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Objective This study examined the in vitro activity of iclaprim and comparators against 40 Listeria monocytogenes clinical isolates mostly (95%) from patients with bloodstream infections (BSI) from the United States, Australia/New Zealand, Latin America, and Europe collected between 2012-2018 were tested. Methods Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. Results The iclaprim MIC90 value for all L. monocytogenes was 0.015 µg/ml. The MIC50/90 values for iclaprim were 4-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all L. monocytogenes. Conclusions Iclaprim demonstrated lower MIC values than trimethoprim against a collection (2012-2018) of L. monocytogenes clinical isolates mostly from patients with blood stream infections from the United States, Australia/New Zealand, Latin America, and Europe.

Introduction. Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. Aim. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. Methodology. Six-hundred-two patients with wound infections from two Phase 3, double-blinded, randomized, multicenter, active controlled trials (REVIVE-1/–2) were evaluated in a post hoc analysis of iclaprim 80 mg compared with vancomycin 15 mg kg–1 administered intravenously every 12 h for 5–14 days. The primary endpoint was to determine whether iclaprim was non-inferior (10 % margin) to vancomycin in achieving a ≥20 % reduction from baseline in lesion size 48–72 h after starting study drug (early clinical response [ECR]). Safety was assessed. Results. In REVIVE-1, ECR was 83.5 % with iclaprim versus 79.7 % with vancomycin (treatment difference 3.77%, 95 % CI −4.50%, 12.04%). In REVIVE-2, ECR was 82.7 % with iclaprim versus 76.3 % with vancomycin (treatment difference 6.38%, 95 % CI −3.35%, 16.12%). In the pooled dataset, iclaprim had similar ECR rates compared with vancomycin among wound infection patients (83.2 % vs 78.2 %) with a treatment difference of 5.01 % (95 % CI −1.29%, 11.32%). The safety profile was similar in iclaprim- and vancomycin-treated patients, except for a higher incidence of diarrhea with vancomycin (n=17) compared with iclaprim (n=6) and fatigue with iclaprim (n=17) compared with vancomycin (n=8). Conclusion. Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections.

Background: In this first in human study, PLG0206, a novel engineered cationic antimicrobial peptide was evaluated for safety, tolerability and pharmacokinetics when intravenously administered as a single dose to healthy subjects. Methods: Six cohorts of 8 subjects received escalating single IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1-to-4-hours. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 hours post infusion. Safety and tolerability were assessed throughout the study. Results: The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment emergent adverse events (TEAE) related to PLG0206 was low and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion related reactions, which were mitigated with increasing infusion time and volume. There were no serious adverse events (SAE), life-threatening events, or deaths throughout the study. IV PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. Conclusion: Following a single IV infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of IV PLG0206 as an antimicrobial agent.

BackgroundWe sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI).MethodsRetrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria.ResultsIn total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929–11.499), no medical insurance (aOR 3.451, 95% CI 1.310–9.090), ICU residence (aOR 4.398, 95% CI 1.676–11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158–7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037–1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days,p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%,p p = 0.024)ConclusionsV-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy.

Purpose This 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). Methods A 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. Findings Iclaprim 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. Implications Iclaprim 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.

Purpose Extracellular protein toxins contribute to the pathogenesis of Staphylococcus aureus infections. The present study compared the effects of iclaprim and trimethoprim - two folic acid synthesis inhibitors - with nafcillin and vancomycin on production of Panton-Valentine leukocidin (PVL), alpha haemolysin (AH) and toxic-shock syndrome toxin I (TSST-1) in methicillin-resistant and vancomycin-intermediate S. aureus (MRSA and VISA, respectively). Methodology Northern blotting and RT-PCR were used to assess gene transcription; toxin-specific bioassays were used to measure protein toxin production. Results As shown previously, sub-inhibitory concentrations (sub-MIC) of nafcillin increased and prolonged MRSA toxin gene transcription and enhanced PVL, TSST-1 and AH production. Sub-inhibitory doses of iclaprim and trimethoprim delayed maximal AH gene (hla) transcription and suppressed AH production; both drugs delayed, but neither reduced, maximal TSST-1 production. Trimethoprim significantly increased lukF-PV expression and PVL production compared to both untreated and iclaprim-treated cultures. Higher concentrations of iclaprim and trimethoprim markedly suppressed MRSA growth, mRNA synthesis and toxin production. In VISA, iclaprim, vancomycin and nafcillin variably increased tst and hla expression, but only nafcillin increased toxin production. Despite its ability to increase hla expression, iclaprim was the most potent inhibitor of AH production. Conclusions We conclude that, due to its ability to suppress toxin production, iclaprim should be effective against severe staphylococcal infections caused by toxin-producing MRSA and VISA strains, especially given its ability to concentrate at sites of infection such as skin and skin structures and the lung.

Among hospitalized adults who received vancomycin for their skin and skin structure infection (SSSI), patients who experienced acute kidney injury (AKI) had considerably higher 30-day readmission rates. Nearly half of the observed 30-day readmissions were due to non-SSSI-related reasons, which is consistent with the persistent organ dysfunction observed among patients with AKI.

Iclaprim, a diaminopyrimidine antimicrobial, was compared with vancomycin for treatment of patients with acute bacterial skin and skin-structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). Here, the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies was explored. REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised, multicentre, active-controlled, non-inferiority (margin of 10%) trials, each designed to enrol 600 patients with ABSSSI using identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered intravenously every 12 h for 5-14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size [early clinical response (ECR)] at the early time point (ETP) (48-72 h after starting study drug) in the intent-to-treat population. In REVIVE-1, ECR at the ETP was 80.9% with iclaprim versus 81.0% with vancomycin (treatment difference -0.13%, 95% CI -6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim versus 76.7% with vancomycin (treatment difference 1.58%, 95% CI -5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim versus 78.8% with vancomycin (treatment difference 0.75%, 95% CI -3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (n = 7) compared with iclaprim (n = 0). Iclaprim achieved non-inferiority compared with vancomycin for ECR at the ETP and secondary endpoints with a similar safety profile in two phase 3 studies for treatment of ABSSSI suspected or confirmed as caused by Gram-positive pathogens. [Clinical Trials Registration. NCT02600611 and NCT02607618.].

