Once-Daily Plazomicin for Complicated Urinary Tract Infections.

BACKGROUND: The increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae. METHODS: We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population. RESULTS: Plazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, -3.4 percentage points; 95% confidence interval [CI], -10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum ß-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 µmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group. CONCLUSIONS: Once-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).

ARGONAUT II Study of the In Vitro Activity of Plazomicin against Carbapenemase-Producing Klebsiella pneumoniae.

Plazomicin was tested against 697 recently acquired carbapenem-resistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of >32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate.

Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profiles of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.

Plazomicin is a novel aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem, and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem, or tigecycline human-equivalent doses alone or in combinations of plazomicin-meropenem and plazomicin-tigecycline. Treatments were initiated at 1 h postinfection and continued for 24 h. Efficacy was assessed by determination of mouse survival through 96 h. Compared with the survival of the controls, plazomicin monotherapy produced a significant improvement in survival for all mice infected with the isolates (P < 0.05) and resulted in overall survival rates of 86% (n = 50) and 53.3% (n = 30) for mice infected with isolates with plazomicin MICs of ≤4 and ≥8 mg/liter, respectively (P < 0.05). The survival of the meropenem and tigecycline groups correlated well with susceptibilities of their respective isolates, with incremental increases in survival being observed at lower MIC values. For mice infected with isolate Klebsiella pneumoniae 561 (plazomicin, meropenem, and tigecycline MICs, 8, >32, and 2 mg/liter, respectively), combination therapies showed a significant reduction in mortality compared with that achieved with any monotherapy (P < 0.05). Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably, for mice infected with isolates with plazomicin MICs of ≤4 mg/liter. As evidenced by our current data, coadministration of meropenem or tigecycline could potentially lead to a further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MICs of ≤4 mg/liter, including carbapenem-resistant isolates.

In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes.

Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/MIC90, 0.5/2 µg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 µg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, by applying CLSI breakpoints. The activities of plazomicin were similar among Enterobacteriaceae species, with MIC50 values ranging from 0.25 to 1 µg/ml, with the exception of Proteus mirabilis and indole-positive Proteeae that displayed MIC50 values of 2 µg/ml. For 97 carbapenem-resistant Enterobacteriaceae (CRE), which included 87 isolates carrying blaKPC, plazomicin inhibited all but 1 isolate at ≤2 µg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5 and 95.5% of the gentamicin-resistant isolates, 96.9 and 96.5% of the tobramycin-resistant isolates, and 64.3 and 90.0% of the amikacin-resistant isolates according to CLSI and EUCAST breakpoints, respectively. The activities of plazomicin against Pseudomonas aeruginosa (MIC50/MIC90, 4/16 µg/ml) and Acinetobacter species (MIC50/MIC90, 2/16 µg/ml) isolates were similar. Plazomicin was active against coagulase-negative staphylococci (MIC50/MIC90, 0.12/0.5 µg/ml) and Staphylococcus aureus (MIC50/MIC90, 0.5/0.5 µg/ml) but had limited activity against Enterococcus spp. (MIC50/MIC90, 16/64 µg/ml) and Streptococcus pneumoniae (MIC50/MIC90, 32/64 µg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying blaKPC from U.S. hospitals, supports the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

The Continued Value of Disk Diffusion for Assessing Antimicrobial Susceptibility in Clinical Laboratories: Report from the Clinical and Laboratory Standards Institute Methods Development and Standardization Working Group.

Expedited pathways to antimicrobial agent approval by the U.S. Food and Drug Administration (FDA) have led to increased delays between drug approval and the availability of FDA-cleared antimicrobial susceptibility testing (AST) devices. Antimicrobial disks for use with disk diffusion testing are among the first AST devices available to clinical laboratories. However, many laboratories are reluctant to implement disk diffusion testing for a variety of reasons, including dwindling proficiency with this method, interruptions of the laboratory workflow, uncertainty surrounding the quality and reliability of disk diffusion tests, and a perceived need to report MIC values to clinicians. This minireview provides a report from the Clinical and Laboratory Standards Institute Methods Development and Standardization Working Group on the current standards and clinical utility of disk diffusion testing.

