The incidence and patient outcomes of ABSSSI by iclaprim MIC values in the phase 3 REVIVE trials for treatment of acute bacterial skin and skin structure infections.

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  %.

Pooled analysis of the phase 3 REVIVE trials: randomised, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin-structure infections.

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.].

Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

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 (AUC0-24ss), 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 (Cmaxss) 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 AUC0-24ss, AUC/MIC, and T > MIC while minimizing the probability of a Cmaxss 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 AUC0-24ss, AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a Cmaxss 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.

Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia.

Lysins are bacteriophage-derived enzymes that degrade bacterial peptidoglycans. Lysin CF-301 is being developed to treat Staphylococcus aureus because of its potent, specific, and rapid bacteriolytic effects. It also demonstrates activity on drug-resistant strains, has a low resistance profile, eradicates biofilms, and acts synergistically with antibiotics. CF-301 was bacteriolytic against 250 S. aureus strains tested including 120 methicillin-resistant S. aureus (MRSA) isolates. In time-kill studies with 62 strains, CF-301 reduced S. aureus by 3-log10 within 30 minutes compared to 6-12 hours required by antibiotics. In bacteremia, CF-301 increased survival by reducing blood MRSA 100-fold within 1 hour. Combinations of CF-301 with vancomycin or daptomycin synergized in vitro and increased survival significantly in staphylococcal-induced bacteremia compared to treatment with antibiotics alone (P < .0001). Superiority of CF-301 combinations with antibiotics was confirmed in 26 independent bacteremia studies. Combinations including CF-301 and antibiotics represent an attractive alternative to antibiotic monotherapies currently used to treat S. aureus bacteremia.

Lysins: the arrival of pathogen-directed anti-infectives.

Lysins represent a novel class of anti-infectives derived from bacteriophage. Lysins are bacterial cell-wall hydrolytic enzymes that selectively and rapidly kill (≥3 log c.f.u. in 30 min) specific Gram-positive bacteria providing a targeted therapeutic approach with minimal impact on unrelated commensal flora. The potential for bacterial resistance to lysins is considered low due to targeting of highly conserved peptidoglycan components. Through cutting-edge genetic engineering, lysins can be assembled into large libraries of anti-infective agents tailored to any bacterium of interest including drug-resistant Gram-positive pathogens such as meticillin- and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. Lysins can eliminate bacteria systemically and topically from mucosal surfaces and biofilms, as evidenced by experimental models of sepsis, endocarditis, pneumonia, meningitis, and nasopharyngeal, skin and vaginal decolonization. Furthermore, lysins can act synergistically with antibiotics and, in the process, resensitize bacteria to non-susceptible antibiotics. Clinical trials are being prepared to assess the safety and pharmacokinetic properties of lysins in humans.

Rifaximin--a novel antimicrobial for enteric infections.

Rifaximin is a poorly absorbed rifamycin antimicrobial drug with in vitro activity against Gram-positive, Gram-negative and anaerobic bacteria. The minimal concentration that inhibits 90% of strains of bacterial pathogens (MIC90) ranges between 32 and 64 microg/ml. Less than 1% of the drug is absorbed after oral administration. After three days of therapy, the average fecal level of this drug is 8000 microg/g of stool. Selection of resistant mutants, a problem with the related rifampin, appears to be unusual with rifaximin. Rifaximin shortens the duration of travelers' diarrhea and non-dysenteric diarrheal illness due to enterotoxigenic, enteroaggregative E. coli and Shigella sonnei without major alteration of aerobic fecal flora and without important side effects. The drug has been successfully used in preliminary studies of small bowel bacterial overgrowth syndrome and hepatic encephalopathy. To explain the beneficial effect of the drug on bacterial diarrhea without change in colonic flora or high rates of pathogen eradication, rifaximin may be more active against pathogens in the small bowel rather than the colon and/or the drug may alter the virulence of enteric pathogens in addition to organism inhibition.