Should higher doses or continuous infusions of cefazolin be used for S. aureus bacteremia?

Comment by InpharmD Researcher

Two case reports demonstrate the successful use of high-dose continuous infusion (CI) cefazolin (10 g daily) for treating serious MSSA infections, including recurrent pneumonia and ventriculitis, where standard doses were initially insufficient. While meta-analyses suggest CI of beta-lactams may offer clinical benefits like reduced hospital mortality, their findings are not specific to cefazolin or S. aureus infections. These reports, alongside a study confirming the need for dose adjustment based on renal function, support the potential value of optimized, high-dose CI cefazolin regimens for deep-seated MSSA infections, though further prospective studies are warranted.

cefazolin staphylococcus aureus bacteremia high dose continuous

Background

A 2016 meta-analysis compared clinical outcomes of patients treated with continuous versus intermittent infusion of beta-lactam antibiotics. Three randomized controlled trials with a total of 632 patients having severe sepsis were included for analysis. Rates of hospital mortality and clinical cure were improved in patients receiving continuous versus intermittent infusion (hospital mortality: 19.6% vs. 26.3%, relative risk [RR] 0.74, 95% confidence interval [CI] 0.56 to 1, p= 0.045; clinical cure: 55.4% vs. 46.3%, RR 1.2, 95% CI 1.03 to 1.4, p= 0.021). Additionally, continuous infusion of beta-lactam therapy was significantly associated with reduced odds of hospital mortality censored at 30 days in a multivariate analysis (odds ratio 0.62, 95% CI 0.41 to 0.94, p= 0.03). The authors concluded administration of beta-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality compared to intermittent dosing. Of note, cefazolin was not one of the beta-lactams studied in this analysis. [1]

A 2025 systematic review and meta-analysis assessed whether continuous infusion of β-lactam antibiotics improves clinical outcomes compared to intermittent infusion in adult patients with sepsis or septic shock. This comprehensive analysis synthesized data from eleven randomized controlled trials involving 9,166 patients. The review found that continuous infusion of β-lactams did not result in significant differences in overall mortality (RR 0.94; 95% CI: 0.88–1.01) or ICU mortality (RR 0.94; 95% CI: 0.88–1.01) when compared to intermittent infusion. However, continuous infusion was associated with lower hospital mortality (RR 0.92; 95% CI: 0.85–0.99), higher survival at the end of the study (RR 1.04; 95% CI: 1.02–1.07), and a higher clinical cure rate (RR 1.42; 95% CI: 1.12–1.80). No significant differences were observed in the length of ICU or hospital stay or in the incidence of adverse events. The findings suggest that continuous infusion could potentially reduce hospital mortality and enhance the clinical cure rate in critically ill patients, although its effects on overall mortality and adverse events require further investigation. However, findings are not specific to staphylococcus aureus infection. [2]

References: [1] Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med. 2016;194(6):681-691. doi:10.1164/rccm.201601-0024OC
[2] Tejada DA, García HC, Tomás-Alvarado E, Yangali-Vicente J, Rivera-Lozada O, Barboza JJ. Continuous versus intermittent infusion of β-lactams in patients with sepsis and septic shock: a systematic review and meta-analysis. BMC Infect Dis. 2025;25(1):1138. Published 2025 Sep 26. doi:10.1186/s12879-025-11504-2
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

Should higher doses or continuous infusions of cefazolin be used for S. aureus bacteremia?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

 

Cloxacillin versus cefazolin for meticillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): a prospective, open-label, multicentre, non-inferiority, randomised clinical trial
Design

Prospective, open-label, multicentre, non-inferiority, randomised clinical trial

N= 315
Objective

To compare the efficacy and safety of cefazolin with that of cloxacillin in patients with MSSA bacteremia
Study Groups

Cefazolin (n= 146)

Cloxacillin (n= 146)
Inclusion Criteria

Adults aged ≥18 years with MSSA bacteremia, without intravascular implant or suspicion of CNS infection, and who received antimicrobial therapy active against MSSA within 72 hours before randomisation
Exclusion Criteria

Stage 4 renal failure, pre-established limitation of care, projected life expectancy less than 90 days, previous hypersensitivity reaction to beta-lactams
Methods

Participants were randomly assigned to receive cefazolin (25-50 mg/kg q8h) or cloxacillin (25-50 mg/kg q4-6h; max 12 g/d) intravenously for the first 7 days. Subsequent treatment was investigator's choice with a total duration of ≥14 days. Prescribers were allowed to switch antibiotic treatment after 7 days, as was common practice at the time of the study.
Duration