Activity of plazomicin compared with other aminoglycosides against isolates from European and adjacent countries, including Enterobacteriaceae molecularly characterized for aminoglycoside-modifying enzymes and other resistance mechanisms.

Background: Plazomicin is a next-generation aminoglycoside that was developed to overcome common aminoglycoside-resistance mechanisms. Objectives: We evaluated the activity of plazomicin and comparators against clinical isolates collected from 26 European and adjacent countries during 2014 and 2015 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends (ALERT) global surveillance programme. Methods: All 4680 isolates collected from 45 hospitals were tested for susceptibility to antimicrobials using the reference broth microdilution method. Selected isolates were screened for genes encoding carbapenemases, aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases. Results: Plazomicin (MIC50/90 0.5/2 mg/L) inhibited 95.8% of Enterobacteriaceae at ≤2 mg/L, including carbapenem-resistant Enterobacteriaceae (MIC50/90 0.25/128 mg/L). Plazomicin was more active compared with other aminoglycosides against isolates carrying blaKPC (MIC50/90 0.25/2 mg/L), isolates carrying blaOXA-48-like (MIC50/90 0.25/16 mg/L) and carbapenemase-negative isolates (MIC50/90 0.25/1 mg/L). Approximately 60% of the isolates harbouring blaVIM and blaNDM-1 carried 16S rRNA methyltransferases (mainly rmtB and armA). AME genes were detected among 728 isolates and 99.0% of these were inhibited by plazomicin at ≤2 mg/L. Plazomicin activity against Pseudomonas aeruginosa (MIC50/90 4/8 mg/L) was similar to amikacin activity (MIC50/90 2/16 mg/L). Plazomicin demonstrated activity against CoNS (MIC50/90 0.12/0.25 mg/L) and Staphylococcus aureus (MIC50/90 0.5/1 mg/L). Plazomicin activity was limited against Acinetobacter spp. (MIC50/90 8/>128 mg/L), Enterococcus spp. (MIC50/90 32/128 mg/L) and Streptococcus pneumoniae (MIC50/90 32/64 mg/L). Conclusions: Plazomicin demonstrated activity against Enterobacteriaceae isolates tested in this study, including isolates carrying AMEs and a high percentage of the carbapenem-non-susceptible isolates. Plazomicin displayed activity against staphylococci.

Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates.

Objectives: Plazomicin, a novel aminoglycoside with in vitro activity against MDR Gram-negative organisms, is under development to treat patients with serious enterobacterial infections. We evaluated the activity of plazomicin and comparators against colistin-resistant enterobacterial isolates. Methods: Susceptibility to plazomicin and comparators was tested by broth microdilution for a collection of 95 colistin-resistant enterobacterial isolates collected from 29 hospitals in eight countries. Forty-two isolates (Klebsiella pneumoniae and Klebsiella oxytoca) possessed chromosomally encoded resistance mechanisms to colistin, 21 isolates (Escherichia coli and Salmonella enterica) expressed the mcr-1 gene, 8 isolates (Serratia, Proteus, Morganella and Hafnia) were intrinsically resistant to colistin and 24 isolates (K. pneumoniae, E. coli and Enterobacter spp.) had undefined, non-mcr-1 mechanisms. Susceptibility profiles were defined according to CLSI for aminoglycosides and to EUCAST for colistin and tigecycline. Results: Plazomicin inhibited 89.5% and 93.7% of the colistin-resistant enterobacterial isolates at ≤ 2 and ≤4 mg/L, respectively. MICs of plazomicin were ≤2 mg/L for all of the mcr-1 positive isolates and ≤4 mg/L for all the intrinsic colistin-resistant Enterobacteriaceae. Non-susceptibility to currently marketed aminoglycosides was common: amikacin, 16.8%; gentamicin, 47.4%; and tobramycin, 63.2%. Plazomicin was the most potent aminoglycoside tested with an MIC90 of 4 mg/L, compared with 32, >64 and 64 mg/L for amikacin, gentamicin and tobramycin, respectively. Conclusions: Plazomicin displayed potent activity against colistin-resistant clinical enterobacterial isolates, including those expressing the mcr-1 gene. Plazomicin was more active than other aminoglycosides against this collection of isolates. The further development of plazomicin for the treatment of infections due to MDR Enterobacteriaceae is warranted.

