Antimicrobial Management of Complicated Skin and Soft Tissue Infections in an Era of Emerging Multi-Drug Resistance: Perspectives from 5 Gulf Countries

The number of complicated skin and soft tissue infections (cSSTIs) in the Arabian Gulf region has risen in recent years, particularly those caused by multi-drug resistant (MDR) pathogens. The high prevalence of diabetes, obesity, and associated cardio-metabolic comorbidities in the region renders medical and surgical management of cSSTI patients with MDR infections challenging. An experienced panel of international and regional cSSTI experts (consensus group on cSSTIs) was convened to discuss clinical considerations for MDR infections from societal, antimicrobial stewardship, and cost perspectives, to develop best practice recommendations. This article discusses antibiotic therapies suitable for treating MDR cSSTIs in patients from the Gulf region and recommends that these should be tailored according to the local bacterial ecology by country and region. The article highlights the need for a comprehensive patient treatment pathway and defined roles of each of the multidisciplinary teams involved with managing patients with MDR cSSTIs. Aligned and inclusive definitions of cSSTIs for clinical and research purposes, thorough and updated epidemiological data on cSSTIs and methicillin-resistant Staphylococcus aureus in the region, clearcut indications of novel agents and comprehensive assessment of comparative data should be factored into decision-making are necessary.

Disclosure of a Promising Lead to Tackle Complicated Skin and Skin Structure Infections: Antimicrobial and Antibiofilm Actions of Peptide PP4-3.1

Efficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the new hope for the post-antibiotic era. Thus, future management of cSSTI may include use of peptides that, on the one hand, behave as AMP and, on the other, are able to promote fast and correct skin rebuilding. As such, we combined the well-known cosmeceutical pentapeptide-4 (PP4), devoid of antimicrobial action but possessing collagenesis-boosting properties, with the AMP 3.1, to afford the chimeric peptide PP4-3.1. We further produced its N-methyl imidazole derivative, MeIm-PP4-3.1. Both peptide-based constructs were evaluated in vitro against Gram-negative bacteria, Gram-positive bacteria, and Candida spp. fungi. Additionally, the antibiofilm activity, the toxicity to human keratinocytes, and the activity against S. aureus in simulated wound fluid (SWF) were assessed. The chimeric peptide PP4-3.1 stood out for its potent activity against Gram-positive and Gram-negative bacteria, including against MDR clinical isolates (0.8 ≤ MIC ≤ 5.7 µM), both in planktonic form and in biofilm matrix. The peptide was also active against three clinically relevant species of Candida fungi, with an overall performance superior to that of fluconazole. Altogether, data reveal that PP4-3.1 is as a promising lead for the future development of new topical treatments for severe skin infections.

1118. Population Pharmacokinetics of Contezolid Acefosamil and Contezolid – Rationale for a Safe and Effective Loading Dose Regimen

Background Contezolid (CZD) is a novel oral oxazolidnone with comparable activity and potentially improved safety compared to current oxazolidinones. The intravenous (IV) double prodrug contezolid acefosamil (CZDa) is converted via MRX-1352 to active CZD. CZDa paired with CZD holds promise as a safe and effective treatment for serious Gram-positive infections such as those caused by methicillin-resistant Staphylococcus aureus. Sequential therapy with CZDa IV followed by CZD oral (PO) offers flexible treatment options in hospital and outpatient settings for conditions such as diabetic foot infections. We aimed to design a CZDa/CZD dosage regimen leveraging population pharmacokinetic modeling (PopPK). Methods PopPK simultaneously fit data from 184 adult subjects. These were 1) plasma concentrations (by LC-MS/MS) of MRX-1352, CZD, and its metabolite MRX-1320 from 66 healthy subjects receiving CZDa (150-2400 mg IV) for up to 10 days, 2) CZD and MRX-1320 concentrations from 44 healthy subjects receiving single CZD PO doses of 400, 800, or 1200 mg with and without food or multiple doses Q12h for up to 28 days, and 3) CZD concentrations from 74 Phase 2 patients receiving CZD 800 mg PO Q12h. PopPK and Monte Carlo simulations were used to optimize CZD exposures. Results CZDa was rapidly converted to MRX-1352, which was converted less rapidly to CZD. CZD was well absorbed and food enhanced its bioavailability. For CZD 800 mg PO with food, apparent total clearance of CZD was 13.1 L/h (22% coefficient of variation) in healthy subjects and 14.5 L/h (53% CV) in patients. The apparent volume of distribution at steady-state was 20.5 L. A loading dose of CZDa 2000 mg IV, then CZDa 1000 mg IV Q12h, and followed by CZD 800 mg PO Q12h achieved areas under the curve (AUC) between 75 and 100 mg*h/L (medians; Figure) on all study days. Compared to CZD AUCs, the MRX-1352 AUCs during IV dosing were higher. While the median MRX-1320 AUCs were lower (18 to 48 mg*h/L), some accumulation was predicted in ~5% of subjects. Conclusion A loading dose of CZDa 2000 mg IV followed by either CZDa 1000 mg IV or CZD 800 mg PO Q12h was predicted to reliably achieve efficacious CZD exposures on day 1 and maintain those exposures throughout therapy. This regimen will be evaluated in Phase 3 studies in complicated skin infections and diabetic foot infections. Disclosures Jürgen B. Bulitta, PhD, MicuRx Pharmaceuticals, Inc. (Consultant) Barry HAFKIN, MD, MicuRx Pharmaceuticals Inc. (Consultant)

