Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis

Miller, William R.; Singh, Kavindra V.; Arias, César A.; Murray, Barbara E.

doi:10.1128/aac.01158-18

Cited by 9 publications

(10 citation statements)

References 18 publications

(26 reference statements)

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“…Interestingly, these investigators found that CzIE and non-CzIE MSSA infections have overall similar outcomes. In addition, studies in rat endocarditis models demonstrate that the use of cefazolin in a CzIE MSSA infection is associated with a more severe disease course which may be ameliorated by the addition of a ␤-lactamase inhibitor with the 1GC (26,32). Such discrepancies could in part be related to differences in populations studied (adults with comorbidities versus otherwise healthy children), as well as measures of treatment success/failure.…”

Section: Discussionmentioning

confidence: 99%

Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

McNeil

Sommer

Boyle

et al. 2020

Antimicrob Agents Chemother

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Background: Select methicillin-susceptible Staphylococcus aureus (MSSA) strains may produce β-lactamases with affinity for first generation cephalosporins (1GC). In the setting of a high inoculum these β-lactamases may promote cleavage of 1GCs, a phenomenon known as the cefazolin inoculum effect (CzIE). We evaluated the prevalence and impact of CzIE on clinical outcomes among MSSA acute hematogenous osteomyelitis (AHO). Methods: MSSA AHO isolates obtained from two children's hospitals between 1/2011- 12/2018 were procured through ongoing surveillance studies. Isolates were tested for CzIE via a macrobroth dilution assay using an inoculum of 107 CFU/ml; CzIE was defined as a cefazolin MIC ≥ 16 μg/ml. Isolates were characterized by accessory gene regulator group (agr). The progression from acute to chronic osteomyelitis was considered an important outcome. Results: 250 cases with viable isolates were included. 14.4% of isolates exhibited CzIE with no observed temporal trend. 4% and 76% of patients received a 1GC as empiric and definitive therapy, respectively. CzIE isolates were more often resistant to clindamycin, belonged to agrIII and associated with development of chronic osteomyelitis. In multivariable analyses, agrIII, multiple surgical debridements, delayed source control and CzIE were independently associated with progression to chronic osteomyelitis. A higher rate of chronic osteomyelitis was observed with CzIE isolates regardless of definitive antibiotic choice. Conclusion: CzIE is exhibited by 14.4% of MSSA AHO isolates in children. CzIE is independently associated with progression to chronic osteomyelitis in cases of AHO irrespective of final antibiotic choice. These data suggest that negative outcomes reported with CzIE may more accurately reflect strain dependent virulence factors rather than true antibiotic failure.

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Section: Discussionmentioning

confidence: 99%

Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

McNeil

Sommer

Boyle

et al. 2020

Antimicrob Agents Chemother

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“…This study is important because it brings ease of application and updates to the IE rat models. Various models of experimental IE have been described to date (5)(6)(7)(8)(9)(10)(11)(12). This study has two important differences from the predefined IE animal models.…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of IE includes endocardial damage, hypercoagulability, and bacteremia. The experimental IE models described to date are based on this pathophysiology (5)(6)(7)(8)(9)(10)(11)(12). Animal models are widely used to investigate new diagnostic methods in IE and to evaluate the efficacy of various antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

“…Organisms such as S. aureus, C. albicans, and Enterococcus faecalis, which have fibronectin receptors on their surface, have been reported to attach more easily to NTBE structure (13). Therefore, after the formation of NBTE, IE has been produced by injecting the microorganisms with the fibronectin receptor on the surface such as S. Aureus, C. Albicans, Enterococcus faecalis into the circulatory system in experimental animal models (5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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An Experimental Infective Endocarditis Model in Rats