Distinctive Binding of Avibactam to Penicillin-Binding Proteins of Gram-Negative and Gram-Positive Bacteria.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that covalently acylates a variety of ß-lactamases, causing inhibition. Although avibactam presents limited antibacterial activity, its acylation ability toward bacterial penicillin-binding proteins (PBPs) was investigated. Staphylococcus aureus was of particular interest due to the reported ß-lactamase activity of PBP4. The binding of avibactam to PBPs was measured by adding increasing concentrations to membrane preparations of a variety of Gram-positive and Gram-negative bacteria prior to addition of the fluorescent reagent Bocillin FL. Relative binding (measured here as the 50% inhibitory concentration [IC50]) to PBPs was estimated by quantification of fluorescence after gel electrophoresis. Avibactam was found to selectively bind to some PBPs. In Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, and S. aureus, avibactam primarily bound to PBP2, with IC50s of 0.92, 1.1, 3.0, and 51 µg/ml, respectively, whereas binding to PBP3 was observed in Streptococcus pneumoniae (IC50, 8.1 µg/ml). Interestingly, avibactam was able to significantly enhance labeling of S. aureus PBP4 by Bocillin FL. In PBP competition assays with S. aureus, where avibactam was used at a fixed concentration in combination with varied amounts of ceftazidime, the apparent IC50 of ceftazidime was found to be very similar to that determined for ceftazidime when used alone. In conclusion, avibactam is able to covalently bind to some bacterial PBPs. Identification of those PBP targets may allow the development of new diazabicyclooctane derivatives with improved affinity for PBPs or new combination therapies that act on multiple PBP targets.

Validation of Sensititre Dry-Form Broth Microdilution Panels for Susceptibility Testing of Ceftazidime-Avibactam, a Broad-Spectrum-ß-Lactamase Inhibitor Combination.

Ceftazidime-avibactam is a broad-spectrum-ß-lactamase inhibitor combination in late-stage clinical development for the treatment of serious infections. In preparation for clinical microbiology laboratory use, a validation experiment was initiated to evaluate a commercial broth microdilution product (Sensititre dried MIC susceptibility system) compared to reference panels using 525 recent clinical isolates. Among 11 pathogen groups, all had Sensititre MIC/reference MIC ratios predominantly at 1 (47.5% to 97.5%), and automated and manual endpoint results did not differ. Enterobacteriaceae MIC comparisons showed a modest skewing of Sensititre MIC results toward an elevated MIC (33.9%), but the essential agreement was 98.9% with 100.0% reproducibility. In conclusion, Sensititre panels produced accurate ceftazidime-avibactam MIC results, allowing quality MIC guidance for therapy following regulatory approvals.

In Vitro Activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a Panel of Older and Contemporary Antimicrobial Agents against Carbapenemase-Producing Gram-Negative Bacilli.

Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo-ß-lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.

Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against ß-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa.

Avibactam, a non-ß-lactam ß-lactamase inhibitor with activity against extended-spectrum ß-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 µg/ml) were lower than those for ceftazidime alone (0.06 to ≥256 µg/ml) against all isolates except for 2 P. aeruginosa isolates (1 blaVIM-positive isolate and 1 blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were ≤4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ≥3-log10 decrease in the number of CFU/ml was observed at 6 h for all Enterobacteriaceae, and a 2-log10 reduction in the number of CFU/ml was observed at 6 h for 3 of the 6 P. aeruginosa isolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused by Enterobacteriaceae and P. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive ß-lactamases.

Contemporary diversity of ß-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent ß-lactamase groups.