Iclaprim is under clinical development for treating acute bacterial skin and skin structure infections (ABSSSI) and nosocomial pneumonia most often due to Gram-positive bacteria, including infections due to drug-resistant bacteria. In two recent Phase III studies of patients with acute bacterial skin and skin structure infections, intravenous iclaprim 80 mg every 12 h was noninferior to dose-adjusted vancomycin. Additional studies are planned for patients with nosocomial pneumonia. Iclaprim represents an alternative for the treatment of severe skin and pulmonary infections due to Gram-positive bacteria.

Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5–14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, −0.13%; 95% confidence interval, −6.42%–6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. Clinical Trials Registration: NCT02600611.

We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam-β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter, including multidrug-resistant and extensively-drug-resistant strains. None of the newer β-lactam-β-lactamase combination drugs showed increased activity compared to that of the older agents against Stenotrophomonas maltophilia or Pandoraea spp.

Staphylococcus aureus is the most common non-gonococcal aetiology of septic arthritis. The efficacy of iclaprim against S. aureus LS-1, a clinical strain identified from a patient with septic arthritis, was studied in MF1 mice to evaluate the activity of iclaprim, which is in clinical development, in preventing joint infections. Iclaprim (2.5-80 mg kg- 1) administered as a single dose via the tail vein reduced the incidence of S. aureus septic arthritis and mortality in an experimental murine model of septic arthritis.

Iclaprim is a novel diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 1365 Gram-positive clinical isolates from patients with skin and skin structure infections (SSSI) from the United States, Asia Pacific, Latin America, Europe, Africa or Middle East collected between 2013 and 2017 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. MIC90 for all S.aureus, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Streptococcus pyogenes, S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae and S. intermedius were 0.12, 0.12, 0.5, 0.03, 0.5, ≤0.004, ≤0.004, 0.12, and 0.008 μg/ml, respectively. The MIC for iclaprim was 8 to 32-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. Iclaprim demonstrated lower MICs than trimethoprim against a collection (2013–2017) of Gram-positive clinical isolates from patients with SSSI from the United States, Asia Pacific, Latin America, and Europe.

The incidence and patient outcomes of Staphylococcus aureus isolates by iclaprim MIC was determined among patients from two phase 3 studies for the treatment of acute bacterial skin and skin structure infections (ABSSSI), REVIVE-1 and -2. Iclaprim MIC90 values were 0.12 µg ml-1 for S. aureus (0.12 µg ml-1 against methicillin-sensitive and 0.25 µg ml-1 against methicillin-resistant S. aureus). The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC > 8 µg ml-1 was 2.0 % (16/790). The clinical outcomes varied by MICs for early clinical response (63-100 %), end of therapy response (81-100 %) and the test of cure response (75-100 %). For microbiological outcomes of these infections, the end of therapy response was 80-100 % and the test of cure response was 88-100 %.

In this pilot study, the in vitro antimicrobial activity of iclaprim, a diaminopyrimidine, tested in combination with other antimicrobials against recent and common Gram-positive and Gram-negative respiratory pathogens, was examined by the checkerboard method. The range of minimal inhibitory concentrations (MICs) for iclaprim against all bacteria tested in the study was 0.03 to >128 µg ml−1. Iclaprim exhibited synergy with sulfamethoxazole against 11 of the 16 bacterial strains tested, with mean fractional inhibitory concentration index (FICI) values of 0.2–0.5. Synergy with sulfamethoxazole was demonstrated against all Gram-positive bacteria and selected Gram-negative bacteria. Neither synergy nor antagonism was observed for combinations of iclaprim with ampicillin, meropenem, tetracycline, levofloxacin, aztreonam, piperacillin/tazobactam, colistin, cefepime or gentamicin against any of the bacterial strains tested. The significant reduction in the MIC values observed with the combination of iclaprim and sulfamethoxazole demonstrates that this regimen could be effective against common Gram-positive and selected Gram-negative respiratory bacteria.

Lower respiratory tract infections (LRTIs) are the leading infectious cause of death and the sixth-leading cause of death overall worldwide. Streptococcus pneumoniae, with more than 90 serotypes, remains the most common identified cause of community-acquired acute bacterial pneumonia. Antibiotics treat LRTIs with a bacterial etiology. With the potential for antibiotic-resistant bacteria, defining the etiology of the LRTI is imperative for appropriate patient treatment. C-reactive protein and procalcitonin are point-of-care tests that may differentiate bacterial versus viral etiologies of LRTIs. Major advancements are currently advancing the ability to make rapid diagnoses and identification of the bacterial etiology of LRTIs, which will continue to support antimicrobial stewardship, and is the focus of this review.

Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, β-hemolytic streptococci, and Streptococcus anginosus group, underwent antibacterial susceptibility testing. Iclaprim had an MIC(90) of 0.12 μg/ml for S. aureus (0.12 μg/ml for methicillin susceptible, 0.25 μg/ml for methicillin resistant), 0.25 μg/ml for β-hemolytic streptococci, and 0.008 μg/ml for S. anginosus group. Iclaprim demonstrated potent activity against these Gram-positive ABSSSI isolates.

