Enoxaparin treatment dosing for venous thromboembolism in pediatric patients with obesity.

BACKGROUND: The optimal enoxaparin dosing for treatment of venous thromboembolism (VTE) in pediatric patients with obesity remains uncertain. We described the mean enoxaparin dose required to attain anti-factor Xa (anti-Xa) levels of 0.5-1 unit/mL in pediatric patients with obesity. METHODS: Pediatric patients with obesity (body mass index [BMI] ≥95th percentile) who received treatment dose of enoxaparin from 2013 to 2022 and had at least one appropriately timed anti-Xa level were retrospectively evaluated. Daily enoxaparin dose required to achieve an anti-Xa level of 0.5-1 unit/mL was reviewed and compared by the severity of obesity. The correlation coefficients between enoxaparin dose requirement and BMI, BMI percentile, and weight were measured by Spearman's rank correlation coefficient. RESULTS: Pediatric patients with obesity (n = 89) required a mean enoxaparin dose of 0.8 ± 0.18 mg/kg twice daily to attain a therapeutic anti-Xa level. Children with BMI 95th-99th percentile and weight ≤100 kg achieved the target level on a significantly higher weight-based enoxaparin dose compared to BMI greater than 99th percentile (0.95 ± 0.15 vs. 0.75 ± 0.15 mg/kg twice daily; p < .001) and weight greater than 100 kg (0.95 ± 0.14 vs. 0.7 ± 0.12 mg/kg twice daily; p < .001). BMI, BMI percentile, and weight showed a moderate to strong negative correlation with enoxaparin dose requirement. CONCLUSIONS: Pediatric patients with obesity required a lower weight-based dose of enoxaparin to achieve a therapeutic anti-Xa than the recommended starting dose of 1 mg/kg twice daily for treatment of VTE. Among obesity indices, weight showed the strongest negative correlation with total daily enoxaparin requirement.

Enoxaparin thromboprophylaxis in hospitalized obese pediatric patients.

BACKGROUND: Enoxaparin is an anticoagulant used for pharmacologic thromboprophylaxis in pediatrics. Enoxaparin pharmacokinetics can be altered in the setting of obesity. Optimal enoxaparin dosing for thromboprophylaxis in children with obesity remains unclear. PROCEDURE: A retrospective review was conducted of pediatric patients who weighed ≥60 kg with BMI ≥ 95th percentile, received enoxaparin for thromboprophylaxis, and had at least one appropriately drawn anti-factor Xa (anti-Xa) from 2013 to 2022. Anti-Xa levels were reviewed for patients initially treated with enoxaparin 30 mg every 12 h. The average daily enoxaparin dose required to achieve an anti-Xa of 0.2-0.4 unit/mL, which was stratified by BMI percentile and weight, was calculated. RESULTS: Of 116 patients (median age 15.8 years) included for analysis, 106 patients were initially treated with enoxaparin 30 mg every 12 h. Anti-Xa levels were <0.2 unit/mL in 53% of patients with BMI > 99th percentile and 54% of patients >100 kg. Ninety-one patients had at least one anti-Xa 0.2-0.4 unit/mL with an average daily enoxaparin dosing of 66 mg. When stratified by severity of obesity, higher doses were required to attain an anti-Xa 0.2-0.4 unit/mL in patients with BMI > 99th percentile compared with those with 95th-99th percentile (67.8 ± 15.7 vs. 62 ± 5.6 mg/day, p = .01). Patients > 100 kg required significantly higher dose than those ≤100 kg (69.1 ± 15.5 vs 61.2 ± 7.3 mg/day, p = .002). CONCLUSIONS: Increased initial dosing and/or anti-Xa level monitoring should be considered in adolescents with severe obesity receiving enoxaparin thromboprophylaxis.

Outbreak report of polymyxin-carbapenem-resistant Klebsiella pneumoniae causing untreatable infections evidenced by synergy tests and bacterial genomes.