Follow-up: up to 90 days
Outcome Measures

Primary: Composite of sterile blood cultures at day 3, survival, and clinical success at day 90

Secondary: Survival at day 90, early bacteriological success, absence of relapse of bacteremia by day 90, clinical success at day 7
Baseline Characteristics   Cefazolin (n=146)

Cloxacillin (n=146)
Age, years (mean) 62.7 ± 15.3

62.8 ± 17.4
Male 106/146 (73%)

107/146 (73%)
Charlson comorbidity score 4.4 ± 3.2

4.3 ± 3.0
At least one comorbid condition 100/146 (68%)

105/145 (72%)
Myocardial infarction 6/146 (4%)

13/145 (9%)
Diabetes requiring medication 28/146 (19%)

19/145 (13%)
Moderate or severe renal disease 21/146 (14%)

21/145 (14%)
Immunosuppression 45/146 (31%)

38/146 (26%)
Presence of a venous access at time of bacteremia diagnosis 38/146 (26%)

43/146 (29%)
Results   Cefazolin (n=146) Cloxacillin (n=146) Treatment difference (95% CI)

p-value
Primary outcome (therapeutic success) 109/146 (75%) 108/146 (74%) -1% (-11 to 9)

0.012
Survival at day 90 134/146 (92%) 134/146 (92%) 0% (-7 to 7)

0.0005
Microbiological success at day 3 136/146 (93%) 135/146 (92%) 1% (-6 to 7)

0.0002
Absence of relapse of bacteremia at day 90 145/146 (99%) 144/146 (99%) 1% (-3 to 4)

<0.0001
Clinical success at day 90 116/144 (81%) 111/139 (80%) 1% (-9 to 10)

0.0041
Adverse Events

Serious adverse events were less frequent in the cefazolin group (15% vs. 27% at end of study treatment, p=0.010). Acute kidney injury was more common in the cloxacillin group (12% vs. 1%, p=0.0002)
Study Author Conclusions

Cefazolin constitutes an alternative to cloxacillin for the treatment of MSSA bacteremia, offering non-inferior clinical efficacy and potentially enhanced tolerability.
Critique

The study's open-label design and exclusion of certain patient populations may limit generalizability. The trial demonstrated non-inferiority of cefazolin with a better safety profile, but the exclusion of patients with severe conditions or those under guardianship may have influenced outcomes. Further research is needed to confirm findings in broader patient populations.

 

References:
[1] [1] Burdet C, Sadani N, Dupieux C, et al. Cloxacillin versus cefazolin for meticillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): a prospective, open-label, multicentre, non-inferiority, randomised clinical trial. Lancet. 2025;406(10517):2349-2359. doi:10.1016/S0140-6736(25)01624-1

 

Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram
Design

Retrospective study using population pharmacokinetics modeling

N= 162
Objective To describe and analyze the pharmacokinetics of cefazolin in patients with bacteremia or infective endocarditis using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose
Study Groups All patients (n= 162)
Inclusion Criteria Adult patients hospitalized and treated with continuous-infusion cefazolin for bacteremia or infective endocarditis, followed by therapeutic drug monitoring
Exclusion Criteria Patients who received any type of dialysis during treatment
Methods

Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin. The influence of renal function, total body weight, body mass index, body surface area, ideal weight, lean body weight, height, and age was tested. A dosing nomogram was developed using the absolute value of the glomerular filtration rate (aGFR) to determine the optimal daily dose required to achieve target concentrations.
Duration Data collection: January 2013 to September 2018
Outcome Measures

Analysis of pharmacokinetics from cefazolin use, daily dose and dose range
Baseline Characteristics   All patients (n= 162)
% of male patients 63%
% of patients with infective endocarditis 20%
Age, median years (IQR) 68 (54-80)
Height, cm 169 (161-175)
Weight, kg 73 (63-86)
BMI, kg/m² 26 (22-29)
LBW, kg 61 (54-68)
IWR, kg 60 (56-67)
BSA, m² 1.84 (1.68-1.99)
Serum creatinine concn, μmol/liter 74 (56-122)
eGFR, ml/min/1.73 m² 84.7 (50.8-105.4)
aGFR, ml/min 84.7 (50.8-105.4)
Results   All patients (n= 162)
Cefazolin plasma concentrations samples collected 346
Median daily dose, mg/day 6,000
Dose range, mg/day 500 to 12,000
Patients with aGFR ≥90 ml/min 58%
Patients with aGFR ≥120 ml/min 16%
Adverse Events Not specifically reported in the study
Study Author Conclusions

The study confirms the interest of posology adaptation of cefazolin according to aGFR. The developed nomogram can assist in determining the optimal daily dose of cefazolin to achieve target concentrations in patients with bacteremia or infective endocarditis.
Critique

The study provides a useful tool for dose adaptation of cefazolin based on renal function, but it is limited by its retrospective nature and lack of clinical outcome data. The absence of cefazolin free fraction measurements and reliance on estimators for renal function are additional limitations. Prospective validation of the nomogram is needed.