Iclaprim is a selective bacterial dihydrofolate reductase (DHFR) inhibitor. Although there are alternative options for the treatment of acute bacterial skin and skin structure infections (ABSSSI), iclaprim is differentiated from other available antibiotics. Areas covered: Iclaprim is under clinical development for ABSSSI. This review summarizes the mechanism of action, pharmacokinetics, microbiology, clinical development program, and the differentiation of iclaprim from other antibiotics. Expert commentary: Iclaprim has a different mechanism of action (DHFR inhibitor) compared to most other antibiotics, is active and rapidly bactericidal against Gram-positive pathogens including antibiotic-resistant pathogens, and suppresses bacterial exotoxins (alpha hemolysin, Panton Valentine leukocidin, and toxic shock syndrome toxin-1). Compared to trimethoprim, iclaprim has lower MIC

Objectives The objective of this study was to determine the in vitro activity of iclaprim and comparator agents against 7618 Gram-positive clinical isolates collected in the periods 2004–2006, 2012–2014 and 2015–2016. Methods Antimicrobial susceptibility testing was performed by the broth microdilution method and the minimum inhibitory concentrations (MICs) were interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Results Iclaprim MIC50/MIC90 values were 0.06/0.12 μg/mL for Staphylococcus aureus, including methicillin-susceptible and methicillin-resistant strains, and 0.015/0.03, 0.12/0.5 and 0.03/0.06 μg/mL, respectively, for Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus dysgalactiae over 8 years within the period from 2004 to 2016. Iclaprim was 8–32-fold more potent than trimethoprim. Against S. aureus, including methicillin-resistant strains, iclaprim was more active than standard-of-care intravenous antibiotics used to treat Gram-positive skin infections. Iclaprim was up to 16-fold more potent than vancomycin and linezolid and was 4–8-fold more potent than daptomycin. Conclusions Iclaprim demonstrated potent and consistent activity among Gram-positive clinical isolates collected globally between 2004 and 2016.

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, −5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02607618","term_id":"NCT02607618"}}NCT02607618.)

The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against Staphylococcus aureus ATCC 29213 and Staphylococcus pneumoniae ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for S. aureus ( R 2 , 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (% T >MIC) were strongly associated with effect ( R 2 , 0.86 for both parameters) for S. pneumoniae .

Background Opioid addiction in the United States has reached epidemic proportions threatening public health. This analysis evaluates the baseline characteristics and bacterial causes of ABSSSI in patients who were IVDU from two parallel Phase 3 trials comparing the treatment of iclaprim with vancomycin. Methods A total of 621 patients who were IVDU from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed both separately and pooled. This post-hoc analysis summarizes the baseline bacterial causes of ABSSSI identified among IVDU. Per protocol, ABSSSI (major abscesses, cellulitis, or wound infections) were defined as having either the presence of purulent or seropurulent drainage before or after surgical intervention of the wound or at least 3 of the following signs and symptoms: discharge, erythema (extending at least 2 cm beyond the wound edge in any direction), swelling and/or induration, heat and/or localized warmth, and/or pain and/or tenderness to palpation. IVDU was defined based on subjected-reported medical history. At the baseline visit, ABSSSI were sampled for microbiological culture. Cultures were performed locally, and isolates were submitted to the central microbiology laboratory. Results Among IVDU with ABSSSI, average age was 44 years, 67.6% were male, average lesion size was 322 cm2, 10.8% had abnormal renal function (CrCl ≤ 90 mL/minute), and 3.9% had bacteremia. The bacterial causes of ABSSSI among IVDU are shown in the Table. Conclusion IVDU, a growing population, are vulnerable to ABSSSI. S. aureus, including MRSA, and S. anginosus group were the most commonly identified bacterial causes of ABSSSI in patients who are IVDU. Therefore, antibiotic selection should cover these bacteria among IVDU who present with an ABSSSI. Disclosures All authors: No reported disclosures.

Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC 0–24ss ), AUC/MIC, and time above the MIC during the dosing interval ( T > MIC), while QTc prolongation was associated with the maximal concentration at steady state ( C maxss ) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC 0–24ss , AUC/MIC, and T > MIC while minimizing the probability of a C maxss of ≥800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC 0–24ss , AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a C maxss of ≥800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials.

New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and nosocomial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at –10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at –10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at –10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital-acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. This article will provide an update to the chemistry, preclinical, pharmacology, microbiology, clinical and regulatory status of iclaprim.

Iclaprim is a bacterial dihydrofolate reductase inhibitor in Phase 3 clinical development for the treatment of acute bacterial skin and skin structure infections and hospital-acquired bacterial pneumonia caused by Gram-positive bacteria. Daptomycin, linezolid, and vancomycin are commonly used antibiotics for these indications. With increased selective pressure to these antibiotics, outbreaks of bacterial resistance to these antibiotics have been reported. This in vitro pilot study evaluated the activity of iclaprim against methicillin-resistant Staphylococcus aureus (MRSA) isolates, which were also not susceptible to daptomycin, linezolid, or vancomycin. Iclaprim had an MIC ≤ 1 µg/ml to the majority of MRSA isolates that were nonsusceptible to daptomycin (5 of 7 (71.4%)), linezolid (26 of 26 (100%)), or vancomycin (19 of 28 (66.7%)). In the analysis of time-kill curves, iclaprim demonstrated ≥ 3 log10 reduction in CFU/mL at 4–8 hours for tested strains and isolates nonsusceptible to daptomycin, linezolid, or vancomycin. Together, these data support the use of iclaprim in serious infections caused by MRSA nonsusceptible to daptomycin, linezolid, or vancomycin.

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and surveillance data prior to 2006 suggested that iclaprim was active against Gram-positive pathogens including emerging drug-resistant pathogens. In an era of increasing antimicrobial resistance, we undertook testing iclaprim and comparators against 931 Gram-positive clinical isolates from the United States and Europe collected between 2015 and 2016. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing criteria. MIC50/MIC90 was 0.03/0.12 for all Staphylococcus aureus, 0.06/0.06 for methicillin-susceptible S. aureus, 0.03/0.12 for methicillin-resistant S. aureus, 0.12/0.5 for Streptococcus agalactiae, ≤0.015/≤0.015 for Streptococcus anginosus, 0.03/0.06 for Streptococcus dysgalactiae, and ≤0.015 /0.03 μg/mL for Streptococcus pyogenes. Iclaprim was active against a contemporary collection (2015–2016) of Gram-positive bacteria isolated from the skin or soft tissue from patients with SSSI from the United States and Europe.

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim–sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose–response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 μg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 μg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia.

