was met with 85% and 83% rates of early clinical response in tedizolid and linezolid groups, respectively (difference 2.6%, 95% CI –3.0% to 8.2%). Pooled data from ESTABLISH-1 and ESTABLISH-2 indicated a lower frequency of thrombocytopenia in tedizolid-treated than in linezolid-treated patients.ConclusionTedizolid offers the option of an intravenous to oral switch, allows once-daily administration, and presents lower risk of myelotoxicity when a 6-day course is used for the treatment of ABSSSI. Greater economic cost associated with this antibiotic could be offset by its shorter treatment duration and possibility of oral administration in routine clinical practice, although either sponsored or nonsponsored postmarketing observational experience remains essential for ultimately confirming the effectiveness and tolerability of tedizolid outside clinical trials.

Omadacycline in community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections: a profile of its use

Omadacycline (Nuzyra™) is an orally bioavailable, first-in-class, semisynthetic aminomethylcycline antibacterial. A derivative of minocycline, omadacycline has a novel structure that overcomes common mechanisms of tetracycline resistance. In vitro, omadacycline had broad-spectrum activity against Gram-positive, Gram-negative, and atypical bacteria that can cause community-acquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infections (ABSSSI). In clinical trials, omadacycline was noninferior to moxifloxacin and linezolid in terms of early clinical response rates in patients with CABP and ABSSSI, respectively. Omadacycline was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity.

A Pooled Analysis of the Safety and Efficacy of Iclaprim Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Patients With Intravenous Drug Use: Phase 3 REVIVE Studies

PurposeThis analysis evaluates the efficacy and safety of iclaprim versus vancomycin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in patients who were intravenous drug users (IVDUs). MethodsA total of 621 patients who were IVDUs from 2 parallel Phase III, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed separately and pooled. This post hoc analysis summarizes the efficacy and safety profile of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg administered intravenously during 2 h every 12 h for 5–14 days among this population. The primary end point of these studies was to determine whether iclaprim was noninferior (10% margin) to vancomycin in achieving a ≥20% reduction in lesion size at 48–72 h after initiation of treatment with the study drug (early clinical response) in the intent-to-treat population. The safety profile was assessed based on adverse events and laboratory parameters. FindingsIclaprim had higher early clinical response rates (85.8%; 95% CI, 81.5%–89.4%) compared with vancomycin (79.8%; 95% CI, 74.8%–84.2%) among patients with ABSSSIs who were IVDUs, with a treatment difference of +6.00% (95% CI, 0.06–12.0). The safety profile was similar in the iclaprim and vancomycin arms, with 3.7% and 5.0%, respectively, of patients discontinuing study therapy because of adverse events and 1.9% and 3.4%, respectively, of patients developing serious adverse events. ImplicationsIclaprim had a higher early clinical response rate and favorable safety profile compared with vancomycin for the treatment of ABSSSIs in patients who were IVDUs. Iclaprim may be a valuable treatment option for ABSSSIs in this patient population.

Benzylpenicillin versus wide-spectrum beta-lactam antibiotics as empirical treatment of Haemophilus influenzae-associated lower respiratory tract infections in adults; a retrospective propensity score-matched study

There is consensus that definitive therapy for infections with H. influenzae should include antimicrobial agents with clinical breakpoints against the bacterium. In Scandinavia, benzylpenicillin is the recommended empirical treatment for community-acquired pneumonia (CAP) except in very severe cases. However, the effect of benzylpenicillin on H. influenzae infections has been debated. The aim of this study was to compare the outcomes of patients given benzylpenicillin with patients given wide-spectrum beta-lactams (WSBL) as empirical treatment of lower respiratory tract H. influenzae infections requiring hospital care. We identified 481 adults hospitalized with lower respiratory tract infection by H. influenzae, bacteremic and non-bacteremic. Overall, 30-day mortality was 9% (42/481). Thirty-day mortality, 30-day readmission rates, and early clinical response rates were compared in patients receiving benzylpenicillin (n = 199) and a WSBL (n = 213) as empirical monotherapy. After adjusting for potential confounders, empirical benzylpenicillin treatment was not associated with higher 30-day mortality neither in a multivariate logistic regression (aOR 2.03 for WSBL compared to benzylpenicillin, 95% CI 0.91–4.50, p = 0.082), nor in a propensity score-matched analysis (aOR 2.14, 95% CI 0.93–4.92, p = 0.075). Readmission rates did not significantly differ between the study groups, but early clinical response rates were significantly higher in the WSBL group (aOR 2.28, 95% CI 1.21–4.31, p = 0.011), albeit still high in both groups (84 vs 81%). In conclusion, despite early clinical response rates being slightly lower for benzylpenicillin compared to WSBL, we found no support for increased mortality or readmission rates in patients empirically treated with benzylpenicillin for lower respiratory tract infections by H. influenzae.