Escherichia coli (328 isolates), Klebsiella pneumoniae (296), Klebsiella oxytoca (44), and Proteus mirabilis (33) isolates collected during 2012 from the nine U.S. census regions and displaying extended-spectrum-ß-lactamase (ESBL) phenotypes were evaluated for the presence of ß-lactamase genes, and antimicrobial susceptibility profiles were analyzed. The highest ESBL rates were noted for K. pneumoniae (16.0%, versus 4.8 to 11.9% for the other species) and in the Mid-Atlantic and West South Central census regions. CTX-M group 1 (including CTX-M-15) was detected in 303 strains and was widespread throughout the United States but was more prevalent in the West South Central, Mid-Atlantic, and East North Central regions. KPC producers (118 strains [112 K. pneumoniae strains]) were detected in all regions and were most frequent in the Mid-Atlantic region (58 strains). Thirteen KPC producers also carried blaCTX-M. SHV genes encoding ESBL activity were detected among 176 isolates. Other ß-lactamase genes observed were CTX-M group 9 (72 isolates), FOX (10), TEM ESBL (9), DHA (7), CTX-M group 2 (3), NDM-1 (2 [Colorado]), and CTX-M groups 8 and 25 (1). Additionally, 62.9% of isolates carried ≥2 ß-lactamase genes. KPC producers were highly resistant to multiple agents, but ceftazidime-avibactam (MIC50/90, 0.5/2 µg/ml) and tigecycline (MIC50/90, 0.5/1 µg/ml) were the most active agents tested. Overall, meropenem (MIC50, ≤0.06 µg/ml), ceftazidime-avibactam (MIC50, 0.12 to 0.5 µg/ml), and tigecycline (MIC50, 0.12 to 2 µg/ml) were the most active antimicrobials when tested against this collection. NDM-1 producers were resistant to all ß-lactams tested. The diversity and increasing prevalence of ß-lactamase-producing Enterobacteriaceae have been documented, and ceftazidime-avibactam was very active against the vast majority of ß-lactamase-producing strains isolated from U.S. hospitals.

Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic.

TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC(90), 0.015 µg/ml), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC(90), 0.03 µg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤ 0.12 µg/ml. A postantibiotic effect of >2 h was observed after exposure to TD-1792.

Specificity of induction of the vanA and vanB operons in vancomycin-resistant enterococci by telavancin.

Telavancin is a bactericidal, semisynthetic lipoglycopeptide indicated in the United States for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria and is under investigation as a once-daily treatment for nosocomial pneumonia. The related vanA and vanB gene clusters mediate acquired resistance to glycopeptides in enterococci by remodeling the dipeptide termini of peptidoglycan precursors from D-alanyl-D-alanine (D-Ala-D-Ala) to D-alanyl-D-lactate (D-Ala-D-Lac). In this study, we assessed the ability of telavancin to induce the expression of van genes in VanA- and VanB-type strains of vancomycin-resistant enterococci. Vancomycin, teicoplanin, and telavancin efficiently induced VanX activity in VanA-type strains, while VanX activity in VanB-type isolates was inducible by vancomycin but not by teicoplanin or telavancin. In VanA-type strains treated with vancomycin or telavancin, high levels of D-Ala-D-Lac-containing pentadepsipeptide were measured, while D-Ala-D-Ala pentapeptide was present at very low levels or not detected at all. In VanB-type strains, vancomycin but not telavancin induced high levels of pentadepsipeptide, while pentapeptide was not detected. Although vancomycin, teicoplanin, and telavancin induced similar levels of VanX activity in VanA-type strains, these organisms were more sensitive to telavancin, which displayed MIC values that were 32- and 128-fold lower than those of vancomycin and teicoplanin, respectively.

Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia.