The objective of this study was to demonstrate the efficacy of iclaprim in a neutropenic rat lung infection model with methicillin-resistant Staphylococcus aureus (MRSA) entrapped in alginate beads. An inoculum of 5.25 × 105 colony-forming units (CFU)/mL of S. aureus strain AH1252 was administered intratracheally to rats with prepared alginate bacteria suspensions. Beginning 2 h post-infection, rats received: (1) iclaprim 80 mg/kg (n = 16); (2) iclaprim 60 mg/kg (n = 16), or (3) vancomycin 50 mg/kg (n = 24), for 3 days via subcutaneous (SC) injection every 12 h. Twelve hours after the last treatment, rats were euthanized and lungs collected for CFU determination. Iclaprim administered at 80 mg/kg or 60 mg/kg or vancomycin 50 mg/kg SC twice a day for 3 days resulted in a 6.05 log10 CFU reduction (iclaprim 80 mg/kg compared with control, p

Purpose The primary objective of this Phase II study was to compare the clinical cure rates of 2 iclaprim dosages versus vancomycin in the treatment of patients with nosocomial pneumonia suspected or confirmed to be caused by gram-positive pathogens. Methods This study was a double-blind, randomized, multicenter trial. A total of 70 patients were randomized 1:1:1 to receive iclaprim 0.8 mg/kg IV q12h (iclaprim q12h; n = 23), iclaprim 1.2 mg/kg IV q8h (iclaprim q8h; n = 24), or vancomycin 1 g IV q12h (vancomycin; n = 23) for 7 to 14 days. The primary end point was clinical cure in the intention-to-treat population at test of cure (TOC; 7 [1] days’ posttreatment) visit. Findings The baseline and demographic characteristics of patients treated with either iclaprim or vancomycin were comparable. Cure rates in the intention-to-treat population were 73.9% (17 of 23), 62.5% (15 of 24), and 52.2% (12 of 23) at the TOC visit in the iclaprim q12h, iclaprim q8h, and vancomycin groups, respectively (iclaprim q12h vs vancomycin, P = 0.13; iclaprim q8h vs vancomycin, P = 0.47). The death rates within 28 days of the start of treatment were 8.7% (2 of 23), 12.5% (3 of 24), and 21.7% (5 of 23) for the iclaprim q12h, iclaprim q8h, and vancomycin groups (no statistically significant differences). The adverse event profile of both iclaprim dosing regimens was similar to that of vancomycin. Implications Iclaprim had clinical cure rates and a safety profile comparable with vancomycin among patients with nosocomial pneumonia. Iclaprim could be an important new therapeutic option for the treatment of nosocomial pneumonia, and a pivotal clinical trial is warranted to evaluate its safety and efficacy in this indication.

Background Trimethoprim inhibits sodium channels in the distal portion of the renal tubule, thereby impairing renal potassium excretion. Trimethoprim has been associated with a greater risk of hyperkalemia compared with other antibiotics (amoxicillin, nitrofurantoin, cefalexin, ciprofloxacin). An analysis of Phase 3 studies was conducted to determine whether iclaprim, under development for ABSSSI and also a selective bacterial dihydrofolate reductase inhibitor like trimethoprim, is associated with hyperkalemia, relative to vancomycin, an antibiotic not associated with hyperkalemia. Methods A post-hoc safety analysis was conducted on pooled results of two Phase 3, double-blind, randomized (1:1), active-controlled trials (REVIVE-1/-2) in patients with ABSSSI. These trials compared iclaprim 80 mg fixed doses with vancomycin 15 mg/kg; both administered intravenously every 12 hours for 5–14 days. Hyperkalemia was defined as serum potassium (K) ≥5.5 mmol/L, if normal at baseline, while on study drug. Hyperkalemia was compared between treatment groups and stratified subgroup comparisons were performed. Results Demographics and baseline disease characteristics were similar between the pooled iclaprim and vancomycin groups (table). Hyperkalemia occurred during treatment in 1.5% (9/592) and 2.5% (15/599) of patients treated with iclaprim and vancomycin, respectively. Of the patients with hyperkalemia, one patient in each treatment group had moderate to severe renal impairment (creatinine clearance [CrCl] 15–59 mL/minute). Among patients with moderate to severe renal impairment on any RAS, KSD or K supplements, hyperkalemia occurred in 1/16 and 0/16 patients in the iclaprim and vancomycin groups, respectively, and in 2/83 and 0/46 patients with mild to no renal impairment. No patients with hyperkalemia experienced adverse events of palpitations, chest pain, myalgia, muscular weakness or fatigue. Conclusion No differences in hyperkalemia were seen between the iclaprim and vancomycin groups in the Phase 3 REVIVE studies. In general, few cases of hyperkalemia occurred among patients with renal impairment treated with concomitant angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers treated with iclaprim. Disclosures All authors: No reported disclosures.

Background The incidence and outcomes of patients with S. aureus isolates with an iclaprim MIC >8 µg/mL, a concentration that is not systemically achievable, were determined among patients from two Phase 3 studies for the treatment of ABSSSI, REVIVE-1 and -2. Methods REVIVE-1 and REVIVE-2 studies were 600-patient, double-blinded, randomized (1:1), active-controlled trials among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg (adjusted for renal function), both administered intravenously over 2 hours every 12 hours for 5–14 days. Patients had a bacterial skin infection suspected or confirmed to be due to a Gram-positive pathogen with a lesion size ≥75 cm2. An early clinical response (ECR) was defined as a ≥20% reduction in lesion size compared with baseline at the early time point (ETP) 48–72 hours after the start of administration of the study drug in the intent-to-treat (ITT) population. A clinical cure, defined as complete resolution of all signs and symptoms of ABSSSI was measured at the end of therapy (EOT) and test of cure (TOC) visit, 7–14 days after the last dose of study drug. At baseline, EOT and TOC visits, ABSSSIs were sampled for microbiological culture and broth microdilution susceptibility testing conducted in accordance with CLSI M7. Results The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC >8 µg/mL was 2.0% (16/790). Six were MSSA and 10 were MRSA. The clinical outcomes of these infections included ECR of 63% (10/16), EOT response of 81.3% (13/16) and the TOC response of 75% (12/16). For microbiological outcomes of these infections, the end of therapy response was 92.9% (13/14) and the test of cure response was 92.3% (12/13). In comparison, there was less variation in vancomycin MICs among the S. aureus isolates. For patients who were randomized to vancomycin and had a pathogen identified from their ABSSSI, the pooled ECR was 82.6% (242 of 293) at a vancomycin MIC of 0.5–1 µg/mL and one isolate from a patient with ECR had a MIC of 2 µg/mL. Conclusion Patients receiving iclaprim had good clinical and microbiological responses against S. aureus isolates with an iclaprim MIC >8 µg/mL, which are uncommon (2.0%). Disclosures All authors: No reported disclosures.