 

References:
[1] Bellouard R, Deschanvres C, Deslandes G, et al. Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram. Antimicrob Agents Chemother. 2019;63(10):e00806-19. Published 2019 Sep 23. doi:10.1128/AAC.00806-19

 

High-dose cefazolin on consecutive hemodialysis in anuric patients with Staphylococcal bacteremia
Design

Retrospective analysis

N= 27
Objective To assess the outcomes and safety of treating MSSA bacteremia with high-dose cefazolin administered during hemodialysis sessions
Study Groups

Cefazolin (n= 14)

Cloxacillin (n= 13)
Inclusion Criteria Patients with MSSA-positive blood cultures drawn within 48 hours of hospitalization or symptomatic with no other infection cause if positive after 48 hours; HD vintage >36 months
Exclusion Criteria Patients <21 years old, died within 2 days of hospitalization, polymicrobial or non-MSSA bacteremia, received standard 1 g cefazolin daily initially
Methods Retrospective identification of HD patients with MSSA bacteremia treated with 2-3 g cefazolin on HD. Historical controls received cloxacillin. Outcomes like mortality, LOS, cost, recrudescence, and ADRs were assessed
Duration June 2009 to December 2009
Outcome Measures

Primary: 30-day mortality, infection recrudescence

Secondary: Length of stay (LOS), hospitalization cost, adverse drug reactions (ADRs)
Baseline Characteristics   Cefazolin (N=14) Cloxacillin (N=13)
Mean age (y) 50 ± 12 50 ± 14
Gender (male %) 64.3 53.8
Diabetes mellitus (%) 79 77
Vascular access - Tunneled catheter (%) 43 46
Vascular access - Arteriovenous fistula (AVF) (%) 43 39
Vascular access - Arteriovenous graft (AVG) (%) 14 15
Results   Cefazolin (n=14) Cloxacillin (n=13) p-value
30-day mortality (%) 7 15 0.14
Recrudescence (%) 0 15 0.14
Length of stay (days) 10 20 <0.05
Hospitalization cost (US$) 8262.00 15367.00 <0.05
Adverse Events

Cefazolin was associated with 3 idiosyncratic adverse drug reactions: 2 cases of Steven Johnson syndrome and 1 case of severe leukopenia
Study Author Conclusions

Cefazolin dosed on each HD in MSSA bacteremia leads to earlier discharge and less cost. Larger prospective studies are warranted to fully assess its safety and efficacy.
Critique

The study's retrospective design and small sample size limit the generalizability of the findings. The study was conducted in a specific population with moderate comorbidity scores, which may not reflect broader patient demographics. The high catheter utilization rate may also impact the study's applicability to other settings.

 

References:
[1] Renaud CJ, Lin X, Subramanian S, Fisher DA. High-dose cefazolin on consecutive hemodialysis in anuric patients with Staphylococcal bacteremia. Hemodial Int. 2011;15(1):63-68. doi:10.1111/j.1542-4758.2010.00507.x

 

Twice daily cefazolin is effective for treatment of serious methicillin-sensitive Staphylococcus aureus infection in an outpatient parenteral antimicrobial therapy program
Design

Retrospective analysis

N= 111
Objective

To evaluate the safety, efficacy and outcomes after 90 days of follow-up for patients with serious infections caused by MSSA treated with twice daily cefazolin by an outpatient parenteral antimicrobial therapy (OPAT) program
Study Groups

All patients (n= 111)
Inclusion Criteria

Patients admitted to the Alfred Health OPAT program from 1 January 2010 until 31 July 2016 with a positive culture result demonstrating MSSA, without the presence of other organisms, and received definitive therapy with cefazolin on the OPAT program
Exclusion Criteria

Patients with another organism isolated on culture, received any other antimicrobial as part of their OPAT therapy, or received part of their care during the definitive antimicrobial therapy at an alternative health service
Methods

Cases were identified through an Australian Hospital database. Patients received cefazolin monotherapy on the OPAT program. Patients weighing 80 kg or more received 3 g BID, while those under 80 kg received 2 g BID. Dosages were adjusted for patients with significantly impaired renal function.
Duration

January 2010 to July 2016
Outcome Measures

Primary: Treatment success (completion of antimicrobial regimen without premature discontinuation or change of therapy, and without treatment relapse or recurrence within 90 days)

