Personalized CZA‐ATM dosing against an XDR E. coli in liver transplant patients; the application of the in vitro hollow fiber system
Zahra SadoukiEmmanuel WeySatheesh IypeDavid NasrallaJonathan R. PottsMichael SpiroAlan WilliamsTimothy D. McHughFrank Kloprogge
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Abstract Background A patient with an extensively drug‐resistant (XDR) New Delhi metallo‐β‐lactamase (NDM) and oxacillinase (OXA‐48) producing Escherichia coli (E. coli ) infection was awaiting orthotopic liver transplant. There is no standardized antibiotic prophylaxis regimen; however, in line with the Infectious Diseases Society of America guidance, an antibiotic prophylactic regimen of ceftazidime‐avibactam 2.5 g TDS with aztreonam 2 g three times a day (TDS) IV was proposed. Methods The hollow fiber system (HFS) was applied to inform the individualized pharmacodynamic outcome likelihood prior to prophylaxis. Results A 4‐log reduction in CFU/mL in the first 10 h of the regimen exposure was observed; however, the killing dynamics were slow and six 8‐hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFS supported the use of the regimen for infection clearance; however, it highlighted the need for several infusions. Standard local practice is to administer prophylaxis antibiotics at induction of orthotopic liver transplantation (OLT); however, the HFS provided data to rationalize earlier dosing. Therefore, the patient was dosed at 24 h prior to their OLT induction and subsequently discharged 8 days after surgery. Conclusion The HFS provides a dynamic culture solution for informing individualized medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient's infection. image .Keywords:
Aztreonam
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Pharmacodynamics
Bacteremia
We report the isolation of a clinical isolate of Klebsiella pneumoniae that showed resistance to ceftazidime (MIC: 8 μg/ml), susceptibility to aztreonam (MIC: 2 μg/ml) and cefotaxime (MIC: 0.015 μg/ml). A synergistic effect between clavulanic acid and ceftazidime or aztreonam against this strain was also observed. The strain hyper-produced SHV-1 penicillinase (990 U/g) which is encoded by a self-transferrable plasmid of at least 150 kb. That the ceftazidime-resistance phenotype could be due to hyperproduction of SHV-1 penicillinase is supported by the study of a spontaneous ceftazidime-resistant mutant in vitro obtained from an Escherichia coli strain containing plasmid p453 encoding the SHV-1. Indeed, this mutant hyperproducing SHV-1 (2200 U/g) was resistant to ceftazidime (MIC: 16 μg/ml) and aztreonam (MIC: 8 μg/ml) but susceptible to cefotaxime (MIC: 0.03 ng/ml). Clavulanic acid showed a synergistic effect when associated with ceftazidime or aztreonam. In contrast, the hyperproduction of TEM-1 (790 U/g) did not confer a ceftazidime- and aztreonam-resistant phenotype while hyperproduction of both TEM-1 and SHV-1 increased the resistance to amoxycillin/clavulanic acid and to cephalothin.
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CTX-M-19 is a recently identified ceftazidime-hydrolyzing extended-spectrum beta-lactamase, which differs from the majority of CTX-M-type beta-lactamases that preferentially hydrolyze cefotaxime but not ceftazidime. To elucidate the mechanism of ceftazidime hydrolysis by CTX-M-19, the beta-lactam MICs of a CTX-M-19 producer, and the kinetic parameters of the enzyme were confirmed. We reconfirmed here that CTX-M-19 is also stable at a high enzyme concentration in the presence of bovine serum albumin (20 micro g/ml). Under this condition, we obtained more accurate kinetic parameters and determined that cefotaxime (k(cat)/K(m), 1.47 x 10(6) s(-1) M(-1)), cefoxitin (k(cat)/K(m), 62.2 s(-1) M(-1)), and aztreonam (k(cat)/K(m), 1.34 x 10(3) s(-1) M(-1)) are good substrates and that imipenem (k(+2)/K, 1.20 x 10(2) s(-1) M(-1)) is a poor substrate. However, CTX-M-18 and CTX-M-19 exhibited too high a K(m) value (2.7 to 5.6 mM) against ceftazidime to obtain their catalytic activity (k(cat)). Comparison of the MICs with the catalytic efficiency (k(cat)/K(m)) of these enzymes showed that some beta-lactams, including cefotaxime, ceftazidime, and aztreonam showed a similar correlation. Using the previously reported crystal structure of the Toho-1 beta-lactamase, which belongs to the CTX-M-type beta-lactamase group, we have suggested characteristic interactions between the enzymes and the beta-lactams ceftazidime, cefotaxime, and aztreonam by molecular modeling. Aminothiazole-bearing beta-lactams require a displacement of the aminothiazole moiety due to a severe steric interaction with the hydroxyl group of Ser167 in CTX-M-19, and the displacement affects the interaction between Ser130 and the acidic group such as carboxylate and sulfonate of beta-lactams.
