Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations (original) (raw)
Related papers
Acta Pathologica Microbiologica Scandinavica Series B: Microbiology, 2009
The in vitro activity of ceftazidime has been compared with those of another third-generation cephalosporin, cefotaxime, and the aminocyclitol aminoglycoside, gentamicin. A total of I 1,521 clinical isolates of aerobic bacteria were employed, and an agar diffusion method was used for sensitivity testing. The MIC-values were calculated from regression lines. The mean inhibition zones for ceftazidime against Gram-positive organisms were significantly less than those against Gram-negative isolates (23 mm vs. 33 mm, pc0.0001). Cefotaxime inhibited 74.0 %, gentamicin 66.3 % and ceftazidime 20.4 % of the Grampositive isolates at a concentration of< 2 mg/ml. Ceftazidime and cefotaxime were equally active against fermentative Gram-negative rods, inhibiting 92.7 % of each of these isolates at 2 mg/l. Against Ps. aeruginosa. ceftazidime (MIC9@ 2.2 mg/l) was found to be almost as active as gentamicin (MIC,, 1.2 mg/l), and far more active than cefotaxime (MIC,, 434 mg/l). Gentamicin was the most active agent against Acinetohacter sp. (MIC90 6.0 mg/l), followed by ceftazidime (MICw 18 mg/l) and cefotaxime (MIC90 83 mg/l).
Journal of Antimicrobial Chemotherapy, 2014
Ceftazidime-avibactam (MIC 50/90 , 0.12/0.25 g/ml) inhibited 99.9% (20,698/20,709) of Enterobacteriaceae isolates at <8 g/ml. This compound was active against resistant subsets, including ceftazidime-nonsusceptible Enterobacter cloacae (MIC 50/90 , 0.25/ 0.5 g/ml) and extended-spectrum -lactamase (ESBL) phenotype isolates. An ESBL phenotype was noted among 12.4% (1,696/ 13,692 isolates from targeted species) of the isolates, including 776 Escherichia coli (12.0% for this species; MIC 50/90 , 0.12/0.25 g/ml), 721 Klebsiella pneumoniae (16.3%; MIC 50/90 , 0.12/0.25 g/ml), 119 Klebsiella oxytoca (10.3%; MIC 50/90 , 0.06/0.25 g/ ml), and 80 Proteus mirabilis (4.9%; MIC 50/90 , 0.06/0.12 g/ml) isolates. The most common enzymes detected among ESBL phenotype isolates from 2013 (n ؍ 743) screened using a microarray-based assay were CTX-M-15-like (n ؍ 307), KPC (n ؍ 120), SHV ESBLs (n ؍ 118), and CTX-M-14-like (n ؍ 110). KPC producers were highly resistant to comparators, and ceftazidimeavibactam (MIC 50/90 , 0.5/2 g/ml) and tigecycline (MIC 50/90 , 0.5/1 g/ml; 98.3% susceptible) were the most active agents against these strains. Meropenem (MIC 50/90 , <0.06/<0.06 g/ml) and ceftazidime-avibactam (MIC 50/90 , 0.12/0.25 g/ml) were active against CTX-M-producing isolates. Other enzymes were also observed, and ceftazidime-avibactam displayed good activity against the isolates producing less common enzymes. Among 11 isolates displaying ceftazidime-avibactam MIC values of >8 g/ml, three were K. pneumoniae strains producing metallo--lactamases (all ceftazidime-avibactam MICs, >32 g/ml), with two NDM-1 producers and one K. pneumoniae strain carrying the bla KPC-2 and bla VIM-4 genes. Therapeutic options for isolates producing -lactamases may be limited, and ceftazidime-avibactam, which displayed good activity against strains, including those producing KPC enzymes, merits further study in infections where such organisms occur.