Polymyxin-carbapenem-resistant Klebsiella pneumoniae (PCR-Kp) with pan (PDR)- or extensively drug-resistant phenotypes has been increasingly described worldwide. Here, we report a PCR-Kp outbreak causing untreatable infections descriptively correlated with bacterial genomes. Hospital-wide surveillance of PCR-Kp was initiated in December-2014, after the first detection of a K. pneumoniae phenotype initially classified as PDR, recovered from close spatiotemporal cases of a sentinel hospital in Rio de Janeiro. Whole-genome sequencing of clinical PCR-Kp was performed to investigate similarities and dissimilarities in phylogeny, resistance and virulence genes, plasmid structures and genetic polymorphisms. A target phenotypic profile was detected in 10% (12/117) of the tested K. pneumoniae complex bacteria recovered from patients (8.5%, 8/94) who had epidemiological links and were involved in intractable infections and death, with combined therapeutic drugs failing to meet synergy. Two resistant bacterial clades belong to the same transmission cluster (ST437) or might have different sources (ST11). The severity of infection was likely related to patients' comorbidities, lack of antimicrobial therapy and predicted bacterial genes related to high resistance, survival, and proliferation. This report contributes to the actual knowledge about the natural history of PCR-Kp infection, while reporting from a time when there were no licensed drugs in the world to treat some of these infections. More studies comparing clinical findings with bacterial genetic markers during clonal spread are needed.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii.

Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL against the 50 isolates, there was a median 2-fold reduction in MEM and TGC MICs. In the TKAs, the COL+MEM combination was synergistic in 45 (90%) isolates and bactericidal in 43 (86%) isolates at 24 hours, whereas the COL+TGC combination TKAs demonstrated synergy in 32 (64%) isolates and bactericidal activity was shown in 28 (56%) isolates. Additionally, sulbactam (SUL) and TGC were added to the COL+MEM dual therapy regimen to assess the possible utility of a triple therapy regimen against five non-responsive isolates. The COL+MEM+SUL and COL+MEM+TGC regimens effectively restored synergy in (5/5) 100% of the isolates. The results of this study demonstrate the potential utility of COL combinations in the treatment of carbapenem-resistant isolates.

Impact of Daptomycin Dose Exposure Alone or in Combination with ß-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model.

Enterococcus faecium strains are commonly resistant to vancomycin and ß-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Biofilm Model.

Infections caused by biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) bacteria are challenging due to increasing antibiotic resistance. Synergistic activities of lipopeptides and lipoglycopeptides with ß-lactams have been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg of body weight and 10 mg/kg every 24 h [q24h]) alone and in combination with ceftaroline (CPT) (600 mg every 8 h [q8h]) or rifampin (RIF) (450 mg every 12 h [q12h]) against two biofilm-producing MRSA strains (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacies of the antibiotic combinations over 72 h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens and CPT alone demonstrated killing but did not reach bactericidal reduction at 72 h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains, with a rapid decrease in CFU/ml at 4 h that was bactericidal and maintained over the 72-h experiment (-Δ3.75 log10 CFU/ml from baseline; P < 0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24 h, with MIC values exceeding 32 mg/liter. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that TLV at 7.5 and 10 mg/kg q24h are equally effective in eradicating biofilm-associated MRSA strains in vitro.

Impact of cefazolin co-administration with vancomycin to reduce development of vancomycin-intermediate Staphylococcus aureus.

