Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase-Negative Staphylococcus spp., Including Multidrug-Resistant Strains

ABSTRACTStaphylococcus aureusand coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptibleS. aureus(MSSA), and methicillin-resistantS. aureus(MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (includingspa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. AllS. aureusand CoNS strains were inhibited by Debio1452 concentrations of ≤0.12 and ≤0.5 μg/ml, respectively. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/ml, and the MIC90s ranged from 0.008 to 0.03 μg/ml. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/ml). AmongS. aureusstrains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents.

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The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

mBio ◽

10.1128/mbio.01140-20 ◽

2020 ◽

Vol 11 (3) ◽

Cited By ~ 4

Author(s):

Wooseong Kim ◽

Guijin Zou ◽

Wen Pan ◽

Nico Fricke ◽

Hammad A. Faizi ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Lipid Bilayers ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Cross Resistance ◽

Lead Compound ◽

Neutral Form ◽

Cationic Form ◽

Antibiotic Resistant ◽

Content Type

ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.

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Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Foods ◽

10.3390/foods9040439 ◽

2020 ◽

Vol 9 (4) ◽

pp. 439 ◽

Cited By ~ 1

Author(s):

Vanessa Silva ◽

Telma de Sousa ◽

Paula Gómez ◽

Carolina Sabença ◽

Madalena Vieira-Pinto ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Agents ◽

Methicillin Resistant Staphylococcus Aureus ◽

Multidrug Resistant ◽

Diffusion Method ◽

Spa Typing ◽

Disk Diffusion Method ◽

Methicillin Resistant ◽

Resistance To Penicillin ◽

Mrsa Strains

Methicillin-resistant Staphylococcus aureus (MRSA) are one of the main pathogens associated with purulent infections. MRSA clonal complex 97 (CC97) has been identified in a wide diversity of livestock animals. Therefore, we aimed to investigate the antibiotic resistance profiles of MRSA strains isolated from purulent lesions of food-producing rabbits. Samples from purulent lesions of 66 rabbits were collected in a slaughterhouse in Portugal. Samples were seeded onto ORSAB plates with 2 mg/L of oxacillin for MRSA isolation. Susceptibility to antibiotics was tested by the disk diffusion method against 14 antimicrobial agents. The presence of resistance genes, virulence factors and the immune evasion cluster (IEC) system was studied by polymerase chain reaction. All isolates were characterized by multilocus sequence typing (MLST), agr and spa typing. From the 66 samples analyzed, 16 (24.2%) MRSA were detected. All strains were classified as multidrug-resistant as they were resistant to at least three classes of antibiotics. All isolates showed resistance to penicillin, erythromycin and clindamycin. Seven isolates were resistant to gentamicin and harbored the aac(6′)-Ie-aph (2″)-Ia gene. Resistance to tetracycline was detected in 10 isolates harboring the tet(K) gene. The IEC genes were detected in three isolates. MRSA strains belonged to CC97, CC1, CC5, CC15 or CC22. The isolates were assigned to six different spa types. In this study we found a moderate prevalence of multidrug-resistant MRSA strains in food-producing rabbits. This may represent concern for food safety and public health, since cross-contamination may occur, leading to the spread of MRSA and, eventually, the possibility of ingestion of contaminated meat.

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Intravitreal Injection of the Chimeric Phage Endolysin Ply187 Protects Mice from Staphylococcus aureus Endophthalmitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00126-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4621-4629 ◽

Cited By ~ 53

Author(s):

Pawan Kumar Singh ◽

David M. Donovan ◽

Ashok Kumar

Keyword(s):

Staphylococcus Aureus ◽

Intravitreal Injection ◽

Structural Integrity ◽

Therapeutic Potential ◽

Neutrophil Infiltration ◽

Multidrug Resistant ◽

Lytic Enzyme ◽

Resistant Bacteria ◽

Content Type ◽

Mrsa Strains

ABSTRACTThe treatment of endophthalmitis is becoming very challenging due to the emergence of multidrug-resistant bacteria. Hence, the development of novel therapeutic alternatives for ocular use is essential. Here, we evaluated the therapeutic potential of Ply187AN-KSH3b, a chimeric phage endolysin derived from the Ply187 prophage, in a mouse model ofStaphylococcus aureusendophthalmitis. Our data showed that the chimeric Ply187 endolysin exhibited strong antimicrobial activity against both methicillin-sensitiveS. aureusand methicillin-resistantS. aureus(MRSA) strains, as evidenced by MIC determinations, reductions in turbidity, and disruption of biofilms. Moreover, exposure ofS. aureusto Ply187 for up to 10 generations did not lead to resistance development. The intravitreal injection of chimeric Ply187 (at 6 or 12 h postinfection) significantly improved the outcome of endophthalmitis, preserved retinal structural integrity, and maintained visual function as assessed by electroretinogram analysis. Furthermore, phage lysin treatment significantly reduced the bacterial burden and the levels of inflammatory cytokines and neutrophil infiltration in the eyes. These results indicate that the intravitreal administration of a phage lytic enzyme attenuates the development of bacterial endophthalmitis in mice. To the best of our knowledge, this is the first study demonstrating the therapeutic use of phage-based antimicrobials in ocular infections.