Diagnostic Microbiology and Infectious Disease, 1987
The efficacy of ceftazidime alone and combined with amikacin was studied in a rabbit model simulating closed-space infections at locally neutropenic sites. Six strains of Pseudomonas aeruginosa, and six Enterobacteriaceae (two strains each of Klebsiella pneumoniae and Serratia marcescens and one strain each of Escherichia coli and Citrobacter ~reundii) in pooled rabbit serum were each inoculated into separate subcutaneous semipermeable chambers. Intramuscular antibiotic therapy was begun 4 hr later with ceftazidime (50 mg/kg) alone and combined with amikacin (15 mg/kg) for Enterobacteriaceae or ceftazidime (100 mg/kg) alone and combined with amikacin (15 mg/kg)for pseudomonads every 6 hr for 16 doses. Amikacin alone was ineffective for all 12 strains. Ceftazidime alone was successful (>15.5 log~o colony forming units (CFU)/ml decrease from drug-free control) in eliminating five of six Enterobacteriaceae but was not successful against any of the pseudomonads. Ceftazidime plus amikacin was successful against the same five of six Enterobacteriaceae and five of six pseudomonads. The best in vitro tests for the prediction of in vivo outcome were high inoculum (>17 log~o CFU/ml) susceptibility, checkerboard synergism testing, and conventional inoculum time-kill rates at concentrations of antimicrobials simulating extravascular levels obtained in vivo.
Antimicrobial Agents and Chemotherapy, 1983
Ceftazidime was administered intravenously or intramuscularly or both in doses of 1 to 6 g per day to 33 patients with serious gram-negative bacillary infections (12 pulmonary, 10 urinary tract, 4 soft tissue, 4 intraabdominal, and 3 miscellaneous infections). Twenty-one patients were septicemic. We identified 20 isolates of members of the family Enterobacteriaceae and 13 isolates of Pseudomonas aeruginosa. Seventeen patients had failed to respond to previous antimicrobial therapy. A total of 23 patients were clinically cured, 7 patients improved, and 3 patients failed to respond to therapy. The selection or emergence of resistant organisms during treatment (mostly Candida spp., Staphylococcus aureus, and enterococci) was noted in 11 patients. Toxicity was minimal (reversible mild liver function abnormalities and eosinophilia). The results of this study suggest that ceftazidime is an effective and well-tolerated new cephalosporin for the therapy of serious infections due to susceptible gram-negative organisms.
International journal of antimicrobial agents, 2015
Recent clinical isolates of key Gram-negative and Gram-positive bacteria were collected in 2012 from hospitalised patients in medical centres in four European countries (France, Germany, Italy and Spain) and were tested using standard broth microdilution methodology to assess the impact of 4mg/L avibactam on the in vitro activities of ceftazidime, ceftaroline and aztreonam. Against Enterobacteriaceae, addition of avibactam significantly enhanced the level of activity of these antimicrobials. MIC90 values (minimum inhibitory concentration that inhibits 90% of the isolates) of ceftazidime, ceftaroline and aztreonam for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii and Morganella morganii were reduced up to 128-fold or greater when combined with avibactam. A two-fold reduction in the MIC90 of ceftazidime to 8mg/L was noted in Pseudomonas aeruginosa isolates when combined with avibactam, whereas little effect of avibactam was...
Enfermedades Infecciosas y Microbiología Clínica, 2017
Introduction: Antimicrobial resistance in Enterobacteriaceae is increasing worldwide and is making treating infections caused by multidrug-resistant Enterobacteriaceae a challenge. The use of -lactam agents is compromised by microorganisms harboring extended-spectrum -lactamases (ESBLs) and other mechanisms of resistance. Avibactam is a non -lactam agent that inhibits clinically relevant -lactamases, such as ESBL and AmpC. The ceftazidime-avibactam combination (CAZ-AVI) was recently approved for use in certain complicated infections, and may provide a therapeutic alternative for infections caused by these microorganisms. Methods: The in vitro activity of CAZ and CAZ-AVI (AVI at a fixed concentration of 4 mg/L) was tested against 250 clinical isolates of Enterobacteriaceae using broth microdilution. EUCAST breakpoint criteria were used for CAZ, and FDA criteria for CAZ-AVI. Clinical isolates included bacteria producing extendedspectrum -lactamases (ESBLs) and acquired AmpC -lactamases (AACBLs). Porin loss in Klebsiella pneumoniae was also evaluated. Results: The combination of AVI with CAZ displayed excellent activity against clinical isolates of ESBLproducing Escherichia coli and Klebsiella pneumoniae, rendering all the ceftazidime-resistant isolates susceptible to ceftazidime. CAZ-AVI retained activity against porin-deficient isolates of K. pneumoniae producing ESBLs, AACBLs, or both, although MIC values were higher compared to porin-expressing isolates. CAZ-AVI rendered all the ceftazidime-resistant AACBL-producing Enterobacteriaceae tested susceptible to ceftazidime. Conclusion: CAZ-AVI showed potent in vitro activity against clinical isolates of Enterobacteriaceae producing ESBLs and/or AACBLs, including K. pneumoniae with loss of porins.