OBJECTIVES: Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA). This study characterizes the microbiological activity of telavancin against vancomycin-susceptible S. aureus (VSSA), hVISA and VISA strains. METHODS: Reference strains of VSSA, hVISA and VISA were assessed for potential telavancin heteroresistance by population analysis. In addition, the efficacies of telavancin (40 mg/kg subcutaneously every 12 h for 4 days) and vancomycin (110 mg/kg subcutaneously every 12 h for 8 days) were compared in a neutropenic murine model (immunocompromised female non-Swiss albino mice) of bacteraemia caused by hVISA strain Mu3. Blood and spleen bacterial titres were quantified from cohorts of mice euthanized pre-treatment and at 24 h intervals post-treatment for 8 days. RESULTS: Telavancin was active against all strains of S. aureus tested, with MIC values < or =0.5 mg/L. Population analyses revealed no evidence of subpopulations with reduced susceptibility to telavancin. In the murine bacteraemia model of hVISA infection, all animals were bacteraemic pre-treatment and mortality was 100% within 16-24 h post-infection in untreated animals. Treatment with telavancin was associated with lower spleen bacterial titres, lower rates of bacteraemia and lower overall mortality than treatment with vancomycin. CONCLUSIONS: These in vitro and pre-clinical in vivo studies demonstrate that telavancin has the potential to be efficacious in infections caused by hVISA.

A Broken Antibiotic Market: Review of Strategies to Incentivize Drug Development.

The threat posed by infections arising from antimicrobial-resistant bacteria is a global concern. Despite this trend, the future development of new antimicrobial agents is currently very uncertain. The lack of commercial success for newly launched antimicrobial agents provides little incentive to invest in the development of new agents. To address this crisis, a number of push and pull incentives have been constructed to support antimicrobial drug development. Push incentives, which are designed to lower the cost of developing new antimicrobial agents, include grants, contracts, public-private partnerships, tax credits, and clinical trial networks. Pull incentives, which are designed to facilitate higher financial returns for a newly launched antimicrobial agent, include those that decrease the time for a regulatory review, extend patent exclusivity, or provide premium pricing. Such incentives may also include direct, advanced, or milestone payments or they may be insurance-based whereby healthcare systems pay for the right to access an antimicrobial agent rather than the number of units administered. Another strategy involves the re-evaluation of interpretive criteria for in vitro susceptibility testing (susceptibility breakpoints) of old antimicrobial agents using the same standards applied to that of new agents, which will allow for an accurate determination of antimicrobial resistance. Although each of the above-described strategies will be important to ensure that antimicrobial agents are developed in the decades to come, the update of susceptibility breakpoints for old agents is a strategy that could be implemented quickly and one that could be the most effective for incentivizing drug developers and financiers to reconsider the development of antimicrobial agents.

Efficacy of telavancin against glycopeptide-intermediate Staphylococcus aureus in the neutropenic mouse bacteraemia model.

OBJECTIVES: The aim of the study was to compare the efficacies of telavancin and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous vancomycin-intermediate S. aureus (hVISA) in a neutropenic murine bacteraemia model. METHODS: Immunocompromised mice (female non-Swiss albino, 18-30 g) were inoculated intraperitoneally with 10(7) cfu/mL of GISA (strain HIP-5836 or Mu50) or hVISA (strain Mu3). Infected mice received a subcutaneous dose of telavancin (40 mg/kg) or vancomycin (110 mg/kg) at 4 and 16 h post-inoculation. Control animals received a subcutaneous dose of vehicle at 4 h post-inoculation only. Blood and spleen bacterial titres were quantified in drug-treated mice at 16, 28 and 52 h post-inoculation. RESULTS: Telavancin was 8-fold more potent than vancomycin against HIP-5836 (MIC 1 versus 8 mg/L), 16-fold more potent against Mu50 (MIC 0.5 versus 8 mg/L) and 8-fold more potent against Mu3 (MIC 0.25 versus 2 mg/L). Telavancin produced significant (P < 0.05) and sustained reductions in blood and spleen titres from pre-treatment levels in mice infected with HIP-5836, Mu50 or Mu3. Vancomycin lowered blood and spleen HIP-5836 counts transiently, but did not lower blood or spleen Mu50 or Mu3 counts significantly at any timepoint. Reductions in blood and spleen HIP-5836 and Mu3 titres and in spleen Mu50 titres at 52 h post-inoculation were significantly greater with telavancin than vancomycin (P < 0.05). CONCLUSIONS: Telavancin was more efficacious than vancomycin in clearing infections caused by GISA strains HIP-5836 and Mu50 and hVISA strain Mu3 in a neutropenic mouse bacteraemia model. Further evaluation of telavancin for GISA and hVISA bacteraemia is warranted.