OBJECTIVE: Development of antimicrobial resistance during monotherapy of complicated methicillin-resistant Staphylococcus aureus bacteremia is problematic due to cross-resistance between vancomycin (VAN) and daptomycin, the only approved agents for this condition. Our objective was to demonstrate that development of resistance under conditions of suboptimal VAN (200 mg q 12 h) exposure in S. aureus can be attenuated by addition of cefazolin (CFZ). METHODS: Two strains of S. aureus, 1 methicillin-susceptible Staphylococcus aureus (MSSA) (RN9120) and 1 methicillin-resistant S. aureus (MRSA) (JH1), were evaluated. The organisms were exposed to subtherapeutic VAN concentrations in a 1-compartment pharmacokinetic/pharmacodynamic model combined with recycling in the presence and absence of CFZ. Changes in MIC to glyco/lipopeptides and ß-lactams along with susceptibility to human cathelicidin LL-37 killing were studied. Population analysis profiles (PAPs) were performed to detect changes in VAN heteroresistance. RESULTS: VAN MIC of both organisms increased from 1 to 4 mg/L within 144 h under subtherapeutic VAN exposure. Increase in VAN MIC was associated with increased glyco/lipopeptides MICs. Additionally, increased survival in LL-37 killing assays from 40% to >90% accompanied the increase in VAN MIC. Addition of CFZ prevented the emergence of VAN-intermediate S. aureus. PAPs demonstrated an attenuation of VAN area under the curve shift (reduced organism selection with higher MICs values) when suboptimal VAN exposure was accompanied with CFZ compared to VAN alone (MSSA 17.81 versus 36.027, MRSA -0.35 versus 17.92, respectively). Given the emerging data on the clinical benefits of ß-lactam adjunctive therapy in refractory MRSA bacteremia, additional studies on a larger collection of clinical isolates are needed to establish the utility of VAN plus CFZ for treatment of MRSA bacteremia.

Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for health care-associated infections, and treatment options are limited. Tedizolid (TZD) is a novel oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP) has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD and DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs). TZD simulations of 200 mg once daily and DAP simulations of 6 mg/kg of body weight and 10 mg/kg once daily were tested alone and in the combinations TZD plus DAP at 6 mg/kg or DAP at 10 mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine the antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents. Against both strains 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 h. In all cases, DAP alone was statistically superior to DAP plus TZD. When the combination was stopped after 96 h, transitioning to DAP at 6 mg/kg or DAP at 10 mg/kg alone resulted in better antibacterial activity than either of the TZD-plus-DAP combinations, further demonstrating antagonistic effects. Against MRSA, we demonstrated that TZD and DAP have antagonistic activity that hinders their overall antimicrobial efficacy. The exact nature of this antagonistic relationship is still undetermined, but its presence warrants further study of the potentially harmful grouping of the two antibiotics in clinical use.

Genomic characterization of an extensively drug-resistant KPC-2-producing Klebsiella pneumoniae ST855 (CC258) only susceptible to ceftazidime-avibactam isolated in Brazil.

In this study, we describe the genetic features of an XDR KPC-2-producing Klebsiella pneumoniae isolate by using whole-genome sequencing, its clinical-epidemiological context and susceptibility against antimicrobial combinations. The isolate belongs to clonal complex 258 and harbors several acquired genes and mutations associated with antimicrobial resistance.

Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs).

Objectives: Among viridans group streptococcal infective endocarditis (IE), the Streptococcus mitis group is the most common aetiological organism. Treatment of IE caused by the S. mitis group is challenging due to the high frequency of ß-lactam resistance, drug allergy and intolerability of mainstay antimicrobial agents such as vancomycin or gentamicin. Daptomycin has been suggested as an alternative therapeutic option in these scenarios based on its excellent susceptibility profile against S. mitis group strains . However, the propensity of many S. mitis group strains to rapidly evolve stable, high-level daptomycin resistance potentially limits this approach. Methods: We evaluated the activity of 6 mg/kg/day daptomycin alone or in combination with gentamicin, ceftriaxone or ceftaroline against two daptomycin-susceptible S. mitis group strains over 96 h in a pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations. Results: Daptomycin alone was not bactericidal and high-level daptomycin resistance evolved at 96 h in both organisms. Combinations of daptomycin + ceftriaxone and daptomycin + ceftaroline demonstrated enhanced killing activity compared with each antibiotic alone and prevented emergence of daptomycin resistance at 96 h. Use of gentamicin as an adjunctive agent neither improved the efficacy of daptomycin nor prevented the development of daptomycin resistance. Conclusions: Addition of ceftriaxone or ceftaroline to daptomycin improves the bactericidal activity against S. mitis group strains and prevents daptomycin resistance emergence. Further investigation with combinations of daptomycin and ß-lactams in a large number of strains is warranted to fully elucidate the clinical implications of such combinations for treatment of S. mitis group IE.

