Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12, Pseudomonas aeruginosa and Staphylococcus aureus

Hayes, Michael; Orr, David C.

doi:10.1093/jac/12.2.119

Cited by 93 publications

(69 citation statements)

References 13 publications

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“…As this turnover is a system property, the lag time of killing is independent of antibiotic concentration. The delay between the binding of ceftazidime to PBP3 and cellular death is consistent with data from the literature (27,39,62,63). Previous studies used exponential functions to describe the functional adaptation or lag time of growth or killing (36,42,49,64).…”

Section: Discussionsupporting

confidence: 87%

Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa

Bulitta

Yang

et al. 2009

Antimicrob Agents Chemother

107

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Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic/ pharmacodynamic (PKPD) mathematical model accommodating a range of CFUo. Time-kill experiments using ceftazidime at seven concentrations up to 128 mg/liter (MIC, 2 mg/liter) were performed in duplicate against P. aeruginosa PAO1 at five CFUo from 10 5 to 10 9 CFU/ml. Samples were collected over 24 h and fit by candidate models in NONMEM VI and S-ADAPT 1.55 (all data were comodeled). External model qualification integrated data from eight previously published studies. Ceftazidime displayed approximately 3 to 4 log 10 CFU/ml net killing at 10 6.2 CFUo and concentrations of 4 mg/liter (or higher), less than 1.6 log 10 CFU/ml killing at 10 7.3CFUo, and no killing at 10 8.0 CFUo for concentrations up to 128 mg/liter. The proposed mechanism-based model successfully described the inoculum effect and the concentration-independent lag time of killing. The mean generation time was 28.3 min. The effect of an autolysin was assumed to inhibit successful replication. Ceftazidime concentrations of 0.294 mg/liter stimulated the autolysin effect by 50%. The model was predictive in the internal cross-validation and had excellent in silico predictive performance for published studies of P. aeruginosa ATCC 27853 for various CFUo. The proposed PKPD model successfully described and predicted the pronounced inoculum effect of ceftazidime in vitro and integrated data from eight literature studies to support translation from time-kill experiments to in vitro infection models.Pseudomonas aeruginosa is an opportunistic, gram-negative pathogen responsible for high morbidity and mortality (19). P. aeruginosa has multiple mechanisms of resistance to antibiotics, including efflux pumps, the enzymatic degradation of antibiotics by, e.g., beta-lactamases, and target structure alteration (19,25,45). Due to its remarkable ability to resist killing by antibiotics (45), many P. aeruginosa isolates from nosocomial infections are multidrug resistant. The proportion of ceftazidime-resistant P. aeruginosa isolates from intensive care units increased from approximately 14% in 1997 to 24% in 2003 in the United States (23).Infections with a high bacterial density at the initiation of antibiotic therapy may present a therapeutic problem, including a higher risk for the emergence of resistance due to the larger number of bacteria present and the higher probability of having at least one resistant bacterial cell within a large initial inoculum (CFUo) (32). The probability of the emergence of resistance may be substantially increased at high CFUo, as the amplification of resistant subpopulations has been demonstrated to occur secondarily to low-intensity antimicrobial exposure (60). The inoculum effect was first described by Kirby (34)...

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Section: Discussionsupporting

confidence: 87%

Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa

Bulitta

Yang

et al. 2009

Antimicrob Agents Chemother

107

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“…Moreover, we first revealed the cellular morphological changes via an electron microscope. The prolonged cells and the leakage of content were originally thought to be the results of by cell wall detriment like β-lactam [16].…”

Section: Discussionmentioning

confidence: 99%

Antibacterial Activity of Three Medicinal Lasianthus (Rubiaceae) Extracts on Human Resistant Pathogenic Bacteria