Acinetobacter baumannii bacteremia is becoming more prevalent and is associated with increasing morbidity and mortality. Escalating antibacterial resistance further contributes to therapeutic dilemmas, enhanced infection control support and poorer outcomes in patients infected with these bacteria. A retrospective analysis of patients whose blood cultures produced A. baumannii from January 2007 through January 2013 was performed. Data regarding the epidemiologic features, antimicrobial susceptibility and outcomes of patients with A. baumannii bacteremia were collected and analyzed. Sixty A. baumannii isolates each from a different patient were identified. The Charlson Comorbidity Index (≥3) was the greatest among patients with multi-drug resistance (MDR) compared to intermediate drug resistance (IDR) and pan-sensitive (PS) A. baumannii. The mean APACHE II scores for MDR, IDR and PS A. baumannii bacteremia were 21, 15 and 11, respectively (P < 0.05, MDR v. PS). Seventy-three percent of the isolates were resistant to quinolones, 44% to piperacillin/tazobactam, 45% to amikacin, 22% to imipenem, 0% to ticarcillin/clavulanate, and 0% to polymyxin. Among 28 patients with MDR A. baumannii bacteremia, 20 received inadequate empiric treatment, and 16 of these patients died (80%). Of the remaining eight patients with MDR bacteremia who received adequate empiric antibiotics, only two died (25%). The severity of underlying illness, degree of antibiotic resistance and receiving inadequate initial antibiotic therapy are associated with mortality among patients with bacteremia due to A. baumannii.

We conducted a study to assess the characteristics, treatment and outcomes associated with Clostridium difficile associated diarrhea in a Veterans Affairs Medical Center. Fifty-eight consecutive individual cases of C. difficile infection in 2013 were observed within the Veterans Affairs New Jersey Health Care System (VA NJHCS). We molecularly typed all 58 individual strains and identified the associated characteristics, treatment and outcomes. Forty-four out of 58 specimens (76%) which were probed had characteristics of the epidemic strain BI/NAP1/027 making this virulent strain to be the predominate strain at the VA NJHCS. All C. difficile BI/NAP1/027 strains were resistant to fluoroquinolones and sensitive to fidaxomicin, metronidazole and vancomycin. Fidaxomicin had the most potent in vitro activity (MIC90 = 0.5 μg/ml) against the BI/NAP1/027 strain. Twenty-six of 44 patients (59%) with the virulent strain were from a long-term care facility (LTCF). Patients possessing the virulent strain from the LTCF had a mean APACHE II score of 14.1 and a predicted death rate of 21.9%. Two-third of patients were treated with metronidazole alone (mean APACHE II scores 9.6), and one-third required oral vancomycin and metronidazole (mean APACHE II scores 14.1). There were no C. difficile infection related deaths. C. difficile BI/NAP1/027, an epidemic strain, is the endemic strain at the VA NJHCS, but no increased mortality was seen with infection with this strain.

Background: Complicated skin and skin structure infections (cSSSIs) due to Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are associated with significant morbidity. Re-ducing MRSA carriage has been a focus of infection control interventions. The prevalence of MRSA colonization after successful treatment of a MRSA cSSSI is unknown. Methods: Secondary analysis of a randomized controlled trial comparing linezolid and vancomycin for the treatment of MRSA cSSSI. Adult patients that had a colonization culture, confirmed MRSA cSSSI, received at least one dose of study treatment, and had an outcome recorded at end of study. Patient, clinical characteristics and prevalence of colonization were compared by treatment regimens. A multivariate regression model identified predictors of MRSA colonization at EOS. Results: There were 456 patients evaluated. The prevalence of MRSA colonization was higher for vancomycin treated patients compared to linezolid treated patients at end of treatment (EOT) (28% vs. 5%, p < 0.001) and EOS (34% vs. 22%, p < 0.01). Independent predictors of colonization at EOS after treatment for a MRSA cSSSI included diagnosis, primarily driven by abscess, black race, treatment with vancomycin, MRSA mixed infection and male gender. Conclusion: Patients treated with linezolid for a cSSSI had less MRSA colonization at EOT and EOS compared to those treated with vancomycin. Multiple independent predictors of MRSA colonization were identified. Additional studies evaluating the relationship of MRSA colonization after treatment of cSSSI are needed.

Data from a prospective, randomized, open-label, active-controlled, multicenter, Phase 4 study comparing oral or intravenous linezolid with intravenous vancomycin for treatment of complicated skin and soft-tissue infections caused by methicillin resistant Staphylococcus aureus was used to determine the association between staphylococcal cassette chromosome mec (SCCmec) type and patient’s clinical presentation, infection severity, intravenous therapy duration and length of stay (LOS). Compared to SCCmec types I, II, and III, SCCmec type IV, PVL+ was associated with more frequent presentation of abscesses, lower severity scores, and shorter intravenous therapy duration and LOS in both treatment groups.