Role of Combination Antimicrobial Therapy for Vancomycin-Resistant Enterococcus faecium Infections: Review of the Current Evidence.

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including ß-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed.

Use of Ceftaroline Fosamil in Children: Review of Current Knowledge and its Application.

Ceftaroline is a novel cephalosporin recently approved in children for treatment of acute bacterial skin and soft tissue infections and community-acquired bacterial pneumonia (CABP) caused by methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae and other susceptible bacteria. With a favorable tolerability profile and efficacy proven in pediatric patients and excellent in vitro activity against resistant Gram-positive and Gram-negative bacteria, ceftaroline may serve as a therapeutic option for polymicrobial infections, CABP caused by penicillin- and ceftriaxone-resistant S. pneumoniae and resistant Gram-positive infections that fail first-line antimicrobial agents. However, limited data are available on tolerability in neonates and infants younger than 2 months of age, and on pharmacokinetic characteristics in children with chronic medical conditions and those with invasive, complicated infections. In this review, the microbiological profile of ceftaroline, its mechanism of action, and pharmacokinetic profile will be presented. Additionally, clinical evidence for use in pediatric patients and proposed place in therapy is discussed.

ß-Lactamase Inhibitors Enhance the Synergy between ß-Lactam Antibiotics and Daptomycin against Methicillin-Resistant Staphylococcus aureus.

The evidence for using combination therapy for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections is growing. In this study, we investigated the synergistic effect of daptomycin (DAP) combined with piperacillin-tazobactam and ampicillin-sulbactam against MRSA in time-kill experiments. Six of eight strains demonstrated synergy between DAP and the ß-lactam-ß-lactamase inhibitor (BLI) combination. In 5/8 strains, the synergy occurred only in the presence of the BLI, highlighting a role for BLIs in peptide-ß-lactam synergy.

Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia.

Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA). The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA. Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays. Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log10-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h. A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains. A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo This combination may warrant consideration for future clinical study in MSSA bacteremia.

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model.

Daptomycin (DAP) is being used more frequently to treat infections caused by vancomycin-resistant enterococcus (VRE). DAP tends to be less active against enterococci than staphylococci and may require high doses or combination therapy to be bactericidal. Fosfomycin (FOF) has activity against VRE and has demonstrated synergistic bactericidal activity with DAP in vitro The objective of this study was to evaluate the activity of DAP alone and in combination with FOF against VRE in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activity of DAP at 8 and 12 mg/kg of body weight/day (DAP 8 and DAP 12, respectively) and FOF of 40 mg/kg intravenously every 8 h, alone and in combination, were evaluated against 2 vancomycin-resistant Enterococcus faecium strains (8019 and 5938) and 2 vancomycin-resistant E. faecalis strains (V583 and R7302) in an in vitro PK/PD model over 72 h. Cell surface charge in the presence and absence of FOF was evaluated by zeta potential analysis. Daptomycin-boron-dipyrromethene (bodipy) binding was assessed by fluorescence microscopy. The addition of FOF to DAP 8 and DAP 12 resulted in significantly increased killing over DAP alone at 72 h for 8019, V583, and R7302 (P < 0.05). Therapeutic enhancement was observed with DAP 12 plus FOF against 8019, V583, and R7302. Cell surface charge became more negative after exposure to FOF by ∼2 to 8mV in all 4 strains. Daptomycin-bodipy binding increased by 2.6 times in the presence of fosfomycin (P < 0.0001). The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge. Further studies to clarify the role of intravenous FOF are warranted.

Evaluation of Pharmacodynamic Interactions Between Telavancin and Aztreonam or Piperacillin/Tazobactam Against Pseudomonas aeruginosa, Escherichia coli and Methicillin-Resistant Staphylococcus aureus.