Macrolide therapy for community-acquired pneumonia due to atypical pathogens: outcome assessment at an early time point

BackgroundTherapy directed against atypical pathogens in patients with community-acquired pneumonia (CAP) is often recommended. This post-hoc analysis evaluated the effect of addition of a macrolide to ceftaroline fosamil or ceftriaxone treatment in atypical CAP. MethodsTwo phase 3, double-blind, comparative safety and efficacy studies of ceftaroline fosamil vs. ceftriaxone, FOCUS 1 and FOCUS 2, enrolled adults with CAP. Only FOCUS 1 included 24-h adjunctive clarithromycin therapy for all patients on day 1. Day 4 and test-of-cure (TOC) outcomes were compared for adjunctive vs. no adjunctive therapy. ResultsOf 1240 enrolled patients, 130 patients with CAP due to atypical pathogens alone were included (FOCUS 1, n = 64; FOCUS 2, n = 66). Among patients infected with Mycoplasma pneumoniae and/or Chlamydophila pneumoniae alone, a higher clinical response rate was observed with clarithromycin plus ceftaroline fosamil or ceftriaxone compared with treatment without additional clarithromycin at day 4 [38/49 (77.6%; FOCUS 1) vs. 24/43 (55.8%; FOCUS 2)], but not at the TOC assessment [42/49 (85.7%; FOCUS 1) vs. 41/43 (95.3%; FOCUS 2)]. In patients infected with Legionella pneumophila alone, a higher clinical response rate with adjunctive clarithromycin therapy was observed at the TOC assessment alone [12/12 (100%; FOCUS 1) vs. 14/19 (73.7%; FOCUS 2)]. The unadjusted odds ratio of a favourable clinical response at day 4 with adjunctive clarithromycin vs. no adjunctive clarithromycin was 2.4 (95% confidence interval 1.1–5.1; P = 0.0299) for all pathogens combined. ConclusionsThese results suggest that empirical antibiotic therapy against atypical pathogens may improve early clinical response rate. This hypothesis is best evaluated in a prospective trial.

Single-Dose Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections.

Intravenous dalbavancin (Dalvance®, Xydalba®), first approved as a two-dose regimen for the treatment of acute bacterial skin and skin structure infections (ABSSSI), has now been additionally approved as a single-dose regimen. This narrative review discusses the pharmacological properties of intravenous dalbavancin and its clinical efficacy and tolerability as a single-dose regimen in the treatment of adult patients with ABSSSI. Single-dose dalbavancin is an effective and generally well tolerated treatment option for adults with ABSSSI, with noninferior efficacy to the two-dose dalbavancin regimen with regard to early clinical response (at 48-72h) and low rates of adverse events. Clinical success rates at days 14 and 28 also did not significantly differ between the single- and two-dose dalbavancin regimens; neither did clinical success rates at day 14 when analysed by baseline pathogen. It has a broad spectrum of activity against common ABSSSI-related pathogens, and a favourable pharmacokinetic profile allowing for the convenience of single-dose administration. Thus, dalbavancin presents a promising alternative to conventional antibacterials for the treatment of ABSSSI in adult patients.