Background There are few data on dose optimization and clinical outcomes of antimicrobial agents based on patients' weight, despite the rising prevalence of obesity. Because there are physiologic, pharmacologic, and dosing differences related to weight, it is important to evaluate the impact of weight on antimicrobial agents to optimize clinical outcomes. Objectives This study compared effects of weight on efficacy and safety in patients treated with linezolid or vancomycin for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods We analyzed data from 2 clinical trials of patients randomized to receive a fixed dose of linezolid or weight-based dosing of vancomycin for the treatment of cSSSIs or NP caused by MRSA. For each study, patients were stratified into quartiles (Q1–4 [lowest to highest weight, respectively]). Clinical success, microbiologic success, and adverse events (AEs) were evaluated. Results The analysis included 632 patients with cSSSIs (linezolid, n=316; vancomycin, n=316) and 447 patients with NP (linezolid, n=224; vancomycin, n=223). Among patients with cSSSIs, clinical success rates at the study end with fixed-dose linezolid were similar across all weight quartiles and similar to weight-based dosing of vancomycin for Q1–3. Among Q4 (the highest weight quartile [97–295 kg]), clinical success with vancomycin was significantly lower compared with linezolid (69.5% vs 86.2%; P = 0.03). Among patients with NP, no significant differences in success rates between fixed-dose linezolid and weight-based dosing of vancomycin were observed across all quartiles. Frequencies of AEs were consistent across the quartiles for both indications and by treatment. Conclusions Except for Q4 within the vancomycin-treated patients for MRSA cSSSI, the efficacy of fixed-dosed linezolid and weight-based dosing of vancomycin was maintained across all weight quartiles and MRSA infection types. The AEs were consistent with the known safety profiles of each drug regardless of weight quartile. ClinicalTrials.gov identifiers: NCT00087490 and NCT00084266.

Objectives Uncovering heterogeneities in longitudinal patterns (trajectories) of opioid use among individuals with opioid use disorder can increase our understanding of disease progression and treatment responses to improve care. The present study aims to identify distinctive opioid use trajectories and factors associated with these patterns among participants randomized to treatment with methadone (MET) or buprenorphine + naloxone (BUP). Methods Growth mixture modeling was applied to identify distinctive opioid use trajectories among 795 opioid users after their enrollment in a multisite trial during 2006 to 2009, with follow-up interviews conducted during 2011 to 2014. Results Four distinctive trajectories were identified based on opioid use over the follow-up period: low use (42.0%), high use (22.3%), increasing use (17.1%), and decreasing use (18.6%). Greater odds of being in the high use group (relative to low use) was associated with Hispanics (relative to African American, odds ratio [OR] 3.21), injection drug use (OR 2.12), higher mental health functioning at baseline (OR 1.23), location on the West Coast (vs East Coast, OR 2.15), and randomization to BUP (relative to MET, OR 1.53). High use and increasing use groups had greater severity in problems related to drug, employment, legal, and social/family relationships, and worsened mental health functioning at follow-up. Participation in treatment significantly accounted for both within and between-group differences in opioid use. Conclusions Continued treatment is necessary to reduce risk for opioid use and related adverse consequences, particularly among individuals (eg, injecting drug) at risk for consistently high level of opioid use.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and altered bowel habits in the absence of specific organic pathology. Although the underlying pathogenesis of IBS is not well-understood, small intestinal bacterial overgrowth (SIBO) or other abnormalities in the gut flora is believed to contribute to the development of a subset of IBS cases. Rifaximin is a poorly absorbed antimicrobial with activity against enteric pathogens. A number of studies have shown a significant improvement in IBS symptoms with antibiotic therapy including rifaximin. In this review, we discuss the pharmacokinetics, in vitro susceptibility profile, and efficacy and safety data from clinical trials of rifaximin treatment of IBS.

We evaluated drug efficacy and safety among patients with and without vascular disease who were treated with linezolid or vancomycin for a lower-extremity complicated skin and skin structure infection (cSSSI) caused by methicillin-resistant Staphylococcus aureus (MRSA).We pooled data from two randomized clinical trials evaluating the efficacy and safety of linezolid 600 mg intravenously (IV) or orally every 12 h and vancomycin 15 mg/kg or 1 g IV every 12 h for the treatment of cSSSI caused by culture-proved MRSA.There were 477 patients for analysis. Among patients with vascular disease (linezolid n=139, vancomycin n=135), the clinical success rate was 80.4% and 66.7% (p=0.02) for patients treated with linezolid and vancomycin, respectively. Among patients without vascular disease (linezolid n=91, vancomycin n=112), the clinical success rate was 94.5% and 89.4%, respectively (p=0.24). Linezolid-treated patients had fewer IV catheter-site complications and less kidney impairment but more frequent thrombocytopenia than those who received vancomycin, regardless of the presence or absence of vascular disease.Linezolid is an effective treatment for patients with and without vascular disease who have a lower-extremity cSSSI caused by MRSA. The safety data were consistent with the known safety profiles of linezolid and vancomycin given for this indication.

BackgroundLinezolid is active against a broad range of gram-positive pathogens and has the potential to also affect production of bacterial toxins and host immune function.ObjectiveTo assess the evidence for direct effects of linezolid on bacterial toxin synthesis and modulation of host immune responses.MethodsLiterature searches were performed of the PubMed and OVID databases. Reviews and non–English language articles were excluded. Articles with information on the effect of linezolid on bacterial toxin synthesis and immune responses were selected for further review, and data were summarized.ResultsSubstantial in vitro evidence supports effects of linezolid on bacterial toxin production; however, the strength of the evidence and the nature of the effects are mixed. In the case of Staphylococcus aureus, repeated observations support the inhibition of production of certain staphylococcal toxins (Panton-Valentine leukocidin, protein A, and α- and β-hemolysin) by linezolid, whereas only solitary reports indicate inhibition (toxic shock syndrome toxin-1, coagulase, autolysins, and enterotoxins A and B) or stimulation (phenol-soluble modulins) of toxin production by linezolid. In the case of Streptococcus pyogenes, there are solitary reports of linezolid inhibition (protein M, deoxyribonuclease, and streptococcal pyrogenic exotoxins A, B, and F) or stimulation (immunogenic secreted protein 2 and streptococcal inhibitor of complement-mediated lysis) of toxin production, whereas published evidence for effects on streptolysin O production is conflicting. In vitro data are limited, but suggest that linezolid might also have indirect effects on host cytokine expression through inhibition of bacterial production of toxins. In vivo data from preclinical animal studies and a single clinical study in humans are limited and equivocal insofar as a potential role for linezolid in modulating the host inflammatory response; this is due in part to the difficulty in isolating antimicrobial effects and toxin synthesis inhibitory effects of linezolid from any secondary effects on host inflammatory response.ConclusionsAvailable evidence supports the possibility that linezolid can inhibit, and in some cases stimulate, toxin production in clinically relevant pathogens. However, more research will be needed to determine the potential clinical relevance of those findings for linezolid.