INTRODUCTION: In clinical trials comparing telavancin (TLV) with vancomycin for treatment of hospital-acquired pneumonia, TLV demonstrated lower clinical cure rates than vancomycin in patients who had mixed gram-positive and -negative infections and were concomitantly treated with either aztreonam (ATM) or piperacillin/tazobactam (PTZ). Here, we investigated therapeutic interactions between TLV and ATM or PTZ in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model under simulated reduced renal function conditions. METHODS: In vitro one-compartment PK/PD models were run over 96 h simulating TLV 10 mg/kg every 48 h, ATM 500 mg every 8 h and PTZ continuous infusion 13.5 g over 24 h alone and in combination against P. aeruginosa, E. coli and methicillin-resistant S. aureus (MRSA). The efficacy of antimicrobials was evaluated by plotting time-kill curves and calculating the reduction in log10 cfu/ml over 96 h. RESULTS: Against both MRSA strains, TLV was rapidly bactericidal at 4 h and maintained its activity over 96 h with no observed antagonism by either ATM or PTZ. PTZ maintained bacteriostatic and bactericidal activities against E. coli ATCC 25922 and clinical strain R1022 at 96 h, whereas both strains regrew as soon as 24 h in ATM models. Against P. aeruginosa ATCC 27853, regrowth was noted at 24 h in models simulating ATM and PTZ. The addition of TLV to ATM or PTZ had no appreciable impact on activity against the two E. coli strains and P. aeruginosa strain. CONCLUSIONS: The combinations of TLV and either ATM or PTZ did not demonstrate any antagonistic activity. Clinical variables and patient characteristics should be further explored to determine possible reasons for discrepancies in outcomes. FUNDING: Theravance Biopharma Antibiotics, Inc.

Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro, Hollow-Fiber Model.

Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP+TOL-TAZ), DAP+TOL, DAP+TAZ, and DAP+CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 µg/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP+CFZ against both strains. The combination of DAP+TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP+TOL and DAP+TAZ were not bactericidal. No other regimens were bactericidal. DAP+TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP+TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP+CFZ demonstrated enhancement against both strains. The combination of DAP+CFZ warrants further clinical study.

Oritavancin Combinations with ß-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci.

Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 µg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 µg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 µg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.

Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist.

OBJECTIVE: To summarize the pharmacokinetic and pharmacodynamic properties of ticagrelor, a selective P2Y12 receptor antagonist, and evaluate its role in the treatment of patients with acute coronary syndromes (ACS). DATA SOURCES: A literature search was conducted in MEDLINE (1966-November 2009), International Pharmaceutical Abstracts (1970-November 2009), and EMBASE (1990-November 2009) using the MeSH terms and key words AZD6140, ticagrelor, P2Y12 receptor antagonist, cardiovascular disease, ACS, atherothrombosis, and platelets. STUDY SELECTION AND DATA EXTRACTION: Selected studies evaluated the pharmacology, pharmacokinetics, pharmacodynamics, safety, and efficacy of ticagrelor for the treatment of ACS. DATA SYNTHESIS: Ticagrelor selectively and reversibly blocks the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation. Optimal dosing strategy as determined by ticagrelor's pharmacokinetic and pharmacodynamic profile is a loading dose of 180 mg followed by 90 mg by mouth twice daily. At these doses, greater platelet inhibition is observed with ticagrelor as compared to clopidogrel 75 mg once daily in both clopidogrel-experienced and -naïve patients. Studies in patients experiencing ACS concluded that ticagrelor reduced the rate of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and overall mortality compared to clopidogrel without increasing major bleeding when administered with standard therapy for ACS. There was no significant difference in the risk of stroke with ticagrelor compared to clopidogrel; however, intracranial bleeding was more common with ticagrelor. Ticagrelor is well tolerated; however, minor bleeding, dyspnea, hypotension, nausea, and ventricular pauses were reported more frequently than with clopidogrel. Reversible inhibition with ticagrelor may allow for more rapid surgical intervention after discontinuation, suggesting greater flexibility in treatment of ACS. CONCLUSIONS: Ticagrelor's improved pharmacokinetic and pharmacodynamic profile builds upon the limitations of currently available P2Y12 receptor antagonists. Ticagrelor represents a promising approach for the prevention of cardiovascular events in patients with ACS.