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We report the isolation of a clinical isolate of Klebsiella pneumoniae that showed resistance to ceftazidime (MIC: 8 μg/ml), susceptibility to aztreonam (MIC: 2 μg/ml) and cefotaxime (MIC: 0.015 μg/ml). A synergistic effect between clavulanic acid and ceftazidime or aztreonam against this strain was also observed. The strain hyper-produced SHV-1 penicillinase (990 U/g) which is encoded by a self-transferrable plasmid of at least 150 kb. That the ceftazidime-resistance phenotype could be due to hyperproduction of SHV-1 penicillinase is supported by the study of a spontaneous ceftazidime-resistant mutant in vitro obtained from an Escherichia coli strain containing plasmid p453 encoding the SHV-1. Indeed, this mutant hyperproducing SHV-1 (2200 U/g) was resistant to ceftazidime (MIC: 16 μg/ml) and aztreonam (MIC: 8 μg/ml) but susceptible to cefotaxime (MIC: 0.03 ng/ml). Clavulanic acid showed a synergistic effect when associated with ceftazidime or aztreonam. In contrast, the hyperproduction of TEM-1 (790 U/g) did not confer a ceftazidime- and aztreonam-resistant phenotype while hyperproduction of both TEM-1 and SHV-1 increased the resistance to amoxycillin/clavulanic acid and to cephalothin.
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Recently, natural variants of TEM-1 β-lactamase with amino acid substitutions at residues 237-240 have been identified that have increased hydrolytic activity for extended-spectrum antibiotics such as ceftazidime. To identify the sequence requirements in this region for a given antibiotic, a random library was constructed that contained all possible amino acid combinations for the 3-residue region 237-240 (ABL numbering system) of TEM-1 β-lactamase. An antibiotic disc diffusion method was used to select mutants with wild-type level activity or greater for the extended-spectrum cephalosporin ceftazidime and the monobactam aztreonam. Mutants that were selected for optimal ceftazidime hydrolysis contained a conserved Ala at position 237, a Ser for Gly substitution at position 238, and a Lys for Glu at position 240. Mutants selected for aztreonam hydrolysis exhibited a Gly for Ala substitution at position 237, a Ser for Gly substitution at position 238, and a Lys/Arg for Glu at position 240. The role of the A237G substitution in differentiating between ceftazidime and aztreonam was further investigated by kinetic analysis of the A237G, E240K, G238S:E240K, and A237G:G238S:E240K enzymes. The A237G single mutant and the G238S:E240K double mutant exhibited increases in catalytic efficiency for both ceftazidime and aztreonam. However, the triple mutant A237G:G238S:E240K, displayed a 12-fold decrease in catalytic efficiency for ceftazidime but a 3-fold increase for aztreonam relative to the G238S:E240K double mutant. Thus, the A237G substitution increases ceftazidime hydrolysis when present alone but antagonizes ceftazidime hydrolysis when it is combined with the G238S:E240K substitutions. In contrast, the A237G substitution acts additively with the G238S:E240K substitutions to increase aztreonam hydrolysis. Recently, natural variants of TEM-1 β-lactamase with amino acid substitutions at residues 237-240 have been identified that have increased hydrolytic activity for extended-spectrum antibiotics such as ceftazidime. To identify the sequence requirements in this region for a given antibiotic, a random library was constructed that contained all possible amino acid combinations for the 3-residue region 237-240 (ABL numbering system) of TEM-1 β-lactamase. An antibiotic disc diffusion method was used to select mutants with wild-type level