What literature exists evaluating the use of prolonged or extended infusions of beta-lactam antibiotics, compared with standard intermittent infusions, in the treatment of invasive gram-positive infections such as bacteremia?

Comment by InpharmD Researcher

There are limited clinical studies directly comparing prolonged infusion versus intermittent infusion of beta-lactam antibiotics for invasive gram-positive bacteremia. However, existing clinical guidelines and pharmacokinetic/pharmacodynamic data support the use of prolonged infusion strategies. Prolonged infusion involves extending the duration of administration to optimize the time during which drug concentrations remain above the minimum inhibitory concentration (MIC). This may be achieved by infusing the antibiotic over at least 50% of the dosing interval or by administering it as a continuous infusion. Evidence from guideline recommendations and pharmacodynamic studies suggests that this strategy is associated with improved clinical outcomes, including a statistically significant reduction in mortality compared with intermittent dosing. Consequently, at least one guideline recommends considering prolonged infusion of beta-lactams as a standard-of-care approach in the management of sepsis and septic shock in critically ill patients. Nevertheless, the current body of evidence remains limited, and further high-quality studies are needed to confirm these findings, particularly in the context of invasive gram-positive bacteremia.

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Background

International consensus recommendations have been developed for the use of prolonged-infusion (PI) beta-lactam antibiotics, endorsed by major healthcare and pharmacological societies including the American College of Clinical Pharmacy and the Infectious Diseases Society of America among others. The guidelines address the optimization of pharmacokinetic and pharmacodynamic parameters to combat emerging resistance and interpatient variability in drug exposures. PI dosing, which involves extending infusion duration to increase the time the drug concentration remains above the minimum inhibitory concentration (MIC), has been shown to potentially improve patient outcomes in various populations. The consensus provides recommendations for PK/PD targets, therapeutic drug monitoring, and addresses concerns related to drug stability and the need for further research. The overall evidence indicates that PI beta-lactam antibiotics can offer improved efficacy and similar safety profiles compared to standard infusion, especially in severely ill adult patients, though further studies are recommended to refine these approaches. [1]

The 2021 "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock" provided updated recommendations for the management of sepsis and septic shock in adult patients within hospital settings. The guidelines emphasized early screening and administration of treatment protocols, highlighting the importance of performance improvement programs for sepsis that include structured screening methods and adherence to sepsis bundles. Regarding treatment strategies, the guidelines recommended a strong focus on the early administration of appropriate empiric antimicrobials, ideally within one hour of recognizing potential septic shock. They also add that for administration of beta-lactam antibiotics, prolonged IV infusion either as an extended infusion (antibiotic infused over at least half of the dosing interval) or as a continuous infusion instead of the conventional intermittent infusion (infusion ≤ 30 minutes) is preferred. Although this a weak recommendation with moderate quality of evidence, they state that there is significant reduction in short-term mortality with prolonged infusion compared to intermittent infusion. The guidelines underscore the importance of individualizing treatment based on ongoing clinical assessment and emphasize the need for continuous reassessment of therapy effectiveness, particularly concerning antimicrobial de-escalation and the management of fluid balance. [2]

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. [3]

A 2024 review and meta-analysis of 18 randomized clinical trials compared prolonged versus intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock. This comprehensive investigation, which included 9,108 participants across multiple continents, aimed to evaluate whether prolonged infusions were associated with reduced 90-day mortality and other clinically significant outcomes. The primary outcome focused on all-cause 90-day mortality, with secondary outcomes including intensive care unit (ICU) mortality and clinical cure rates.The investigators found that prolonged β-lactam antibiotic infusions were associated with a statistically significant reduction in 90-day mortality, with a pooled estimated risk ratio of 0.86 and a 99.1% probability of benefit compared to intermittent infusions. Additionally, prolonged infusions resulted in a decreased risk of ICU mortality and an increased likelihood of clinical cure. The meta-analysis underscored a high degree of certainty regarding the mortality benefit, thus suggesting that prolonged infusions should be considered a standard care approach in managing sepsis and septic shock in intensive care settings. The comprehensive analysis adds substantial evidence supporting the superiority of prolonged infusion techniques in this critically ill population. [4]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Level of evidence

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

Please see Tables 1-3 for your response.

Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis The BLING III Randomized Clinical Trial
Design	International, open-label, randomized clinical trial N= 7202
Objective	To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis
Study Groups	Continuous infusion (n= 3498) Intermittent infusion (n= 3533)
Inclusion Criteria	Adult ICU patients (≥18 years) with a documented site or strong suspicion of infection, treated with piperacillin-tazobactam or meropenem within the previous 24 hours, and meeting one or more organ dysfunction criteria
Exclusion Criteria	Patients who received antibiotics for >24 hours, requiring kidney replacement therapy at randomization, advanced life support deemed inappropriate, known allergy to antibiotic, imminent death, aged <18, previously enrolled, or pregnant
Methods	Participants were randomized to receive a 24-hour dose of a β-lactam antibiotic by continuous or intermittent infusion. Continuous infusion was administered over 24 hours, while intermittent infusion was administered over 30 minutes. The treatment continued for the duration of the course or until ICU discharge.
Duration	March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023
Outcome Measures	Primary: All-cause mortality within 90 days after randomization Secondary: Clinical cure up to 14 days, new acquisition, colonization or infection with multiresistant organism or C. difficile, ICU mortality, in-hospital mortality
Baseline Characteristics		Continuous infusion (n= 3498)	Intermittent infusion (n= 3533)
	Age, mean (SD), years	59.3 (16.4)	59.6 (16.1)
	Sex,No. (%) Female Male	1190 (34.0) 2308 (66.0)	1233 (34.9) 2300 (65.1)
	Weight, mean (SD) [No.], kg	82.7 (22.6) [3493]	82.7 (22.9) [3530]
	Height, mean (SD) [No.], cm	170.5 (9.9) [3468]	170.3 (10.2) [3509]
	APACHE II score, mean (SD) [No.]	19.6 (7.6) [3495]	19.5 (7.4) [3529]
	Received antibiotics Other than piperacillin-tazobactam or meropenem in the 24 h prior to randomization, No./total (%)	2340/3496 (66.9)	2460/3532 (69.6)
Results		Continuous Infusion (n= 3498)	Intermittent Infusion (n= 3533)	Absolute Difference,% (95% CI)	Odds Ratio (95% CI)	P value
	All-cause mortality at day 90, No./total (%)	864/3474 (24.9)	939/3507 (26.8)	−1.9 (−4.9 to 1.1)	0.91 (0.81 to 1.01)	.08
	Clinical cure at day 14, No./total (%)	1930/3467 (55.7)	1744/3491 (50.0)	5.7 (2.4 to 9.1)	1.26 (1.15 to 1.38)	<.001
	New acquisition, colonization, or infection with an MRO or C difficile, No./total (%)	253/3498 (7.2)	266/3533 (7.5)	−0.3 (−1.9 to 1.4)	0.96 (0.80 to 1.15)	.65
	All-cause ICU mortality, No./total (%)	595/3474 (17.1)	645/3507 (18.4)	−1.3 (−4.0 to 1.4)	0.92 (0.81 to 1.04)	.35
	All-cause hospital mortality, No./total (%)	808/3474 (23.3)	878/3507 (25.0)	−1.8 (−4.8 to 1.2)	0.91 (0.81 to 1.02)	.27
Adverse Events	10 adverse events in the continuous infusion group (0.3%) and 6 adverse events in the intermittent infusion group (0.2%), including 1 serious adverse event in the continuous infusion group
Study Author Conclusions	The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients.
Critique	The study was robust with a large sample size and international collaboration, enhancing its generalizability. However, the open-label design may introduce bias, and the lack of blinding could affect subjective outcomes. The study's applicability to regions with high antibiotic resistance is uncertain, and the use of intermittent dosing prior to randomization in the continuous group may have influenced results.

References:
[1] [1] Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs Intermittent -Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA. 2024;332(8):629-637. doi:10.1001/jama.2024.9779