Objectives and methods: The present study’s objective was to evaluate serotonin toxicity with concomitant use of linezolid or comparators and serotonergic agents from 20 Phase III and IV comparator-controlled clinical studies on treatment of various Gram-positive infections. All reported adverse events were evaluated for serotonin toxicity using exact and surrogate terms consistent with Sternbach Criteria and Hunter Serotonin Toxicity Criteria. Results: Baseline demographics and co-morbidities were similar between linezolid and comparator groups. No patients in either group were reported to have adverse events identified as serotonin toxicity. Among the patients receiving at least one serotonergic agent, 9 of the 2208 (0.41%) linezolid patients and 3 of the 2057 (0.15%) comparator patients met the Sternbach Criteria [risk ratio (RR) 2.79; 95% confidence interval (95% CI) 0.76 –10.31]; 3 (0.14%) of the linezolid patients and 1 (0.05%) of the comparator patients met the Hunter Serotonin Toxicity Criteria (RR 2.79; 95% CI 0.29 –26.85). No patients met both criteria. Most patients meeting criteria for serotonin toxicity had past or present co-morbidities that may have contributed to or overlapped with reported adverse events. Conclusions: While the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk appears to be low. Based on the large database of Phase III and IV studies included in our analysis, we did not find enough evidence to conclude that linezolid-induced serotonin toxicity was different from that of comparators.

The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150 mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r-alone group) were also pooled with group B subjects from 3 similar phase I drug-drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC(0-12,ss)) and steady-state maximum measured plasma concentration over a dosing interval (C(max,ss)) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C(12,ss)) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355.

Objective The aim of the study was to compare all-cause adverse events (AEs) and those caused by intravenous (IV) catheter-site complications (IVCSCs) using data from a previously published study of the use of linezolid or vancomycin for treatment of complicated skin and skin structure infections (cSSSI) suspected or proven to be caused by methicillin-resistant Staphylococcus aureus. Methods To examine the incidence of AEs caused by the 2 antibiotic treatments, we conducted a post hoc analysis of data from a prospective, open-label, randomized, multicenter phase 4 study. Patients were randomized to treatment with either oral (PO) or IV linezolid 600 mg every 12 hours or with IV vancomycin 15 mg/kg every 12 hours with dose adjustment as needed. Study treatment was administered for 7 to 14 days. We excluded patients with baseline bacteremia (n = 11) and those who started on PO linezolid (n = 215). We analyzed data only from patients who received at least 1 dose of IV study medication. Results Patient demographics and types of cSSSI were comparable among patients receiving linezolid (n = 315) and vancomycin (n = 511). Mean durations of IV therapy for patients receiving linezolid and vancomycin were 4.5 days and 7.6 days (1,418 and 3,884 patient-days, respectively). All-cause AEs were reported in 50% and 51% of patients in the linezolid and vancomycin groups, respectively; all-cause IVCSCs were reported in 2% and 7%, respectively. Treatment-related IVCSCs were reported in 1 patient in the linezolid group and 16 patients in the vancomycin group. Conclusions The overall rate of AEs was similar among patients receiving linezolid and vancomycin, but AEs caused by IVCSCs were more frequent among patients receiving vancomycin and rare episodes of bacteremia and sepsis were more common in the linezolid group.

Background: Antimicrobial resistance among Streptococcus pneumoniae is of concern. Up to 30% of pneumococcal isolates worldwide are multidrug resistant. Objective: The objective of this analysis was to assess the effectiveness of linezolid for the treatment of pneumonia caused by S pneumoniae , including multidrug-resistant S pneumoniae (MDRSP). Methods: Data from 7 Phase II and III clinical trials that assessed the efficacy of linezolid in community- or hospital-acquired pneumonia were pooled. Adults and children (aged ≤12 years) received linezolid 600 mg and 10 mg/kg, respectively, IV or PO q12h for 7 to 14 days, with the exception of patients with documented bacteremia who could be treated for up to 28 days. Patients with a confirmed baseline isolate of S pneumoniae , including MDRSP, were assessed for clinical and microbiological outcomes. MDRSP was defined as an isolated strain of S pneumoniae that was resistant to ≥3 classes of antibiotics. Clinical cure was defined as the resolution of clinical signs and symptoms of pneumonia compared with baseline, with either improvement or absence of progression of abnormalities on chest radiography. Microbiological eradication was defined as documented or presumed eradication at the test-of-cure (TOC) visit. Results from patients with indeterminate or missing outcomes at TOC were not included in the analyses. Results: Of the patients with no bacteremia and treated with linezolid, 19 adults had MDRSP and 165 had non-MDRSP, and 3 children had MDRSP and 7 had non-MDRSP. Clinical cure and microbiological eradication rates were not significantly different between those infected with an MDRSP or non-MDRSP pathogen, respectively, in adults (16/19 [84%] and 150/164 [91%]) and children (3/3 [100%] and 7/7 [100%]). Conclusion: Linezolid was efficacious for the treatment of pneumonia caused by S pneumoniae, including multidrug-resistant strains.