activity or greater for the extended-spectrum cephalosporin ceftazidime and the monobactam aztreonam. Mutants that were selected for optimal ceftazidime hydrolysis contained a conserved Ala at position 237, a Ser for Gly substitution at position 238, and a Lys for Glu at position 240. Mutants selected for aztreonam hydrolysis exhibited a Gly for Ala substitution at position 237, a Ser for Gly substitution at position 238, and a Lys/Arg for Glu at position 240. The role of the A237G substitution in differentiating between ceftazidime and aztreonam was further investigated by kinetic analysis of the A237G, E240K, G238S:E240K, and A237G:G238S:E240K enzymes. The A237G single mutant and the G238S:E240K double mutant exhibited increases in catalytic efficiency for both ceftazidime and aztreonam. However, the triple mutant A237G:G238S:E240K, displayed a 12-fold decrease in catalytic efficiency for ceftazidime but a 3-fold increase for aztreonam relative to the G238S:E240K double mutant. Thus, the A237G substitution increases ceftazidime hydrolysis when present alone but antagonizes ceftazidime hydrolysis when it is combined with the G238S:E240K substitutions. In contrast, the A237G substitution acts additively with the G238S:E240K substitutions to increase aztreonam hydrolysis.
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A clinical strain of Escherichia coli isolated from pleural liquid with high levels of resistance to cefotaxime, ceftazidime, and aztreonam harbors a novel CTX-M gene (bla(CTX-M-32)) whose amino acid sequence differs from that of CTX-M-1 by a single Asp240-Gly substitution. Moreover, by site-directed mutagenesis we demonstrated that this replacement is a key event in ceftazidime hydrolysis
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A clinical strain of Escherichia coli (strain Ec 41553) that was resistant to ceftazidime produced a TEM-type beta-lactamase with a pI of 5.4. Clavulanic acid restored the ceftazidime activity, thus suggesting an extended spectrum beta-lactamase (ESBL). The gene encoding ESBL was located in a plasmid of 57 kb. After cloning and sequencing, the ESBL (TEM-29B) showed one amino acid replacement with respect to the TEM-1 sequence, Arg-164 to His. This change increased mainly the rate of hydrolysis of ceftazidime but not of cefotaxime and aztreonam. The relevance of this substitution in the increase of ceftazidime MIC is thus stressed.
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To determine if susceptibility to aztreonam could be predicted from cefotaxime or ceftazidime disc diffusion testing, 919 Enterobacteriaceae and 187 Pseudomonas aeruginosa clinical strains were studied. The correlation coefficient between the diameters of inhibition zones was 0⋅9 for cefotaxime versus aztreonam and ceftazidime versus aztreonam comparisons in Enterobacteriaceae and 0⋅75 for ceftazidime versus aztreonam comparison in P. aeruginosa. For 99% of the Enterobacteriaceae, there was no risk in predicting susceptibility to aztreonam on the basis of cefotaxime or ceftazidime susceptibility tests. To minimize the risk of the remaining 1% of the strains being erroneously classified as susceptible to aztreonam, ceftoaxime should be tested in preference to ceftazidime, and the production of extended-spectrum β-lactamases should be tested for using the cefotaxime-clavulanate disc synergy test. For P. aeruginosa strains, susceptibility to aztreonam could be accurately predicted from ceftazidime susceptibility tests for ticarcillin susceptible strains, but for ticarcillin resistant strains, susceptibility to aztreonam should be tested.
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