Continuous Cefazolin Infusion to Treat Bone and Joint Infections: Clinical Efficacy, Feasibility, Safety, and Serum and Bone Concentrations
Design	Single-center, retrospective cohort study N= 94
Objective	To evaluate the clinical efficacy, feasibility, and safety of the prolonged administration of continuous intravenous cefazolin in a cohort of patients and to determine serum cefazolin levels and bone concentrations in several of them
Study Groups	All patients (N= 94)
Inclusion Criteria	Treated for a bone and/or joint infection with continuous intravenous cefazolin for ≥ 2 weeks with two or more serum cefazolin-concentration determinations
Exclusion Criteria	Not explicitly stated
Methods	Patients received cefazolin intravenously through a central venous catheter with a loading dose of 1 g infused over 10 minutes when the daily dose was ≤ 4 g or 2 g when the daily dose was > 4 g, followed by a continuous infusion of 60 to 80 mg/kg of body weight/day dissolved in 50 mL of 5% dextrose and administered over 12 hours twice a day via infusion pump. All patients received combined antibiotic therapy. Patients were discharged to home with parenteral antibiotic therapy on an outpatient basis when the treatment duration exceeded 3 weeks, the local and general evolution of the infection was favorable, the function of the affected joint or limb had been recovered, the treatment was well tolerated, and they could be assisted at home with the performance of daily activities. Antibiotic therapy was administered twice a day at home. Serum cefazolin levels were determined at least twice for each patient with the first blood sample obtained between days 2 and 10 of cefazolin treatment, and the second was obtained between days 11 and 21, with a minimum of 5 days occurring between the times of collection of the two samples. The target serum steady-state concentration was 40 to 70 mg/L; values below that range were considered underdosing, and those above that range were considered overdosing; the patients' daily cefazolin doses were increased or decreased (20 to 25% of the daily dose) accordingly.
Duration	February 2005 to May 2007
Outcome Measures	Number of patients with relapse, reinfection, death, cure, and probable cure Relapse: positive cultures of joint aspirate or intraoperative specimens that grew the same bacterium Reinfection: new infection with another pathogen Death: Death was considered infection-related when it was associated with uncontrolled sepsis or treatment-related when it was associated with a complication arising during or following surgery or while the patient was receiving antibiotic therapy and in the absence of severe sepsis. Cure: absence of clinical, biological, and radiological signs of infection after 2 years of follow-up Probable cure: absence of clinical, biological, and radiological signs of infection after 1 year of follow-up
Baseline Characteristics		All patients (N= 94)
	Median age, years (range)	56 (18 to 92)
	Male	55 (58.5%)
	Median weight, kg (range)	73 (45 to 130)
	Median creatinine clearance, mL/min (range)	110 (30 to 150)
	American Society of Anesthesiology score ≥ 3	9 (9.6%)
	Type of infection Joint arthroplasty infection Chronic osteomyelitis Septic arthritis/osteoarthritis Spondylodiscitis	44 (47%) 34 (36.2%) 16 (17%) 2 (2.1%)
	Pathogen isolated Staphylococcus aureus Coagulase-negative staphylococcus Streptococcus species Gram-positive anaerobic bacteria Polymicrobial	56 (59.6%) 9 (9.6%) 7 (7.4%) 18 (19.1%) 8 (8.5%)
	Median daily dose, g (range)	6 (4 to 16)
	Median duration of treatment, days (range)	42 (14 to 82)
	Median serum cefazolin concentrations, mg/L (range) Days 2-10 Days 11-21	63 (13 to 203) 57 (29 to 128)
Results	Endpoint	Patients remaining during follow-up (n= 88)
	Relapse with S. aureus infection	5 (5.7%)
	Death	1 (1.1%)
	Cured	53 (60.2%)
	Probably cured	29 (33%)
	Reinfection results were not reported. Bone cefazolin levels were determined for eight patients. The median duration of cefazolin therapy before sampling was 7 days (range 6 to 62 days). The median cefazolin bone concentration and bone concentration/serum concentration ratio were 13.5 μg/g (range 3.5 to 29 μg/g) and 0.25 (range 0.06 to 0.41), respectively.
Adverse Events	Two patients experienced cefazolin-related adverse events. The first patient developed Clostridium difficile colitis, and the second became confused. The serum cefazolin levels were relatively high (127 mg/L) in the second patient at nearly twice the upper limit targeted. Cefazolin was definitively stopped for the first patient and was intermittently stopped for the second patient, whose daily dose was tapered.
Study Author Conclusions	Prolonged treatment of bone and joint infections with continuous intravenous cefazolin is feasible, effective, well-tolerated, safe, and convenient to administer, making continuous cefazolin a strong candidate for home therapy.
InpharmD Researcher Critique	This study is limited by its retrospective design, which has the potential to lead to inherent biases. Additionally, only 8 patients had concentrations sampled from their bones, which limits conclusions on the potential bone penetration from cefazolin continuous infusion. A prospective study that includes a more homogeneous population is needed to confirm the efficacy of cefazolin for a specific infection since this cohort of patients had various infections at different sites caused by various pathogens.