Background The objective of this evaluation was to provide an analysis of pooled efficacy data from two parallel Phase 3 trials of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, compared with vancomycin for the treatment of patients with wound infections including surgical site infections (SSI). Methods A pooled analysis of patients with wound infections was conducted from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2), which included a total of 602 patients with wound infections. The data were analyzed separately and then pooled to determine the efficacy of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg. Both drugs were administered intravenously every 12 hours for 5 to 14 days according to the investigator assessment of clinical response. The primary endpoint of these studies was to determine whether iclaprim was noninferior (NI; 10% margin) to vancomycin in achieving a ≥20% reduction in lesion size (early clinical response [ECR] at 48 to 72 hours after initiation of the study drug (early time point [ETP]), compared with baseline in the intent-to-treat (ITT) population. Results Iclaprim had similar ECR rates at ETP compared with vancomycin among the subset of patients with wound infections (see table). The median treatment duration for both iclaprim and vancomycin was 7 days (range 5–14 days). Conclusion In this post-hoc analysis of the REVIVE studies, iclaprim achieved NI to vancomycin in both studies, based on ECR at ETP, in the subgroup of patients with wound infections. These results suggest that iclaprim may be a valuable treatment option for patients with wound infections, including SSI, suspected or confirmed to be due to Gram-positive pathogens. Disclosures D. Huang, Motif BioSciences: Employee, Salary. G. R. Corey, Motif BioSciences: Board Member, Consulting fee. T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. T. P. Lodise Jr., Motif BioSciences: Board Member, Consulting fee. W. O’Rirodan, Motif BioSciences: Board Member, Consulting fee. M. Wilcox, Motif BioSciences: Board Member, Consulting fee. T. M. File Jr., Motif BioSciences: Board Member, Consulting fee. M. Dryden, Motif BioSciences: Board Member, Consulting fee. B. Balser, Motif BioSciences: Consultant, Consulting fee. E. Desplats, Motif BioSciences: Consultant, Consulting fee.

The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355 ⁄ r) with emtricitabine (FTC) ⁄ tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC ⁄ TDF (200 ⁄ 300 mg) once daily (QD) for 7 days and then co-administered with BILR 355 ⁄ r( 150⁄ 100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355 ⁄ r( 150⁄ 100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administra- tion with BILR 355 ⁄ r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC0-24,ss, Cmax,ss and C0-12,ss were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC0-24,ss, Cmax,ss and C24,ss were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC ⁄ TDF resulted in an 18% increase in AUC0-12,ss, 14% increase in Cmax,ss and 19% increase in C12,ss for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-adminis- tration of FTC ⁄ TDF with BILR 355 ⁄ r. Highly active antiretroviral therapy (HAART), antiretroviral therapy that combines three or more anti-human immunode- ficiency virus (HIV)-1 agents, has proven to be effective in reducing viral load and HIV-1-related mortality and morbid- ity (1,2). The recommended HAART often includes a dual nucleoside reverse-transcriptase inhibitors (NRTI) 'back- bone' with the addition of a protease inhibitor or non- nucleoside reverse transcriptase inhibitor. TRUVADA � (Gilead, Foster City, CA, USA) tablets are fixed-dose combination tablets containing emtricitabine (FTC) (200 mg) and tenofovir disoproxil fumarate (TDF) (300 mg). FTC is a synthetic nucleoside analogue of cyti- dine. Tenofovir DF or TDF, a prodrug of tenofovir, is converted in vivo to tenofovir, an acyclic nucleoside phos- phonate (nucleotide) analogue of adenosine 5¢-monophos- phate (3). Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase and show good efficacy in combating HIV-1 infection. In addition, the FTC ⁄ TDF fixed-dose combination displays a superior safety profile compared with thymidine analogues. After oral administration, FTC is rapidly and nearly completely absorbed, and the systemic FTC is preliminarily eliminated by renal excretion, with 60-70 %o f an oral dose excreted in urine as unchanged drug. After oral administration, TDF is rapidly absorbed and converted to the active form, tenofovir. Urinary excretion is the predominant elimination pathway, with approximately 70-80% of the intravenous dose recov- ered as unchanged drug in the urine. The renal excretion of both FTC and tenofovir is through a combination of glo

Patients with AIDS frequently develop diarrhoeal illness. In this randomized, controlled study, 260 patients were screened for those who had not had diarrhoea in the preceding 3 months and who had received a stable highly active antiretroviral therapy regimen for at least 6 weeks prior to the study enrolment. A total of 148 patients met the inclusion criteria and were enrolled: 75 patients were randomly assigned to an intensive handwashing intervention (i.e. handwashing after defecation, after cleaning infants who had defecated, before preparing food, before eating, and before and after sex) and 73 patients were randomly assigned to the control group. Patients in both groups were called weekly by telephone to determine compliance with handwashing and to determine the number of diarrhoeal episodes for the preceding week. Patients were observed for 1 year. Patients assigned to the intensive handwashing intervention group washed their hands more frequently compared with the control group (seven vs four times a day, respectively; P P Giardia lamblia, Cryptosporidium, Entamoeba histolytica and Shigella flexneri. These data suggest that intensive handwashing reduces diarrhoeal illness in patients with AIDS.

Background & Aims: Antimotility agents provide rapid temporary relief of acute diarrhea, whereas antibiotics slowly cure the illness. Thus, the combination of an antimotility agent and an antibiotic may provide greater therapeutic benefit than either drug alone. This study evaluated the efficacy and safety of rifaximin-loperamide in the treatment of travelers' diarrhea. Methods: Consenting adults with acute diarrhea (≥3 unformed stools in 24 hours with ≥1 symptom of enteric infection) were randomized to receive rifaximin 200 mg 3 times daily for 3 days; loperamide 4 mg initially followed by 2 mg after each unformed stool; or a combination of both drugs using the same dosing regimen. The primary end point was the median time from beginning therapy until passing the last unformed stool. Results: A total of 310 patients completed treatment with rifaximin (n = 102), loperamide (n = 104), or rifaximin-loperamide combination therapy (n = 104). The groups showed demographic similarity. Rifaximin and rifaximin-loperamide significantly reduced the median time until passage of the last unformed stool (32.5 ± 4.14 h and 27.3 ± 4.13 h, respectively) vs loperamide (69 ± 4.11 h; P = .0019). The mean number of unformed stools passed during illness was lower with rifaximin-loperamide (3.99 ± 4.28) compared with rifaximin (6.23 ± 6.90; P = .004) or loperamide alone (6.72 ± 6.93; P = .002). All treatments were well tolerated with a low incidence of adverse events. Conclusions: Rifaximin-loperamide therapy provided rapid symptomatic improvement and greater overall wellness compared with either agent alone.