The role of a defunctioning stoma for colonic and perianal Crohn’s disease in the biological era

Objective: A defunctioning stoma is a therapeutic option for colonic or perianal Crohn’s disease. In the pre-biologic era the response rate to defunctioning in our unit was high (86%), but intestinal continuity was only restored in 11–20%. Few data exist on the outcome of defunctioning since the widespread introduction of biologicals.Material and methods: All patients undergoing a defunctioning stoma for colonic/perianal Crohn’s disease since 2003–2011 were identified from a prospective database. Indications for surgery, medical therapy, response to defunctioning and long-term clinical outcome were recorded. Successful restoration of continuity was defined as no stoma at last follow up.Results: Seventy-six patients were defunctioned (57 with biologicals) and at last follow up, 20 (27%) had continuity restored. Early clinical response rate (<3 months) was 15/76 (20%) and overall response 31/76 (41%). Complex anal fistulae/stenosis were associated with a very low chance of restoring continuity (10% and 0%, respectively), while colitis was associated with a higher chance of restoring continuity (48%). Endoscopic or histological improvement in colitis after defunctioning was associated with a higher rate of restoring continuity (10/16, 63%) compared to no such improvement (4/15, 27%, p = 0.05). Those failing biologics had similar chance of restoration as those not receiving biologics, 15/57 (26%) and 5/19 (26%), respectively.Conclusion: Overall response to colonic defunctioning was 41%. Successful restoration of continuity occurred in 27%, but 48% in the absence of perianal disease. Response is appreciably less in the pre-biologic era, so patient and physician expectations need to be managed appropriately.

Community-acquired Haemophilus influenzae pneumonia--New insights from the CAPNETZ study.

We aimed to identify clinical characteristics and to assess effectiveness of different initial antibiotic regimens in adult patients with community-acquired pneumonia (CAP) caused by Haemophilus influenzae. Characteristics were compared between patients with H. influenzae monoinfection versus CAP of other and unknown aetiology enrolled by the German prospective cohort study CAPNETZ. Impact of initial antibiotic treatment on "early clinical response" according to FDA criteria and overall clinical cure were analysed. H. influenzae was found in 176 out of 2790 patients with pathogen detection (6.3%). Characteristics significantly associated with a H. influenzae CAP (p<0.017) included purulent sputum, prior pneumococcal vaccination and respiratory co-morbidities. Early clinical response rates on day 4 did not differ between patients receiving any mono- versus combination therapy (85.9% versus 88%), but were numerically higher for regimens including any fluoroquinolone (96.7%) and lower under macrolide monotherapy (70%). Initial CURB-65 score and chronic liver disease were identified as negative predictors for "early clinical response". At day 14, overall clinical cure was 91.9%. H. influenzae was a common CAP pathogen, particularly in patients with previous pneumococcal vaccination and respiratory co-morbidities. Severity of illness and chronic liver disease were associated with a lower rate of "early clinical response".

Effects of Diabetes Mellitus and HbA1c on Treatment Prognosis in Uncomplicated Acute Pyelonephritis

Purpose: We investigated potential difference in the clinical features of hospitalized female acute pyelonephritis (APN) patients with and without diabetes mellitus (DM). The additional purpose of the study was to determine whether HbA1c has a role in predicting clinical outcome in terms of morbidity compared with those considered to have normal glycemic control in female APN patients with DM. Materials and Methods: Among the female patients who received inpatients care due to APN from January 2011 to December 2013, 282 patients (86 with DM and 196 without DM) were selected and their medical records were analyzed. Laboratory results (white blood cell, blood urea nitrogen, serum creatinine, fasting plasma glucose, HbA1c) were dichotomized. Primary outcomes for comparison between the groups of patients with or without DM were early clinical response rate and length of in-hospital stay. Subgroup analysis was also performed in DM patients according to HbA1c status (<6.5%, ≥6.5%). Results: In multivariate logistic regression analysis, DM was not found to show independent association with poor early clinical response or longer hospital stay. HbA1c was the common risk factor of poor early clinical response (odds ratio [OR] 4.88, 95% confidence interval [CI] 1.61-14.8) and longer hospital stay (OR 4.20 95% CI 1.52-11.60) in APN patients with DM. Conclusions: Strict glucose control may be more important prognostic factor than presence or absence of DM in APN patients. As a marker of prolonged hospitalization and poor early clinical response, HbA1c can complement the present clinical and laboratory parameters used as guide in the proper treatment of DM patients with APN.