References:
[1] Zeller V, Durand F, Kitzis MD, et al. Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations. Antimicrob Agents Chemother. 2009;53(3):883-887. doi:10.1128/AAC.00389-08

*Twice daily cefazolin is effective for treatment of serious methicillin-sensitive Staphylococcus aureus* infection in an outpatient parenteral antimicrobial therapy program**
Design	Single-center, retrospective cohort study N= 111
Objective	To evaluate the safety, efficacy and outcomes after 90 days of follow up for patients with serious infections caused by methicillin-sensitive S. aureus (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 OPAT program with a positive culture result demonstrating MSSA, without the presence of other organisms; received definitive therapy with cefazolin on the OPAT program and had an invasive infection due to MSSA, defined as any infection other than cellulitis or bursitis
Exclusion Criteria	Another organism (not MSSA) isolated on culture, received any other antimicrobial as part of OPAT therapy, or received care during the definitive antimicrobial therapy at an alternative health service
Methods	Data was collated retrospectively by a single researcher based on the electronic healthcare records. Participants received intermittent dose cefazolin while they were managed via OPAT. Those weighing ≥ 80 kg received a dose of 3 g twice daily, whereas those who weighed < 80 kg were treated with 2 g twice daily. These doses were subsequently adjusted for patients with significantly impaired renal function (creatinine clearance of ≤ 40 mL/minute) based on prescribing information.
Duration	Between January 2010 and July 2016 Follow-up: 90 days
Outcome Measures	Primary outcome: treatment success (completing the antimicrobial regimen without premature discontinuation or change of therapy, and without treatment relapse or recurrence within 90 days of antibiotic discontinuation) Secondary outcome: complications observed during treatment of OPAT, readmission rates, and adverse drug reactions
Baseline Characteristics		All patients (N= 111)
	Age, years (interquartile range [IQR])	61 (44 to 77)
	Male	80 (72%)
	Primary infection site Peripheral osteomyelitis Infective endocarditis/endovascular Vertebral osteomyelitis Unknown Line-related Skin/soft tissue Septic arthritis Epidural abscess Intra-abdominal/pelvis	36 (32%) 12 (11%) 11 (10%) 10 (9%) 10 (9%) 7 (6%) 7 (6%) 5 (5%) 4 (4%)
	Positive blood culture	51 (46%)
	Charlson comorbidity index (IQR)	3 (0 to 5)
Results	Endpoint	All patients (N= 111)
	Cefazolin dose during OPAT 3 g twice daily 2 g twice daily 1.5 g twice daily 1 g twice daily 1 g daily	72 (65%) 32 (29%) 2 (2%) 2 (2%) 3 (3%)
	Antibiotic regimen Duration of intravenous antibiotics, days* Proportion of intravenous antibiotics delivered via OPAT*	41 (25 to 45) 69% (50 to 82%)
	Treatment outcomes Premature antibiotic switch/discontinuation Injection recurrence within 90 days Treatment success	2 (2%) 2 (2%) 107 (96%)
	Complications during OPAT Adverse drug reaction Fall requiring hospital assessment Clostridium difficile colitis Venous access issues Treatment failure Diarrheal illness (not Clostridium difficile) Line infection Postoperative collection	4 (4%) 3 (3%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
	Readmission within 90 days of completion of antimicrobials Acute medical condition (not directly related to initial infection) Elective surgical procedure Relapse of infection Clostridium difficile colitis New alternative infection Complication of previous surgery	11 (10%) 4 (4%) 2 (2%) 1 (1%) 1 (1%) 1 (1%)
	*It was not reported whether the results given in parentheses were IQRs or ranges.
Adverse Events	Common Adverse Events: rash (n= 2), neutropenia (n= 1), itch (n= 1)
	Serious Adverse Events: no clinically significant renal impairment or liver derangement; no death during OPAT program
	Percentage that Discontinued due to Adverse Events: N/A
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.
InpharmD Researcher Critique	The results are limited to an inherent retrospective observational study in nature. Without a direct comparative group of traditional Q8H dosing regimen, the absolute differences in safety and efficacy of twice daily cefazolin can not be concluded. With no verifiable cases of antibiotic failure and low rates of discontinuation, an extended interval of twice daily cefazolin may be considered when prolonged IV treatment is needed.

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 Dec 9;6:2049936119882847. doi:10.1177/2049936119882847. PMID: 31839941; PMCID: PMC6902391.