Cefazolin vs. Antistaphyloccal Penicillins: The Great Debate Annie Heble, PharmD PGY2 Pediatric Pharmacy Resident Children s Hospital Colorado Microbiology Rounds March 22, 2017 Image Source: Buck cartoons
Objectives Review the treatment options for methicillinsusceptible Staphylococcus aureus (MSSA) Compare and contrast nafcillin and cefazolin Discuss the literature surrounding cefazolin for the treatment of invasive MSSA infections
Patient Case AH is a 2-year-old male with fever (Tmax = 39 C) in the setting of a central line PMH: hypoplastic left heart syndrome (s/p Fontan 1 month ago inpatient since operation), chylous chest tube output, Fontan circuit clot (on enoxaparin), pulmonary vein stenosis Allergies: dexmedetomidine (bradycardia) Gram positive cocci in groups identified in 2/2 blood cultures MSSA identified on BCID AH is currently on NO antibiotics! What antibiotic do you recommend starting? Image Source: Pediatricmicro.com
MSSA Infections Deep-seated and Invasive Infections Risk of systemic infections Prolonged treatment courses High rates of morbidity and mortality Lack of novel MSSAspecific antibiotics Lee BJ, et al. Int J Antimicrob Agents. 2017. doi: 10.1016/j.ijantimicag.2016.12.021 [Epub ahead of print].
Treatment of MSSA Infections First-line agents = Antistaphyloccal penicillins (oxacillin, nafcillin) Penetration into bone, tissue, CSF (nafcillin), etc. Alternative = 1 st generation cephalosporins (cefazolin) Penicillin-allergic patients Penetration into bone, tissue, NO CSF, etc. Increased mortality with vancomycin monotherapy in MSSA Schweizer ML, et al. BMC Infectious Diseases. 2011;11:1-7
Coverage Nafcillin vs. Cefazolin Cefazolin = slightly more gram negative coverage Dosing interval Nafcillin = every 4 to 6 hours, continuous infusion Multiple line enteries, difficult for home administration, compatibility issues Cefazolin = every 6 to 8 hours Li, J, et al. Pharmacotherapy. 2017;37(3):346-360. Lexi-Comp. Nafcillin.
Nafcillin vs. Cefazolin PO transition Beneficial for MSSA infections with a PO therapy option PO cephalexin PO dicloxacillin? Poor bioavailability (49-76%), $$$, poor taste Cost- CHCO 2012 Cost Evaluation $20,755 (nafcillin) vs $3,500 (cefazolin) Cost savings = $17,255!!! Li, J, et al. Pharmacotherapy. 2017;37(3):346-360. Wood JB, et al. J Pediatric Infect Dis Soc. 2016;5(4):480-482.
Nafcillin vs. Cefazolin Adverse effects Commonly observed with prolonged therapy Results in treatment changes, interruptions in therapy, increased cost Nafcillin = phlebitis, elevated LFTs, cytopenias β-lactam Adverse Effects Hypersensitivity Rash Diarrhea, nausea, vomiting Bone marrow suppression Interstitial nephritis Hepatotoxicity Nafcillin was associated with more adverse drug events in the outpatient setting compared with cefazolin 31.1% NAF vs. 11.7% CEF (p< 0.001) Rash, renal impairment, liver abnormalities, neutropenia 33.8% discontinued therapy with NAF vs. 6.7% with CEF (p < 0.001) 7.25% of NAF-treated patients were switched to CEF Key: NAF = nafcillin; CEF= cefazolin Li, J, et al. Pharmacotherapy. 2017;37(3):346-360. Youngster I, et al. Clin Infect Dis. 2014;59(3):369-75.
Cefazolin Inoculum Effect Concern for clinical failure with cefazolin in deep-seated MSSA infections Cefazolin hydrolysis by type A β-lactamases (and type C) Anti-staphylococcal penicillins are resistant 100x more β-lactamases with high inocula (endocarditis, osteomyelitis, bacteremia) Cefazolin inoculum effect (CIE) High inocula of MSSA Produce of large quantities of type A β-lactamases Increased degradation of cefazolin and increased MIC 4-fold increase in cefazolin MIC between standard and high inocula Li, J, et al. Pharmacotherapy. 2017;37(3):346-360.
Cefazolin Inoculum Effect Case reports and retrospective reviews describing cefazolin failure in deep-seated infections CIE reported in few studies Case report in 47-year-old male with MSSA native valve endocarditis Received cefazolin initially, but relapsed (fever & positive blood cultures) Resolution of fever & negative blood cultures with transition to nafcillin + valve replacement MSSA strain demonstrated an increased MIC at high inoculum (5x10 7 ) Li, J, et al. Pharmacotherapy. 2017;37(3):346-360. Nannini EC, et al. Clin Infect Dis. 2003;37:1194-1198..
Should cefazolin be avoided in deep-seated MSSA infections?
All About the Source Data describing site of infection and source control as risk factors for treatment failure with MSSA \ Retrospective review comparing OX (n=34) vs. CEF (n=59) for complicated MSSA bacteremia Continuous infusion in 75% of CEF patients and 97% OX patients Clinical cure in 88% (OX) vs. 95% (CEF) (p=0.25) Adverse effects in 30% (OX) vs. 3% (CEF) (0.006) Key: OX = oxacillin; CEF= cefazolin Li, et al. Antimicrob Agents Chemother. 2014;59(9):5117-5124.
Treatment failure more prominent in OX group (47% vs. 24%; p=0.04) More osteoarticular infections (p=0.009), ICU admissions, and multiple sites of metastasis Treatment failures were more likely to have surgical intervention, longer median duration of bacteremia, and osteoarticular sources All About the Source Li, et al. Antimicrob Agents Chemother. 2014;59(9):5117-5124.
Li, J, et al. Pharmacotherapy. 2017;37(3):346-360. Keel RA, Presented at the 48 th Annual Meeting of the IDSA. Vancouver, British Columbia, Canada, 2010. Cefazolin PK/PD and CIE May require higher doses or extended infusions for deep-seated MSSA infections 100-150 mg/kg/day (max= 6g/day) Higher %T>MIC with higher doses, extended infusions, or continuous infusions for CEF with MSSA MIC = 1 Higher MICs observed with CIE Improved survival rates with higher CEF doses in animals with MSSA strains with CIE
Comparison Cefazolin Nafcillin Advantages Less adverse reactions Q6-8H dosing interval Less expensive PO transition option Standard of therapy in guidelines CSF penetration Narrow spectrum of activity Disadvantages Risk of failure with CIE? (New evidence points to no) Poor CSF penetration Broader spectrum of activity Adverse drug reactions (therapy discontinuation, interruptions) Q4-6H dosing interval More expensive Li, J, et al. Pharmacotherapy. 2017;37(3):346-360.
Patient Case What medication would you choose to start patient AH on for treatment of MSSA bacteremia knowing his cardiac history? A: Nafcillin 200 mg/kg/day divided Q4H B: Cefazolin 150 mg/kg/day divided Q8H C: Vancomycin 15 mg/kg Q6H D: Other
Summary Cefazolin and nafcillin differ in regards to cost, coverage, administration, and adverse effects. Cefazolin has historically been avoided in deep-seated MSSA infections due to the risk of failure in the setting of the cefazolin inoculum effect. More recent literature supports the use of cefazolin in this setting.
Cefazolin vs. Antistaphyloccal Penicillins: The Great Debate Questions? Annie Heble, PharmD PGY2 Pediatric Pharmacy Resident Ann.heble@childrenscolorado.org Image Source: Buck cartoons