Use of Gentamicin for Women with Community-Acquired Uncomplicated Acute Pyelonephritis Caused by Gentamicin-Susceptible or -ResistantEscherichia coli:10-Year Experience

The objectives of this study were to evaluate the clinical effectiveness of gentamicin as an initial empirical antimicrobial agent and to determine the effects of gentamicin resistance on clinical outcomes in women with uncomplicated acute pyelonephritis (APN). We analyzed data of 2,033 women with a diagnosis of APN admitted to Catholic University St. Vincent's Hospital. Of those, we enrolled 274 cases of community-acquired uncomplicated APN due to Escherichia coli who received gentamicin as initial antibiotics. Of these 274 patients, 47 patients had gentamicin-resistant (GM-R) E. coli APN, and 227 patients had gentamicin-susceptible (GM-S) E. coli APN. The early clinical response rates were 55.3% (26/47) versus 81.5% (185/227) at 72 hours; 61.7% (29/47) versus 96.9% (220/227) at 96 hours in the GM-R and GM-S groups, which was significantly higher in the GM-S group (p<0.001). Overall clinical cure rates were 100% (47/47) and 99.6% (226/227) in the GM-R and GM-S groups, respectively. APN patients in the GM-R group had longer hospitalization (9.72 ± 3.46 and 7.89 ± 2.27 days; p<0.001) than those in the GM-S group. Resistance of E. coli to gentamicin, bacteremia, and C-reactive protein level showed independent effects on early clinical failure. Aminoglycoside such as gentamicin can be an alternative antibiotic option for initial empirical therapy of community-acquired uncomplicated APN as the fluoroquinolone-sparing or broad-spectrum cephalosporin-sparing agents in an era of increasing antimicrobial resistance, especially in areas where medical resources are limited or antibiotic resistance rate of the uropathogens is high.

Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections

Acute bacterial skin and skin structure infections (ABSSSIs), including cellulitis or erysipelas, major cutaneous abscesses, and wound infections, can be life-threatening and may require surgery and hospitalization. Increasingly, ABSSSIs are associated with drug-resistant pathogens, and many antimicrobial agents have adverse effects restricting their use. Tedizolid phosphate is a novel oxazolidinone in development for the treatment of ABSSSIs. To establish the noninferiority of tedizolid phosphate vs linezolid in treating ABSSSIs and compare the safety of the 2 agents. The Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) was a phase 3, randomized, double-blind, noninferiority trial that was conducted from August 2010 through September 2011 at 81 study centers in North America, Latin America, and Europe. The intent-to-treat analysis set consisted of data from 667 adults aged 18 years or older with ABSSSIs treated with tedizolid phosphate (n = 332) or linezolid (n = 335). A 200 mg once daily dose of oral tedizolid phosphate for 6 days or 600 mg of oral linezolid every 12 hours for 10 days. The primary efficacy outcome was early clinical response at the 48- to 72-hour assessment (no increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours). A 10% noninferiority margin was predefined. In the intent-to-treat analysis set, the early clinical treatment response rates were 79.5% (95% CI, 74.8% to 83.7%) of 332 patients in the tedizolid phosphate group and 79.4% (95% CI, 74.7% to 83.6%) of 335 patients in the linezolid group (a treatment difference of 0.1% [95% CI, -6.1% to 6.2%]). The sustained clinical treatment response rates at the end of treatment (day 11) were 69.3% (95% CI, 64.0% to 74.2%) in the tedizolid phosphate group and 71.9% (95% CI, 66.8% to 76.7%) in the linezolid group (a treatment difference of -2.6% [95% CI, -9.6% to 4.2%]). Results of investigator-assessed clinical treatment success rates at a posttherapy evaluation visit (1-2 weeks after the end-of-treatment visit) were 85.5% (95% CI, 81.3% to 89.1%) in the tedizolid phosphate group and 86.0% (95% CI, 81.8% to 89.5%) in the linezolid group (a treatment difference of -0.5% [95% CI, -5.8% to 4.9%), and were similar for 178 patients with methicillin-resistant Staphylococcus aureus isolated from the primary lesion. Tedizolid phosphate was a statistically noninferior treatment to linezolid in early clinical response at 48 to 72 hours after initiating therapy for an ABSSSI. Tedizolid phosphate may be a reasonable alternative to linezolid for treating ABSSSI. clinicaltrials.gov Identifier: NCT01170221.

Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia

The objective of this study is to assess the distribution of vancomycin minimum inhibitory concentrations (MICs) in methicillin-resistant Staphylococcus aureus (MRSA) isolates and evaluate the efficacy of vancomycin relative to vancomycin MICs in adult patients with MRSA nosocomial pneumonia. This retrospective cohort study involved adults with MRSA nosocomial pneumonia treated with vancomycin. Vancomycin MICs were determined using Etest. Patients with MRSA and vancomycin MICs ≥ 1.5 μg/mL and those with MRSA and MICs ≤ 1 μg/mL were placed in the high- and low-MIC group, respectively. The primary outcomes assessed were clinical response and relapse of MRSA pneumonia within 28 days after vancomycin discontinuation. Secondary outcomes included 28-day mortality, in-hospital mortality and length of hospital stay. Seventy patients met the inclusion criteria. Mean age and mean Acute Physiological and Chronic Health Evaluation (APACHE) II score upon intensive care unit (ICU) admission of these patients were 67.0 years and 25.9, respectively. Thirty-four (48.6%) isolates had high vancomycin MICs, and 36 (51.4%) had low MICs. There were no significant differences in baseline characteristics between the two groups. Early clinical response rates in the low- and high-MIC groups were 63.9% and 35.3%, respectively (p = 0.031). The high-MIC group had an 8% lower final clinical response rate, but this difference was not significant (p = 0.609). The relapse rate within 28 days was significantly higher in the high-MIC group than in the low-MIC group (29.6% versus 6.9%, p = 0.038). On multivariate analysis, infection by high-MIC strains was an independent predictor of early clinical response failure. About half of the MRSA isolates had high vancomycin MIC. Patients infected with these strains showed slower clinical response and higher relapse rate than patients infected with low vancomycin MIC isolates.

Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis

As ciprofloxacin resistance rate of Escherichia coli causing urinary tract infections has been increasing, concern about inappropriate empirical therapy has been arisen. We performed a retrospective cohort study to determine the impact of discordant empirical antimicrobial therapy on outcome of community-acquired bacteremic acute pyelonephritis. Among a total of 164 cases included, ciprofloxacin was empirically used in 80.5%. The most frequent etiologic organism was E. coli (92.1%), of which 20.5% was resistant to ciprofloxacin. Discordant empirical therapy was documented in 29 cases, which included 25 cases caused by ciprofloxacin-resistant E. coli. Discordant therapy resulted in lower early clinical response rate (34.5% vs. 82.2%; P < 0.001) and longer hospital stay (13.3 days vs. 8.7 days; P = 0.002) compared to concordant therapy. However, overall mortality and clinical cure rate did not differ between two groups. Multivariate analyses showed that worse early clinical response was associated with discordant empirical therapy (OR, 11.08; 95% CI, 4.37-28.07) and presentation with septic shock (OR, 8.52; 95% CI, 1.75-41.49). Longer hospital stay was also associated with discordant empirical therapy (OR, 2.47; 95% CI, 1.04-5.84). Discordant empirical therapy, mostly with ciprofloxacin, leads to worse early clinical response and longer hospital stay than concordant therapy in community-acquired bacteremic acute pyelonephritis, although it does not affect on overall mortality or clinical cure rate.