Activity of mecillinam alone and in combination with other beta-lactam antibiotics

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The in vitro activities of azlocillin and cefotaxime in combination and of azlocillin and tobramycin in combination against 100 blood isolates and 50 multidrug-resistant isolates were compared. With both combinations, antibacterial spectrums were complementary. Although synergy against individual strains was infrequently observed (except for azlocillin-cefotaxime against Streptococcus faecalis and azlocillin-tobramycin against Pseudomonas aeruginosa), 97% of blood isolates and 76% of multidrug-resistant isolates were susceptible to azlocillin-cefotaxime, and 94% of blood isolates and 36% of multidrug-resistant isolates were susceptible to azlocillin-tobramycin.Penicillin-aminoglycoside and cephalosporinaminoglycoside antibiotic combinations have broad antibacterial spectrums, are frequently synergistic in vitro, and are commonly used to treat a variety of serious bacterial infections (9). To avoid aminoglycoside toxicity, penicillincephalosporin combinations have also been used, but results using early derivatives have not been optimal (2). In recent years, new penicillins and cephalosporins which have greater potencies and spectrums of activity than their prototypes have been developed (4, 7). Therefore, a reexamination of the potential for using penicillin-cephalosporin combinations as alternatives to 3-lactam-aminoglycoside combinations for treating certain types of infections seems appropriate.In this study, we compared the in vitro activity of azlocillin (a new antipseudomonal penicillin) and cefotaxime (a third generation of cephalosporin) in combination with the activity of azlocillin and tobramycin (an aminoglycoside) (Difco Laboratories, Detroit, Mich.) and an inoculum size of approximately 2 x 105 colony-forming units per ml were used (6). Antibiotics were considered synergistic when there was a fourfold or greater reduction in MICs of both drugs in a combination compared with MICs of individual drugs, antagonistic when there was a fourfold or greater increase in MICs of both drugs or when the addition of an inactive antibiotic to an active antibiotic increased the MIC of the latter by fourfold or more, and indifferent when the results were intermediate. Results were considered indeterminate if the endpoints were not in the range of concentrations tested (0.25 to 256 ,ug/ml for azlocillin and 0.25 to 16 ,ug/ml for cefotaxime and tobramycin).

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confidence: 39%

Comparative in vitro activities of azlocillin-cefotaxime and azlocillin-tobramycin combinations against blood and multi-drug resistant bacterial isolates

Fass¹

1982

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“…It is unclear how ppGpp-induced changes protect against PBP2-active agents (20,22), but it is most plausible that they are somehow compensatory. Notably, amdinocillin-and OP0595-resistant mutants grow as stable round forms under amdinocillin or OP0595 challenge (1,6,23), indicating that PBP2 itself remains vulnerable, an observation keeping with the retention of the enhancer effect.…”

Section: Discussionmentioning

confidence: 77%

Interactions of OP0595, a Novel Triple-Action Diazabicyclooctane, with β-Lactams against OP0595-Resistant Enterobacteriaceae Mutants

