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

Abstract

<jats:p><jats:bold>Background:</jats:bold> Select methicillin-susceptible <jats:italic>Staphylococcus aureus</jats:italic> (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).</jats:p> <jats:p><jats:bold>Methods:</jats:bold> 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 10<jats:sup>7</jats:sup> CFU/ml; CzIE was defined as a cefazolin MIC ≥ 16 μg/ml. Isolates were characterized by accessory gene regulator group (<jats:italic>agr</jats:italic>). The progression from acute to chronic osteomyelitis was considered an important outcome.</jats:p> <jats:p><jats:bold>Results</jats:bold>: 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 <jats:italic>agr</jats:italic>III and associated with development of chronic osteomyelitis. In multivariable analyses, <jats:italic>agr</jats:italic>III, 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.</jats:p> <jats:p><jats:bold>Conclusion</jats:bold>: 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.</jats:p>

β-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value

“…Some have recently questioned the "true MIC" in vivo where host and bacterial factors may differ from the in vitro environment (28,29). In addition, several studies indicate that the inoculum has important implications for antibiotic activity, with high inocula, biofilm-producing cultures reducing susceptibility beyond what can be replicated in the clinical microbiology laboratory (30)(31)(32). For resistant infections and/ or for patients who are critically ill and deteriorating, clinicians could select alternative antibiotic therapy (e.g., a different β-lactam and/or a non-β-lactam) instead of trying to optimize the current regimen with TDM.…”

<p>Acute Hematogenous Osteomyelitis in Children: Clinical Presentation and Management</p>

“…57,58 In a recent study, definitive treatment with a 1GC relative to alternative agents did not increase the likelihood of treatment failure in children with MSSA AHO. 8 Cefazolin may have the additional advantage of providing coverage for K. kingae in toddler age children; K. kingae have relatively high MICs to oxacillin (MIC 90 = 6 µg/mL). 59 The need to provide empiric therapy directed at MRSA should be determined based on local prevalence of MRSA as well as individual patient clinical risk factors (e.g., history of prior MRSA infections).…”

“… 1 , 6 , 7 While children with certain underlying conditions (e.g., hemoglobinopathy) may be at increased risk of AHO, the vast majority of patients lack major medical comorbidities. 8 …”

“…Notably, 5–11% of children with S. aureus AHO require intensive care unit admission. 8 , 18 , 38 Additionally, analgesics and antipyretics should be administered as needed.…”

“… 14 , 18 Long-term complications of AHO have been reported in <1–10% of patients. 1 , 8 , 16 , 18 , 37 , 101 The most common sequelae are recurrence of infection/development of chronic osteomyelitis followed by pathologic fractures. 18 It is generally believed that the biggest risk factors for sequelae include inadequate or inappropriate treatment of acute infection.…”