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Extensive Genetic Diversity Identified among Sporadic Methicillin-Resistant Staphylococcus aureus Isolates Recovered in Irish Hospitals between 2000 and 2012

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02653-13 ◽

2014 ◽

Vol 58 (4) ◽

pp. 1907-1917 ◽

Cited By ~ 23

Author(s):

Peter M. Kinnevey ◽

Anna C. Shore ◽

Grainne I. Brennan ◽

Derek J. Sullivan ◽

Ralf Ehricht ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Agents ◽

Sequence Type ◽

Methicillin Resistant ◽

Content Type ◽

Type Assignment ◽

Antimicrobial Resistance Genes ◽

Microarray Profiling ◽

Mrsa Strains ◽

Ongoing Surveillance

ABSTRACTClonal replacement of predominant nosocomial methicillin-resistantStaphylococcus aureus(MRSA) strains has occurred several times in Ireland during the last 4 decades. However, little is known about sporadically occurring MRSA in Irish hospitals or in other countries. Eighty-eight representativepvl-negative sporadic MRSA isolates recovered in Irish hospitals between 2000 and 2012 were investigated. These yielded unusual pulsed-field gel electrophoresis and antibiogram-resistogram typing patterns distinct from those of the predominant nosocomial MRSA clone, ST22-MRSA-IV, during the study period. Isolates were characterized byspatyping and DNA microarray profiling for multilocus sequence type (MLST) clonal complex (CC) and/or sequence type (ST) and SCCmectype assignment, as well as for detection of virulence and antimicrobial resistance genes. Conventional PCR-based SCCmecsubtyping was undertaken when necessary. Extensive diversity was detected, including 38spatypes, 13 MLST-CCs (including 18 STs among 62 isolates assigned to STs), and 25 SCCmectypes (including 2 possible novel SCCmecelements and 7 possible novel SCCmecsubtypes). Fifty-four MLST-spa-SCCmectype combinations were identified. Overall, 68.5% of isolates were assigned to nosocomial lineages, with ST8-t190-MRSA-IID/IIE ± SCCM1predominating (17.4%), followed by CC779/ST779-t878-MRSA-ψSCCmec-SCC-SCCCRISPR(7.6%) and CC22/ST22-t032-MRSA-IVh (5.4%). Community-associated clones, including CC1-t127/t386/t2279-MRSA-IV, CC59-t216-MRSA-V, CC8-t008-MRSA-IVa, and CC5-t002/t242-MRSA-IV/V, and putative animal-associated clones, including CC130-t12399-MRSA-XI, ST8-t064-MRSA-IVa, ST398-t011-MRSA-IVa, and CC6-t701-MRSA-V, were also identified. In total, 53.3% and 47.8% of isolates harbored genes for resistance to two or more classes of antimicrobial agents and two or more mobile genetic element-encoded virulence-associated factors, respectively. Effective ongoing surveillance of sporadic nosocomial MRSA is warranted for early detection of emerging clones and reservoirs of virulence, resistance, and SCCmecgenes.

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Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02803-15 ◽

2016 ◽

Vol 60 (4) ◽

pp. 2273-2280 ◽

Cited By ~ 51

Author(s):

Robert K. Flamm ◽

Rodrigo E. Mendes ◽

Patricia A. Hogan ◽

Jennifer M. Streit ◽

James E. Ross ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Ribosomal Proteins ◽