Livermore

Warner

Mushtaq

et al. 2016

bOP0595 is a novel diazabicyclooctane which, like avibactam, inhibits class A and C ␤-lactamases. In addition, unlike avibactam, it has antibacterial activity, with MICs of 0.5 to 4 g/ml for most members of the family Enterobacteriaceae, owing to inhibition of PBP2; moreover, it acts synergistically with PBP3-active ␤-lactams independently of ␤-lactamase inhibition, via an "enhancer effect." Enterobacteriaceae mutants stably resistant to 16 g/ml OP0595 were selected on agar at frequencies of approximately 10 ؊7 . Unsurprisingly, OP0595 continued to potentiate substrate ␤-lactams against mutants derived from Enterobacteriaceae with OP0595-inhibited class A and C ␤-lactamases. Weaker potentiation of partners, especially aztreonam, cefepime, and piperacillin-less so meropenem-remained frequent for OP0595-resistant Enterobacteriaceae mutants lacking ␤-lactamases or with OP0595-resistant metallo-␤-lactamases (MBLs), indicating that the enhancer effect is substantially retained even when antibiotic activity is lost. OP0595 is a novel diazabicyclooctane (1, 2) which, like avibactam, inhibits class A and C serine ␤-lactamases. In addition, unlike avibactam, it strongly binds PBP2 of Enterobacteriaceae and has direct antibacterial activity, with MICs of 0.5 to 4 g/ml for many Escherichia coli, Klebsiella, and Enterobacter isolates (1, 2). Finally, like amdinocillin (3-7), it acts as an "enhancer" of the activity of ␤-lactams that bind to other penicillin-binding proteins (PBPs), giving synergies that cannot be explained by ␤-lactamase inhibition (1, 2).The antibacterial activity of OP0595 is vulnerable to mutational resistance (1), and we sought to explore whether the molecule's other activities were retained against such mutants. These studies will inform the choice of clinical partner(s) for OP0595, which is now in phase I development (8). MATERIALS AND METHODSStrains. Parent strains (n ϭ 82) (Table 1) were recent submissions to the United Kingdom reference laboratory or were collected in surveys. Extended-spectrum ␤-lactamase (ESBL) and AmpC cephalosporinase production was inferred from phenotype; carbapenemases were characterized by PCR and sequencing (9, 10).Selection of OP0595-resistant mutants. OP0595-resistant mutants were selected by applying 0.2 ml of overnight broth culture (approximately 5 ϫ 10 8 CFU) to Mueller-Hinton agar (Oxoid, Basingstoke, United Kingdom) containing OP0595 (Meiji Seika Pharma, Yokohama, Japan) (16 g/ml). Morphologically diverse colonies (n ϭ 5 per parent) that grew overnight were subcultured to agar with OP0595 (16 g/ml) and then retained at Ϫ80°C. Susceptibility testing. Mutants and parent strains were recovered on drug-free Mueller-Hinton agar and then subjected to CLSI agar dilution MIC testing (11) with piperacillin (Sigma, Poole, United Kingdom), cefepime (Sequoia Research Products, Pangbourne, United Kingdom), and meropenem (Meiji) alone and with OP0595 (1 to 8 g/ml). Comparators were ceftazidime (Sigma) alone and with 4 g/ml avibactam (Meiji); amdinocillin (mecillinam; Sigma), imi...

“…The low frequency of synergy against Enterobacteriaceae is attributed to the inability of mecillinam to induce morphologically abnormal cells at subinhibitory concentrations and of moxalactam to kill those cells when they are formed. The occurrence of antagonism is unexplained, but such antagonism among 1-lactam antibiotics has been previously observed (1,4,7,9 …”

mentioning

confidence: 99%

“…Moxalactam, like the penicillins, cephalosporins, and cephamycins, preferentially binds to penicillin-binding proteins 1 and 3 of bacterial cells (6). Mecillinam, unlike the penicillins, cephalosporins, and cephamycins, preferentially binds to penicillin-binding protein 2 (10) and has been shown to act synergistically with a variety of those antibiotics (4,8,11). To test the hypothesis that the combination of moxalactam and mecillinam might act synergistically and have extraordinary activity against a broad spectrum of gram-negative enteric bacilli, their in vitro activities, singly and in combination, against 53 multi-drug-resistant Enterobacteriaceae and Pseudomonas spp.…”

mentioning

confidence: 99%

See 1 more Smart Citation

In vitro activity of moxalactam and mecillinam, singly and in combination, against multi-drug-resistant Enterobacteriaceae and Pseudomonas species

Fass¹

1982

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The in vitro interaction of moxalactam and mecillinam against multi-drug-resistant gram-negative enteric bacilli was studied by checkerboard microdilution susceptibility tests and by killing curve kinetics. Against Enterobacteriaceae, the combination was unpredictable; the frequencies of synergy, indifference, and antagonism were 11, 76, and 13%, respectively. Against Pseudomonas sp., the two drugs were consistently indifferent. Overall, the combination of moxalactam and mecillinam was no more active than moxalactam alone.