The Cefazolin Inoculum Effect and the Presence of type A blaZ Gene according to agr Genotype in Methicillin-Susceptible Staphylococcus aureus Bacteremia

Lee, Soon Ok; Lee, Shinwon; Park, Sohee; Lee, Jeong Eun; Lee, Sun Hee

doi:10.3947/ic.2019.51.4.376

Cited by 6 publications

(9 citation statements)

References 38 publications

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“…Accuracy of the CzIE rapid test varies with the type of b-lactamase. The CzIE has been associated with the presence of staphylococcal b-lactamases type A and C (13,(16)(17)(18)(19)(20)(21)(22)(23). The type A enzyme seems to have enhanced activity against nitrocefin and cefazolin, whereas type C has more affinity for cephalothin than cefazolin (37).…”

Section: Resultsmentioning

confidence: 99%

“…The cefazolin inoculum effect (CzIE) is characterized by a marked increase in the MIC when a high bacterial inoculum, typically at least 10 7 CFU/ml, is used to determine the MIC value. The CzIE has been associated with therapeutic failures and increased mortality in deep-seated infections (13)(14)(15), and appears to vary in frequency from 3 to 20% of MSSA isolates from Asia (16)(17)(18) and the United States (19)(20)(21) up to 30 to 54% in MSSA isolates from Latin America (13,22,23).…”

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confidence: 99%

“…The mechanistic basis of the CzIE involves the staphylococcal b-lactamase (BlaZ) enzymes, which belong to the molecular class A and have been classified into four types (A to D) (24). BlaZ types A and C have been the most common types associated with the CzIE (13,(16)(17)(18)(19)(20)(21)(22)(23). The gold standard for identification of the CzIE is by determining cefazolin MICs at high inoculum (MIC-HI) by broth microdilution (21).…”

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A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus

et al. 2021

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The cefazolin inoculum effect (CzIE) has been associated with therapeutic failures and mortality in invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections. A diagnostic test to detect the CzIE is not currently available. We developed a rapid (∼3 h) CzIE colorimetric test to detect staphylococcal-β-lactamase (BlaZ) activity in supernatants after ampicillin induction. The test was validated using 689 bloodstream MSSA isolates recovered from Latin-America and US. Cefazolin MIC determination at high inoculum (107 CFU/mL) was used as reference standard (cut-off of ≥16 μg/mL). All isolates underwent genome sequencing. A total of 257 (37.3%) MSSA exhibited the CzIE by the reference standard method. The overall sensitivity and specificity of the colorimetric test was 82.5% and 88.9%, respectively. Sensitivity in MSSA isolates harboring type A BlaZ (most efficient enzyme against cefazolin) was 92.7% with a specificity of 87.8%. The performance of the test was lower against type B and C enzymes (sensitivities of 53.3% and 72.3%, respectively). When the reference value was set to ≥32 μg/mL the sensitivity for isolates carrying type A enzymes was 98.2%. Specificity was 100% for MSSA lacking blaZ. The overall negative predictive value ranged from 81.4% to 95.6% in Latin-American countries using published prevalence rates of the CzIE. MSSA from US were genetically diverse, with no distinguishing genomic differences from Latin-American MSSA, distributed among 18 sequence types. A novel test can readily identify most MSSA isolates exhibiting the CzIE, particularly those carrying type A BlaZ. In contrast to the MIC determination using high-inoculum, the rapid test is inexpensive, feasible and easy to perform. After minor validation steps, it could be incorporated into the routine clinical laboratory workflow.

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Section: Resultsmentioning

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A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus

et al. 2021

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“…All MSSA isolates were strain-typed by pulsed-field gel electrophoresis, and multilocus sequence type (MLST) was inferred (Supplement). The comprehensive antibiotic resistance database (CARD, https://card.mcmaster.ca/analyze/rgi ) ( 30 ), and BLAST were used to subtype blaZ into types A, B, C, and D ( 9 , 12 , 15 , 19 , 31 ) (Supplement).…”

Section: Methodsmentioning

confidence: 99%

Epidemiology and impact of methicillin-sensitive Staphylococcus aureus with β-lactam antibiotic inoculum effects in adults with cystic fibrosis