Secondary: Complications observed while being treated via OPAT, readmission rates, adverse drug reactions
Baseline Characteristics  

All patients (n= 111)
Age, years (IQR)

61 (44-77)
Male gender

80 (72%)

Location of OPAT care

Home

Aged care facility

Other

 

107 (96%)

2 (2%)

2 (2%)

Primary infection site

Peripheral osteomyelitis

Infective endocarditis/endovascular

Vertebral osteomyelitis

Unknown

Line-related

Skin/soft tissue

Septic arthritis

Epidural abscess

Intra-abdominal/pelvis

Other

 

36 (32%)

12 (11%)

11 (10%)

10 (9%)

10 (9%)

7 (6%)

7 (6%)

5 (5%)

4 (4%)

9 (8%)
Positive blood culture

51 (46%)
Charlson comorbidity index (IQR)

3 (0-5)
Results  

All patients (n= 111)
Treatment success 107 (96%)
Premature antibiotic switch/discontinuation 2 (2%)
Infection recurrence within 90 days follow-up 2 (2%)
Adverse Events 4% of patients experienced an adverse drug reaction (rash, neutropaenia, itch)
Study Author Conclusions

The use of twice daily cefazolin for serious MSSA infection on an OPAT program is safe and effective. Further study is needed to assess for noninferiority to conventional treatment regimes.
Critique

The study's strengths include a large patient cohort and detailed patient record analysis, providing real-world applicability. However, limitations include its retrospective single-centre design, potential observational bias, and incomplete follow-up data if patients received treatment at alternative health services. Additionally, treatment selection bias may exist due to the lack of a comparator arm.

 

References:
[1] [1] Birrell MT, Fuller A. Twice daily cefazolin is effective for treatment of serious methicillin-sensitive Staphylococcus aureus infection in an outpatient parenteral antimicrobial therapy program. Ther Adv Infect Dis. 2019;6:2049936119882847. Published 2019 Dec 9. doi:10.1177/2049936119882847

 

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis

Design

 Case report

Case presentation

A 42-year-old patient with no significant medical history developed MSSA ventriculitis as a complication following an external ventricular drain (EVD) placed for a subarachnoid hemorrhage. After initial empirical therapy, targeted treatment with high-dose continuous infusion cefazolin (10 g daily) and levofloxacin was initiated. The methicillin-susceptible Staphylococcus aureus (MSSA) strain demonstrated an oxacillin MIC of 0.5 mg/L and was resistant to co-trimoxazole and rifampin. Cerebrospinal fluid (CSF) sterilization was achieved 48 hours after starting this regimen. Due to elevated total plasma concentrations, the cefazolin dose was reduced to 8 g daily, which resulted in a lower free fraction and a reduced CSF/plasma free concentration ratio (dropping from 73% to 54%). Despite these pharmacokinetic variations, the measured free cefazolin concentrations in the CSF remained above the typical MSSA epidemiological MIC cutoff of 2 mg/L throughout the entire treatment interval, ensuring 100% fT>MIC. The patient completed a six-week course, with all subsequent CSF cultures remaining sterile.

Study Author Conclusions

 These results support the use of high-dose cefazolin to achieve sufficient meningeal concentrations.

 

References:
[1] [1] Grgoire M, Gaborit B, Deschanvres C, et al. High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis. Antimicrob Agents Chemother. 2019;63(2):e01844-18. Published 2019 Jan 29. doi:10.1128/AAC.01844-18

 

Successful clearance of persistent Staphylococcus aureus pneumonia with high-dose continuous infusion cefazolin

Design

 Case report

Case presentation

A 33-year-old male patient was admitted with community-acquired pneumonia and subsequent complications, leading to a prolonged hospital stay. The patient's pneumonia relapsed twice after two courses of cefazolin administered as an 8 g daily CI regimen, each lasting between 5 to 7 days. It was only after a 14-day course of cefazolin at a higher dose of 10 g daily CI that the infection was successfully cleared. The patient's fever and leukocytosis resolved rapidly. No adverse events or drug-related toxicity were observed during the high-dose cefazolin therapy.

Study Author Conclusions

The case report provides valuable clinical insights into optimizing β-lactam antibiotic therapy through continuous infusion, potentially influencing treatment protocols for severe MSSA infections in critically ill patients.

 

References:
[1] [1] Smelter AA, Frei CR, Smelter DF. Successful clearance of persistent Staphylococcus aureus pneumonia with high-dose continuous infusion cefazolin. ASM Case Rep. 2025;1(3):e00114-24. Published 2025 Mar 31. doi:10.1128/asmcr.00114-24