Köse

Kiş

Yılmaz

et al. 2021

Journal of Basic and Clinical Health Sciences

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Objective: Infective endocarditis (IE) is defined as infection of the endocardial surface of the heart. Updates are needed in the diagnosis and treatment of IE, as well as in animal models of IE. Based on this need, a new model of infective endocarditis induced by S. aureus was described in our study. Methods: This study was performed on 7 Wistar albino male rats, each aged six months and weighing 250-300 g. Underwent the surgical implantation of a 20 G catheter, to gain access to right common carotid artery. Twenty-four hours after implantation, 0.5 ml 100.000 colony forming unit (cfu) of S. aureus was injected via the tail vein and 3 days later echocardiography was performed and rats subsequently sacrificed. IE was later diagnosed histopathologically. Results: Two of the rats were exitus one day after S. auerus was given. The mortality rate of the experiment was 28.5%. Histopathological examination revealed vegetations and bacterial colonization were detected in the endocardium in all rats that protruded from the endocardium to the cardiac cavity. Conclusion:Our study is the first study in the literature to identify the IE rat model using the 20 G catheter. Due to the practical application of the surgical procedure (use of 20 G catheter) in our study, we think that it will provide much convenience to the researchers in the experimental research on IE diagnosis and treatment.

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“…Further, on balancing adverse events vs efficacy metrics, CFZ is generally regarded as a safer option, due to its decreased renal toxicity risk as compared to the antistaphylococcal penicillins (16, 27). However, there remains concern about CFZ efficacy in “high-inoculum” S. aureus infections (e.g., endocarditis) due to the potential for the undetected presence and induction of genes for Types A or C cephalosporinases that hydrolyze CFZ (39, 40). In our current study, CFZ appeared to be unaffected by the high inoculum within SEVs, at least for the NaHCO 3 -responsive strains, 11-11 and MW2, with excellent CFZ bactericidal activity obtained despite starting inocula ≥ 1×10 8 CFU/g.…”

Section: Discussionmentioning

confidence: 99%

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-ResistantStaphylococcus aureus(MRSA) Strains to β-Lactam Antibiotics in anEx VivoSimulated Endocardial Vegetation Model

Rose

Bienvenida

Xiong

et al. 2019

Preprint

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Word Count: 3963 25 2 ABSTRACT 26 Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth 27[CAMHB]) with bicarbonate (NaHCO 3 ) significantly increases β-lactam susceptibility of selected 28 MRSA strains ("NaHCO 3 -responsive"). This "sensitization" phenomenon translated to enhanced 29 β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO 3 -30 mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring 31 simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. 32Four previously described MRSA strains were used: two each exhibiting in vitro "NaHCO 3 -33 responsive" or "NaHCO 3 -nonresponsive" phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were 34 evaluated in CAMHB±NaHCO 3 . Intra-SEV MRSA killing was determined over 72 hr exposure. In 35 both NaHCO 3 -responsive strains, supplementation with 25 mM or 44 mM NaHCO 3 significantly 36 reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤ 4 mg/L) resulting in 37 bactericidal activity (≥ 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro-38 defined NaHCO 3 -nonresponsive MRSA strains showed significant sensitization in the SEV 39 model to either β-lactam. At both NaHCO 3 concentrations, the fractional time-above-MIC was 40 >50% for both CFZ and OXA in the NaHCO 3 -responsive MRSA. Also, in RPMI+10% LB media 41 (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO 3 ), both 42 CFZ and OXA exhibited enhanced bactericidal activity against each NaHCO 3 -responsive strain 43 in the SEV model. Neither CFZ nor OXA exposures selected for high-level β-lactam-resistant 44 mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO 3 45 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate 46 similar enhanced susceptibility in NaHCO 3 -supplemented media in vitro. 47 3 INTRODUCTION 48

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Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis

Cited by 9 publications

References 18 publications

Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

An Experimental Infective Endocarditis Model in Rats

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-ResistantStaphylococcus aureus(MRSA) Strains to β-Lactam Antibiotics in anEx VivoSimulated Endocardial Vegetation Model

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