Chapter e1: Anti-Infective Chemotherapeutic & Antibiotic Agents
PENICILLINS The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a beta-lactam ring essential to their biologic activity. Antimicrobial Action & Resistance The initial step in penicillin action is the binding of the medication to receptors, called penicillin-binding proteins. Aer penicillins attach to receptors, peptidoglycan synthesis is inhibited due to blockage of transpeptidation. The final bactericidal action is to remove an autolytic enzyme inhibitor in the cell wall, which results in cell lysis. Organisms that produce beta-lactamases (penicillinases) are resistant to some penicillins because the beta-lactam ring is broken. Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to penicillins and other beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are not susceptible. Microbial resistance to penicillins is associated with five mechanisms: (1) production of beta-lactamases, (eg, by staphylococci, gonococci, Haemophilus species, and coliform organisms, including extended-spectrum beta-lactamase (ESBL)-producing bacteria); (2) lack of penicillin-binding proteins or decreased ainity of penicillin-binding protein for beta-lactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci, enterococci); (3) impermeability of the cell envelope (eg, by Pseudomonas species); (4) failure to activate autolytic enzymes in the cell wall-"tolerance," (eg, in staphylococci, group B streptococci); and (5) cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans. 1. Natural Penicillins The natural penicillins include penicillin G for parenteral administration (aqueous crystalline for intravenous or benzathine penicillin G for intramuscular administration) or for oral administration (penicillin G and phenoxymethyl penicillin [penicillin V]). They are most active against gram-positive organisms and are susceptible to hydrolysis by beta-lactamases. They are used (1) for infections caused by susceptible and moderately susceptible pneumococci, depending on the site of infection; (2) other streptococci, such as Streptococcus pyogenes, (including anaerobic streptococci); (3) meningococci; (4) non-beta-lactamase-producing staphylococci; (5) Treponema pallidum and other spirochetes; (6) Propionibacterium acnes and other gram-positive anaerobic bacilli; (7) non-diicile clostridia; and (8) actinomyces. See Table 30-4.
Antimicrobial Agents and Chemotherapy, 2013
Ceftolozane/tazobactam, a novel antimicrobial agent with activity against Pseudomonas aeruginosa (including drug-resistant strains) and other common Gram-negative pathogens (including most extended-spectrum--lactamase [ESBL]-producing Enterobacteriaceae strains), and comparator agents were susceptibility tested by a reference broth microdilution method against 7,071 Enterobacteriaceae and 1,971 P. aeruginosa isolates. Isolates were collected consecutively from patients in 32 medical centers across the United States during 2011 to 2012. Overall, 15.7% and 8.9% of P. aeruginosa isolates were classified as multidrug resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% of Enterobacteriaceae were classified as MDR and XDR. No pandrug-resistant (PDR) Enterobacteriaceae isolates and only one PDR P. aeruginosa isolate were detected. Ceftolozane/tazobactam was the most potent (MIC 50/90 , 0.5/2 g/ml) agent tested against P. aeruginosa and demonstrated good activity against 310 MDR strains (MIC 50/90 , 2/8 g/ml) and 175 XDR strains (MIC 50/90 , 4/16 g/ml). Ceftolozane/tazobactam exhibited high overall activity (MIC 50/90 , 0.25/1 g/ml) against Enterobacteriaceae and retained activity (MIC 50/90 , 4/>32 g/ml) against many 601 MDR strains but not against the 86 XDR strains (MIC 50 , >32 g/ml). Ceftolozane/tazobactam was highly potent (MIC 50/90 , 0.25/0.5 g/ml) against 2,691 Escherichia coli isolates and retained good activity against most ESBL-phenotype E. coli isolates (MIC 50/90 , 0.5/4 g/ml), but activity was low against ESBL-phenotype Klebsiella pneumoniae isolates (MIC 50/90 , 32/>32 g/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary, ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary Enterobacteriaceae and P. aeruginosa isolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many MDR and XDR strains.