Matthew G. Stilwell

Antipseudomonal activity of piperacillin/tazobactam: more than a decade of experience from the SENTRY Antimicrobial Surveillance Program (1997–2007)

We evaluated the susceptibility rates for piperacillin/tazobactam tested against Pseudomonas aeruginosa isolates from the Asia-Pacific (APAC), Europe (EU), Latin America (LA), and North America (NA) for 1997 to 2007. A total of 25 460 isolates were tested originating from APAC (4441), EU (7695), LA (4277), and NA (9047). All testing was performed by reference broth microdilution methods. The samples were collected from >110 medical centers and samples averaging >30 nations/year. For this analysis, results from 1997 to 2007, 1997 to 1999, 2005 to 2007, APAC, EU, LA, and NA were assessed against several broad-spectrum beta-lactams, including cefepime, ceftazidime, imipenem, meropenem, and piperacillin alone, for a total of 12 agents overall. Using P. aeruginosa breakpoints (< or =64 microg/mL), piperacillin/tazobactam had the broadest coverage (% susceptible) in 2 regions (EU, LA) and, overall, at 83.6% followed by meropenem (83.0%) > imipenem (79.7%) > piperacillin (79.5%) > cefepime (77.5%) > ceftazidime (75.8%). Other non-beta-lactam activity results were ciprofloxacin at only 71.5% susceptible, but tobramycin and polymyxin B had higher susceptibility rates (81.0% and 99.5%, respectively). Trends toward piperacillin/tazobactam resistance were noted between 1997 to 1999 and 2000 to 2007 in APAC (-11.6% susceptibility), NA (-4.0%), and EU (-2.3%). LA susceptibility rates were lowest overall but actually increased recently by +2.9% (current rate, 79.4% susceptible). For beta-lactamase inhibitor combinations, susceptibility rates were higher for piperacillin/tazobactam when compared in all regions with piperacillin alone (+2.6-7.1%) and greatest for LA isolates. In contrast, ticarcillin/clavulanate susceptibility rates were lower than ticarcillin tested alone in NA (-1.5%, antagonism), and this agent only inhibited 70.3% of isolates worldwide. In conclusion, piperacillin/tazobactam remained a very active beta-lactam when tested in vitro against clinical isolates of P. aeruginosa found in the SENTRY Program (1997-2007). Trends toward slightly decreased susceptibility were noted in all regions over the last decade (except LA); only polymyxins had susceptibility rates at >90%. Resistance surveillance programs should be sustained to document emerging resistance patterns of old and newer agents for difficult-to-treat pathogens such as P. aeruginosa.

Unmet Needs and Prospects for Oritavancin in the Management of Vancomycin-Resistant Enterococcal Infections

The treatment of infections caused by vancomycin-resistant enterococci (VRE) has become an important clinical challenge and compromises the care of critically ill patients. A striking increase in the frequency of nosocomial isolation of multidrug-resistant Enterococcus faecium has dramatically reduced the therapeutic alternatives because the majority of E. faecium isolates are resistant to ampicillin and vancomycin. Only 2 agents have US Food and Drug Administration approval for the treatment of VRE (E. faecium) infections, namely, linezolid and quinupristin/dalfopristin (Q/D). However, the use of these compounds in severe VRE infections is hampered by the lack of in vivo bactericidal activity, reports of therapeutic failures with monotherapy, a requirement for central venous access for administration (Q/D), and adverse-effect profile. The lipopeptide antimicrobial daptomycin has in vitro bactericidal activity against VRE; however, clinical use of this compound for VRE has not been well studied, and the reports of resistance emerging during therapy at the approved doses are worrisome. Tigecycline has in vitro bacteriostatic activity against VRE, but its clinical use for serious enterococcal infections is unclear due to low serum levels and static effect. Thus, current reliable therapies for VRE appear to be limited, and clinical data that use the above compounds are certainly scant. Oritavancin is an investigational semisynthetic glycopeptide with potent in vitro activity against VRE (both VanA and VanB phenotypes). Although review of the available preclinical data indicates that this compound used as a single agent is likely to have important limitations for the treatment of a severe VRE infection (ie, endocarditis), combination of oritavancin with other agents such as aminoglycosides may offer promise and deserves further investigation, as does use of oritavancin for less serious infections as monotherapy for vancomycin-susceptible and multidrug-resistant enterococci.