The United States ◽

23S Rrna ◽

Surveillance Program ◽

Coagulase Negative Staphylococci ◽

Content Type ◽

Mrsa Strains ◽

Viridans Group Streptococci

ABSTRACTThelinezolidexperience andaccuratedetermination ofresistance (LEADER) surveillance program has monitored linezolid activity, spectrum, and resistance since 2004. In 2014, a total of 6,865 Gram-positive pathogens from 60 medical centers from 36 states were submitted. The organism groups evaluated wereStaphylococcus aureus(3,106), coagulase-negative staphylococci (CoNS; 797), enterococci (855),Streptococcus pneumoniae(874), viridans group streptococci (359), and beta-hemolytic streptococci (874). Susceptibility testing was performed by reference broth microdilution at the monitoring laboratory. Linezolid-resistant isolates were confirmed by repeat testing. PCR and sequencing were performed to detect mutations in 23S rRNA, L3, L4, and L22 proteins and acquired genes (cfrandoptrA). The MIC50/90forStaphylococcus aureuswas 1/1 μg/ml, with 47.2% of isolates being methicillin-resistantStaphylococcus aureus. Linezolid was active against allStreptococcus pneumoniaestrains and beta-hemolytic streptococci with a MIC50/90of 1/1 μg/ml and against viridans group streptococci with a MIC50/90of 0.5/1 μg/ml. Among the linezolid-nonsusceptible MRSA strains, one strain harboredcfronly (MIC, 4 μg/ml), one harbored G2576T (MIC, 8 μg/ml), and one containedcfrand G2576T with L3 changes (MIC, ≥8 μg/ml). Among CoNS, 0.75% (six isolates) of all strains demonstrated linezolid MIC results of ≥4 μg/ml. Five of these were identified asStaphylococcus epidermidis, four of which containedcfrin addition to the presence of mutations in the ribosomal proteins L3 and L4, alone or in combination with 23S rRNA (G2576T) mutations. Six enterococci (0.7%) were linezolid nonsusceptible (≥4 μg/ml; five with G2576T mutations, including one with an additionalcfrgene, and one strain withoptrAonly). Linezolid demonstrated excellent activity and a sustained susceptibility rate of 99.78% overall.

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Antibiotic profile of Staphylococcus aureus and Coagulase negative Staphylococci species isolated from raw camel milk from Garissa County, Kenya

East African Journal of Science, Technology and Innovation ◽

10.37425/eajsti.v2i4.364 ◽

2021 ◽

Vol 2 (4) ◽

Author(s):

Elly Kirwa ◽

Abong O Gabriel ◽

Timothy E. Maitho ◽

Mbindyo CM ◽

Abuom T O ◽

...

Keyword(s):

Antimicrobial Agents ◽

Clinical Laboratory ◽

Multidrug Resistant ◽

Camel Milk ◽

Resistant Bacteria ◽

Coagulase Negative Staphylococcus ◽

Coagulase Negative Staphylococci ◽

Cross Sectional ◽

Mannitol Salt Agar ◽

Milk Samples

The emergence of multidrug resistant bacteria in clinically challenging situations is a global concern. Staphylococcus resistance poses a threat to available therapeutic agents in management of camel diseases. S. aureus is often isolated from mastitic camel milk. Coagulase negative Staphylococcus (CoNS) can be pathogenic in humans and animals. This cross-sectional study investigated the antimicrobial resistance phenotypes of Staphylococci species in raw camel milk from Garissa County, Kenya. A total of 231 raw camel milk samples from healthy camels were collected. Disk diffusion was used to determine antimicrobial susceptibility of the isolates. Bacteria were revived in Buffered Peptone Water (BPW). Staphylococcus isolates were cultured on Mannitol Salt agar (MSA) and Blood Agar (BA). Coagulase and catalase tests were used to biochemically characterize the isolates. Antibiotic disks were placed on Mueller Hinton Agar and incubated at 37°C for 24 hours and diameters of zones inhibition measured. The readings were recorded as either susceptible, intermediate, or resistant based on the interpretative breakpoints by the veterinary Clinical Laboratory Standards Institute (CLSI) guidelines. Antimicrobial agents tested included; Ampicillin, Streptomycin, Cephalexin, Erythromycin, Ciprofloxacin, Cefoxitin, Tetracycline and Chloramphenicol. Out of the 231 raw camel milk samples cultured, 52.8% (122/231) Staphylococci isolates were recovered. Among the Staphylococci isolates 83.6% (102) were S. aureus and 16.4% (20) were CoNS. Overall, 83 (68%) isolates were catalase positive and 122 (91.7%) showed β-haemolysis on BA culture. Highest resistance was observed against Cephalexin (81.9%) and Streptomycin (72.1%) while the lowest resistance was seen against Chloramphenicol (1.6%) and Tetracycline (3.3%). MRSA and MRCoNS were reported at 9.8% and 15% of the isolates respectively. MDR was recorded in 43.4% of the isolates resistant to at least 3 or more antimicrobial groups while 39.3% isolates were resistant to 1 or 2 antimicrobial tested. In conclusion, the study showed that CoNS and S