Napiroon¹,

Vajrodaya²,

Santimaleeworagun³

et al. 2017

Eur J Exp Bio

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Aim: To evaluate the activity of medicinal Lasianthus extracts on bacteria and to determine the chemical characters among three medicinal Lasianthus (Rubiaceae) species. Materials and Methods:The phytochemical investigation of L. cyanocarpus, L. hirsutus and L. lucidus were performed using thin layer chromatography and high performance liquid chromatography (HPLC) techniques. Four antibacterial resistant strains including Staphylococcus aureus ATCC 43300 (MRSA), Klebsiella pneumoniae ATCC BAA 1705 (carbapenemase; KPC-producing strain) and Pseudomonas aeruginosa ATCC 27853 (AmpC β-lactamase producing strain) were used. The phytochemical investigation of L. cyanocarpus, L. hirsutus and L. lucidus were performed using thin layer chromatography and high performance liquid chromatography (HPLC) techniques. We also detected the effects of extracts on bacteria by using a scanning electron microscope. Results:The lipophilic extracts from the three plants revealed the terpenoids, coumarin and iridoid. HPLC showed similarities in the chemical profiles of both leaf and stem bark extracts. L. lucidus lipophilic extracts revealed the greatest effect against S. aureus and P. aeruginosa at 400 and 100 µg/mL respectively, whereas L. cyanocarpus extracts prominently affected K. pneumoniae at 400 µg/mL. Cell lysis and leakage of bacteria treated with extracts were observed. Conclusion:Our findings surprisingly showed the potential of antibacterial effect among resistant pathogenic bacteria. We also revealed the comparable signals of the chemical characters from the three Lasianthus. These findings support the traditional use related infectious diseases and it might be possible to further develop the antibiotic agents.

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“…Structurally, it differs from other β-lactamase inhibitors lacking the distinctive 4-membered β-lactam ring, instead containing a 5-membered cyclic urea (8). Mechanistically, avibactam acts similarly to other β-lactamase inhibitors by creating a covalent bond at the activesite serine.…”

Section: Avibactammentioning

confidence: 98%

“…The carboxypropyl group found on the aminothiazolyloximino side chain at position 7 also confers additional stability against β-lactamases produced by Enterobacteriaceae and P. aeruginosa (7). Ceftazidime exerts its activity by binding to penicillin-binding proteins (PBPs) within the cell wall, primarily PBP-3, interfering with cell division and leading to cell death (8). …”

Section: Chemistry and Mechanism Of Action 31 Ceftazidimementioning

confidence: 99%

Ceftazidime/Avibactam: Who Says You Can’t Teach an Old Drug New Tricks?

2016

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-In vitro susceptibility for ceftazidime/avibactam displayed potent activity against many Enterobacteriaceae including extended-spectrum-β-lactamase (ESBL) and carbapenemase-producing strains, as well as Pseudomonas aeruginosa. Phase II clinical trials utilized for approval demonstrated comparable safety and efficacy to imipenem/cilistatin for treatment of complicated urinary tract infections (70.4% vs. 71.4%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (91.2% vs 93.4%). Phase III data displayed non-inferior efficacy of ceftazidime/avibactam compared to doripenem for complicated urinary tract infections (70.2% vs 66.2%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (82.5% vs 84.9%), as well as comparable safety. Ceftazidime/avibactam was well-tolerated but does require renal adjustments. Additionally, 3 case series and a single case report have demonstrated the potential for ceftazidime/avibactam against multidrug resistant organisms for compassionate use or failure after previous therapy. Conclusion: By adding avibactam to ceftazidime, clinicians' antimicrobial armamentarium is expanded, potentially increasing the ability to combat multi-drug resistant gram-negative pathogens, particularly ESBL and carbapenemase-producing organisms, as well as Pseudomonas aeruginosa.

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Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12, Pseudomonas aeruginosa and Staphylococcus aureus

Cited by 93 publications

References 13 publications

Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa

Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa

Antibacterial Activity of Three Medicinal Lasianthus (Rubiaceae) Extracts on Human Resistant Pathogenic Bacteria

Ceftazidime/Avibactam: Who Says You Can’t Teach an Old Drug New Tricks?

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