Activity of Linezolid against 3,251 Strains of Uncommonly Isolated Gram-Positive Organisms: Report from the SENTRY Antimicrobial Surveillance Program

ABSTRACT Linezolid was tested against 32 species of uncommonly isolated gram-positive organisms (3,251 strains) by reference MIC methods and found to be highly active (MIC50 range, 0.25 to 2 μg/ml; MIC90 range, 0.25 to 2 μg/ml). Only one isolate (viridans group streptococcus; 0.03% of tested strains) was resistant to linezolid.

Contemporary tetracycline susceptibility testing: doxycycline MIC methods and interpretive criteria (CLSI and EUCAST) performance when testing Gram-positive pathogens☆

International susceptibility testing breakpoint organizations and regulatory agencies have markedly differing interpretive criteria for the tetracycline class. Here we examined the magnitude of these differences for doxycycline and tetracycline hydrochloride (HCL) when tested against a collection of 13,176 Gram-positive cocci from a worldwide surveillance network (SENTRY Antimicrobial Surveillance Program, 2010). Clinical and Laboratory Standards Institute (CLSI) breakpoints are routinely higher, usually 4-fold, compared to those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST); however, CLSI recently (2013) modified Streptococcus pneumoniae breakpoints (≤ 2 μg/mL in 2012) to ≤ 0.25 and ≤ 1 μg/mL for doxycycline and tetracycline HCL, respectively. We report that these changes are a promising step toward international breakpoint harmonization, but lack a comprehensive approach needed for testing tetracyclines against all Gram-positive cocci. Generally, EUCAST breakpoint criteria showed i) lower spectrums (reduced susceptibility rates) for the tetracyclines, but highest for doxycycline versus all species examined; ii) greater test accuracy (lower predictive categorical errors), especially for tetracycline to predict doxycycline susceptibility (99.91%); and iii) zone diameter correlate breakpoints which are generally available online. Molecular tests for tet resistance genes demonstrate that tet (K) and tet (M) containing strains can occur in the susceptible population of MIC results by both CLSI and EUCAST breakpoint criteria. In summary, doxycycline continues to show greater comparative potency versus tetracycline HCL against all monitored Gram-positive species and the international harmonization of tetracycline breakpoints should be a priority, as the most recent CLSI update only addressed 1 streptococcal species and 2 tetracycline agents.

Comprehensive update of dalbavancin activity when tested against uncommonly isolated streptococci, Corynebacterium spp., Listeria monocytogenes, and Micrococcus spp. (1357 strains).

Dalbavancin is an investigational lipoglycopeptide having an extended serum elimination half-life allowing once-weekly dosing. Data from testing 1357 strains of uncommonly isolated species expand the dalbavancin spectrum details as follows (MIC50/90): β-haemolytic streptococcal serogroups C, F, and G (≤0.03/≤0.03 μg/mL), 7 viridans group of streptococci (≤0.03/≤0.03-0.06 μg/mL), 5 Corynebacterium spp. (0.06/0.12 μg/mL), Listeria monocytogenes (0.06/0.12 μg/mL), and Micrococcus spp. (≤0.03/≤0.03 μg/mL). Among all reported isolates, 99.8% of tested strains were inhibited at dalbavancin MIC values at ≤0.12 μg/mL. Dalbavancin remains very potent against rarer Gram-positive pathogens, using in vitro test experience with organisms cultured through 2011.

Interim susceptibility testing for ceftaroline, a new MRSA-active cephalosporin: selecting potent surrogate β-lactam markers to predict ceftaroline activity against clinically indicated species ☆ ☆☆

Ceftaroline, the bio-active form of parenterally administered ceftaroline fosamil, is a unique broad-spectrum cephalosporin with in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus and was approved for clinical use by the United States Food and Drug Administration in October 2010. In over a year since ceftaroline fosamil approval, no widely used commercial susceptibility test system has added this new compound to its product, therefore requiring use of alternative agar diffusion methods for clinical microbiology laboratories that want to test clinical isolates for ceftaroline susceptibility. An alternative strategy of applying a surrogate β-lactam class marker agent was assessed here, using results from 14,902 organisms (2008-2010) sampled in the USA. Very high and acceptable accuracy (≥ 99.75%) was observed for predicting ceftaroline susceptibility as follows: 1) use of imipenem or meropenem minimum inhibitory concentrations (MICs) at ≤ 8 μg/mL (susceptible and intermediate categories) when testing S. aureus; 2) use of ceftriaxone MIC at ≤ 2 μg/mL (susceptible and intermediate categories) when testing Streptococcus pneumoniae as well as other streptococci (S. pyogenes and S. agalactiae); and 3) use of ceftriaxone, or cefepime, or ceftazidime at ≤ 2 μg/mL (susceptible category) when testing Haemophilus influenzae. Only when testing indicated Enterobacteriaceae species using ceftriaxone susceptibility results did the ceftaroline-nonsusceptible errors increase (4.11%). These presented analyses offer a validated surrogate marker strategy for ceftaroline susceptibility testing, pending development and validation by the commonly used automated systems and agar diffusion commercial methods.

Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008–2011)

Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008-2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC50 values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06-0.5mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC90)=0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all β-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC50 and MIC90 values ranging from ≤ 0.015 mg/L to 0.03 mg/L and from ≤ 0.015 mg/L to 0.5mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results.

Contemporary potencies of minocycline and tetracycline HCL tested against Gram-positive pathogens: SENTRY Program results using CLSI and EUCAST breakpoint criteria

Tetracycline class agents vary widely in their activity against emerging important antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter spp. Also, published susceptibility breakpoints are discordant between the Clinical and Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and regulatory-approved documents. We have assessed the impact of these differences for tetracycline HCL and minocycline when tested against contemporary Gram-positive pathogens. The SENTRY Antimicrobial Surveillance Program (2011) compared minocycline and tetracycline HCL activity via reference methods (M07-A9) using a worldwide collection of S. aureus (SA; 4917 strains with 1955 MRSA), Streptococcus pneumoniae (SPN; 1899), S. pyogenes (GRA; 246), and S. agalactiae (GRB; 217). Regardless of applied categorical breakpoints, minocycline exhibited wider coverage (% susceptible) than tetracycline HCL of 4.5-11.8/0.5-2.6/1.4-2.3/0.4-0.4% for MRSA/SPN/GRB/GRA, respectively. Lower EUCAST susceptible breakpoints produced reduced susceptibility rates for minocycline ranging from no difference (≤0.5 μg/mL) for GRA to -8.9% (≤1 μg/mL) for MRSA (97.2% susceptible by CLSI; 88.3% by EUCAST). Use of tetracycline HCL-susceptible results to predict minocycline susceptibility was very accurate (99.0-100.0%), with absolute categorical agreement rates ranging from 92.1% to 98.4% (CLSI) to 98.4% to 99.6% (EUCAST) for streptococci; greatest predictive error was noted using the CLSI breakpoints (14.7%) compared to EUCAST criteria (only 5.0%; acceptable), both for MRSA testing dominated by false-resistant results for minocycline. In conclusion, minocycline demonstrates continued superior in vitro activity compared to tetracycline HCL when testing SA (especially MRSA) and pathogenic streptococci. When testing tetracyclines, laboratories must recognize the expanded spectrum of minocycline against certain pathogens and utilize methods minimizing interpretive error. We conclude that EUCAST breakpoint criteria (≤0.5 or ≤1 μg/mL) represent the most conservative (better recognize strains with tet resistance mechanisms) and accurate tetracycline breakpoint guidelines for testing contemporary isolates of Gram-positive cocci.

In vitro potency of doripenem tested against an international collection of rarely isolated bacterial pathogens

Doripenem, a new 1beta-methyl parenteral carbapenem, has very broad-spectrum activity against Gram-positive and Gram-negative aerobic bacteria. As noted here, the spectrum and potency extended to many rarely isolated species sampled by the Doripenem Global Surveillance Program. Among the species or species groups with <or=0.14% prevalence (1959 strains tested), doripenem was active against 98.9% of Enterobacteriaceae at <or=0.5 microg/mL. Similarly, more than 90% of other rarely isolated Gram-negative species isolates (Aeromonas spp., Delftia acidovorans, Haemophilus parainfluenzae, Neisseria meningitidis, Ochrobactrum anthropi, Pasteurella multocida, Pseudomonas oryzihabitans, and Pseudomonas stutzeri) were inhibited by <or=2 microg/mL of doripenem. The low-prevalence Gram-positive pathogens were generally less doripenem susceptible with MIC(90) results at >0.25 microg/mL for all tested species except Lactococcus garvieae, Listeria monocytogenes, and Micrococcus spp. In conclusion, doripenem exhibited a very wide spectrum but variable potencies against uncommonly cultured aerobic bacterial pathogens isolated in 2003 to 2007. These results confirm the potential use of this new carbapenem for broad-spectrum empiric or directed antimicrobial therapy.