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Staphylococcus chromogenes, a Coagulase-Negative Staphylococcus Species That Can Clot Plasma

Journal of Clinical Microbiology ◽

10.1128/jcm.03139-15 ◽

2016 ◽

Vol 54 (5) ◽

pp. 1372-1375 ◽

Cited By ~ 13

Author(s):

Danielle Cabral dos Santos ◽

Carla Christine Lange ◽

Pedro Avellar-Costa ◽

Katia Regina Netto dos Santos ◽

Maria Aparecida Vasconcelos Paiva Brito ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Dairy Cows ◽

Coagulase Negative Staphylococcus ◽

Coagulase Negative Staphylococci ◽

Content Type

Staphylococcus chromogenesis one of the main coagulase-negative staphylococci isolated from mastitis of dairy cows. We describeS. chromogenesisolates that can clot plasma. Since the main pathogen causing mastitis is coagulase-positiveStaphylococcus aureus, the coagulase-positive phenotype ofS. chromogenesdescribed here can easily lead to misidentification.

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Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid, Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00484-13 ◽

2013 ◽

Vol 57 (7) ◽

pp. 3178-3181 ◽

Cited By ~ 32

Author(s):

Helio S. Sader ◽

Robert K. Flamm ◽

Ronald N. Jones

Keyword(s):

Antimicrobial Agents ◽

Multidrug Resistant ◽

Coagulase Negative Staphylococci ◽

Methicillin Resistant ◽

Content Type ◽

Microdilution Method ◽

Medical Centers ◽

Broth Microdilution Method ◽

Valuable Treatment

ABSTRACTVancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350Staphylococcus aureusisolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. AmongS. aureusstrains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥2 μg/ml). Ceftaroline was very active againstS. aureusoverall (MIC50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistantS. aureusisolates were susceptible to ceftaroline. AgainstS. aureusisolates with a vancomycin MIC of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml), including methicillin-resistant (MIC50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potentin vitroactivity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03006-15 ◽

2016 ◽

Vol 60 (4) ◽

pp. 2352-2358 ◽

Cited By ~ 14

Author(s):

Jordan R. Smith ◽

Juwon Yim ◽

Animesh Raut ◽

Michael J. Rybak

Keyword(s):

Staphylococcus Aureus ◽

Single Agent ◽

Multidrug Resistant ◽

Content Type ◽

Vancomycin Resistant Enterococci ◽

Complex Models ◽

Vancomycin Resistant ◽

Mrsa Strains ◽

Time Kill

ABSTRACTOritavancin 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.

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Activity of Ceftaroline-Avibactam Tested against Gram-Negative Organism Populations, including Strains Expressing One or More β-Lactamases and Methicillin-Resistant Staphylococcus aureus Carrying Various Staphylococcal Cassette ChromosomemecTypes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00817-12 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4779-4785 ◽

Cited By ~ 57

Author(s):

Mariana Castanheira ◽

Helio S. Sader ◽

David J. Farrell ◽

Rodrigo E. Mendes ◽

Ronald N. Jones

Keyword(s):

Staphylococcus Aureus ◽

Therapeutic Option ◽

Multidrug Resistant ◽

Ceftaroline Fosamil ◽

Methicillin Resistant ◽

Content Type ◽

Surveillance Programs ◽

Spectrum Activity ◽

Mrsa Strains ◽

Lactamase Inhibitor

ABSTRACTCeftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the β-lactamase inhibitor avibactam (formerly NXL104), was tested againstEnterobacteriaceaestrains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well asPseudomonas aeruginosa,Acinetobacterspp., and methicillin-susceptible and methicillin-resistantStaphylococcus aureus(MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity againstEnterobacteriaceaeproducing various β-lactamase types (MIC90, 0.25 to 2 μg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 β-lactamases; MIC90, 2 μg/ml). All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/ml. Ceftaroline-avibactam (MIC90, 0.5 to 1 μg/ml) was more active than meropenem (MIC90, >8 μg/ml) and other comparators when tested against KPC-producing strains.S. aureusstrains, including MRSA with four staphylococcal cassette chromosomemec(SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at ≤2 μg/ml, and the ceftaroline MIC was not adversely affected by the addition of the β-lactamase inhibitor (MIC50/90, 1 and 2 μg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity againstAcinetobacterspp. andP. aeruginosa(MIC50s, 32 and 16 μg/ml, respectively). These results document that ceftaroline-avibactam has potent activity againstEnterobacteriaceaethat produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these β-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistantEnterobacteriaceaeas well as MRSA is warranted.

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