Comparative efficacy of delafloxacin for complicated and acute bacterial skin and skin structure infections: results from a network meta-analysis

Background Delafloxacin is a novel fluoroquinolone with broad antibacterial activity against pathogens causing acute bacterial skin and skin structure infections (ABSSSI). This network meta-analysis (NMA) was conducted to evaluate the relative efficacy of delafloxacin versus other comparators used for managing patients with ABSSSI. Methods A systematic literature review was conducted to identify randomised controlled trials (RCTs) evaluating adults (≥ 18 years) with ABSSSI, complicated SSSI (cSSSI), complicated skin and soft tissue infections (cSSTI) or severe cellulitis with pathogen of gram-positive, gram-negative, or mixed aetiology. OVID MEDLINE®, Embase, Epub Ahead of Print, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched from inception through 12 April 2019. A feasibility assessment was conducted, followed by an NMA, which was run in a Bayesian framework. The interventions included in the NMA encompassed monotherapy or combination therapies of amoxicillin/clavulanate, ampicillin/sulbactam, ceftaroline, ceftobiprole, dalbavancin, daptomycin, delafloxacin, fusidic acid, iclaprim, linezolid, omadacycline, oxacillin + dicloxacillin, standard therapy, tedizolid, telavancin, tigecycline, vancomycin, vancomycin + aztreonam and vancomycin + linezolid. Results A feasibility assessment was performed and evidence networks were established for composite clinical response (n = 34 studies), early clinical response (n = 16 studies) and microbiological response (n = 14 studies) in the overall study population, composite clinical response (n = 4 studies) in obese subpopulation and for composite clinical response (n = 18 studies) and microbiological response (n = 14 studies) in patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. Delafloxacin performed significantly better than fusidic acid, iclaprim, vancomycin, and ceftobiprole for composite clinical response. Delafloxacin was comparable to dalbavancin, daptomycin, fusidic acid, iclaprim, linezolid, omadacycline, tedizolid, vancomycin, vancomycin + aztreonam and vancomycin + linezolid in the analysis of early clinical response, whereas for microbiological response, delafloxacin was comparable to all interventions. In the obese subpopulation, the results favoured delafloxacin in comparison to vancomycin, whilst the results were comparable with other interventions among the MRSA subpopulation. Conclusions Delafloxacin is a promising new antibiotic for ABSSSI demonstrating greater improvement (composite clinical response) compared to ceftobiprole, fusidic acid, iclaprim, telavancin and vancomycin and comparable effectiveness versus standard of care for all outcomes considered in the study.

Plasma and Lung Tissue Pharmacokinetics of Ceftaroline Fosamil in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: An in-vivo Microdialysis Study

Background: Ceftaroline fosamil, a 5th generation cephalosporin antibiotic with activity against MRSA, is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetic data on free lung tissue concentrations in critical patient populations are lacking. Objectives: The aim of this study was to evaluate the pharmacokinetics of the high-dose regimen of ceftaroline in plasma and lung tissue in cardiac surgery patients during intermittent and continuous administration. Materials and Methods: 9 patients undergoing elective cardiac surgery on cardiopulmonary bypass were included in this study and randomly assigned to intermittent or continuous administration. 1800mg ceftaroline fosamil were administered intravenously as either 600mg over 2h q8h (intermittent group) or 600mg over 2h (loading dose) and 1200mg over 22h (continuous group). Interstitial lung tissue concentrations were measured by in-vivo microdialysis. Relevant pharmacokinetic parameters were calculated for each group. Results: Plasma exposure during intermittent and continuous administration were comparable to previously published studies and did not differ significantly between both groups. In-vivo microdialysis demonstrated reliable and adequate penetration of ceftaroline into lung tissue during intermittent and continuous administration. The AUC SS 0-8 and AUC tissue/plasma ratio were descriptively higher in the continuous group. Continuous administration of ceftaroline fosamil achieved significantly higher f T 4x>MIC than intermittent administration for pathogens with a minimal inhibitory concentration of 1mg/L. Conclusion: Ceftaroline showed adequate penetration into interstitial lung tissue of critically ill patients undergoing major cardiothoracic surgery, supporting its use for pneumonia caused by susceptible pathogens.