Svishchuk,

Ebbert,

Waddell

et al. 2023

Antimicrob Agents Chemother

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Staphylococcus aureus is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and small-colony-variants. The inoculum effect (IE) is characterized by reduced β-lactam susceptibility when assessed at high inoculum. The IE associates with worse outcomes in bacteremia and other high-density infections, and may therefore be relevant to CF. The prevalence of IE amongst a CF cohort (age ≥18 years), followed from 2013 to 2016, was investigated. Yearly methicillin-sensitive S. aureus (MSSA) isolates were screened at standard (5 × 10 5 CFU/mL) and high (5 × 10 7 CFU/mL) inoculum against narrow-spectrum anti-Staphylococcal β-lactams and those with anti-pseudomonal activity common to CF. A ≥ 4-fold increase in minimum inhibitory concentration between standard and high inoculum defined IE. Isolates underwent blaZ sequencing and genotyping and were compared against published genomes. Fifty-six percent (99/177) of individuals had MSSA infection. MSSA was observed at ≥10 5 CFU/mL in 44.8% of entry sputum samples. The prevalence of the IE was 25.0%-cefazolin; 13.5%-cloxacillin; 0%-meropenem; 1.0%-cefepime; 5.2%-ceftazidime; and 34.4%-piperacillin-tazobactam amongst baseline MSSA isolates assessed. blaZ A associated with cefazolin IE ( P = 0.0011), whereas blaZ C associated with piperacillin-tazobactam IE ( P < 0.0001). Baseline demographics did not reveal specific risk factors for IE-associated infections, nor were long-term outcomes different. Herein, we observed the IE in CF-derived MSSA disproportionally for cefazolin and piperacillin-tazobactam and this phenotype strongly associated with underlying blaZ genotype. The confirmation of CF being a high density infection, and the identification of high prevalence of MSSA with IE in CF supports the need for prospective pulmonary exacerbation treatment studies to understand the impact of this phenotype.

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“…Устойчивость к пенициллинам зависит как от уровня экс прессии гена blaZ, так и от структурных особенностей его продукта. Выявлена также связь между наличием у изолята инокулюмэффекта к цефазолину и особенно стями генетической структуры локуса agr, ассоцииро ванного с системой «quorum sensing» [13].…”

Section: Introductionunclassified

Cefazolin inoculum effect among methicillinsusceptible Staphylococcus aureus isolated from patients with skin infections

Vaganova

Борисенко

Nesterova

et al. 2021

CMAC

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Objective. To evaluate frequency and intensity of cefazolin inoculum effect among methicillin-susceptible staphylococci isolated from patients with skin infections. Materials and Methods. A total of 80 methicillin susceptible isolates of Staphylococcus aureus were identified by cefoxitin disk-diffusion test and negative results of real-time PCR for mecA gene. Inoculum effect was measured by broth microdilution test with two inocula with concentrations of 5 × 105 CFU/mL and 5 × 107 CFU/mL. The disk-diffusion test with cefoxitin was also performed. Penicillin susceptibility was determined by disk-diffusion method. Beta-lactamase blaZ gene was identified by real-time PCR. Results. The frequency of cefazolin inoculum effect in tested isolates was 30% which is consistent with data from different countries. The MIC values for concentrated inoculum reached CLSI breakpoint for cefazolin resistance in 2.5% of isolates. The isolates with inoculum effect and those without it had the similar MIC values for cefazolin in broth microdilution test for standard inocula and similar diameters of inhibition zone in disk-diffusion test with cefazolin. Penicillin resistance was more frequent in inoculum effect-positive isolates. Beta-lactamase activity is considered as a main cause of cefazolin inoculum effect in staphylococci. The beta-lactamase blaZ gene was identified in the majority of isolates with cefazolin inoculum effect, but it was also prevalent among inoculum effect-negative isolates. Conclusions. Up to 30% of MSSA isolates from skin lesions in dermatological patients from SaintPetersburg are positive for cefazolin inoculum effect. Those isolates are usually characterized by penicillin resistance. Most of the cefazolin inoculum effect-positive isolates also carry beta-lactamase blaZ gene.

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The Cefazolin Inoculum Effect and the Presence of type A blaZ Gene according to agr Genotype in Methicillin-Susceptible Staphylococcus aureus Bacteremia

Cited by 6 publications

References 38 publications

A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus

A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus

Epidemiology and impact of methicillin-sensitive Staphylococcus aureus with β-lactam antibiotic inoculum effects in adults with cystic fibrosis

Cefazolin inoculum effect among methicillinsusceptible Staphylococcus aureus isolated from patients with skin infections

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