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

Abstract

Background
Deep-seated Staphylococcus aureus infections are difficult to treat and require appropriate antibiotic regimens for clinical success. Recent studies have shown that continuous infusion (CI) of β-lactam antibiotics is associated with reduced mortality, though optimal dosages remain to be determined. Here, we present a case in which high-dose cefazolin, at 10 g daily CI, was used to safely and successfully clear methicillin-susceptible S. aureus (MSSA) pneumonia.

Case Summary
A 33-year-old male was admitted to the medical intensive care unit with suspected MSSA community-acquired pneumonia. Over the course of a 43-day hospital stay, the patient’s pneumonia relapsed twice following two 5- to 7-day courses of cefazolin 8 g daily CI. Clearance of the pneumonia was achieved after a 14-day course of cefazolin 10 g daily CI, and the patient was discharged.

Conclusion
Here, we describe a patient with incomplete clearance of MSSA pneumonia despite two 5- to 7-day courses of cefazolin 8 g daily CI. Following a 14-day course of cefazolin 10 g daily CI, the patient’s fever and leukocytosis rapidly resolved without direct evidence of drug-related toxicity. This case report provides evidence for the safe and effective use of high-dose cefazolin CI in the clearance of persistent MSSA pneumonia.

Full text

| Antimicrobial Chemotherapy | Case Report
Successful clearance of persistent Staphylococcus aureus
pneumonia with high-dose continuous infusion cefazolin
Annie A. Smelter,1 Christopher R. Frei,1,2 Dan F. Smelter1,2
AUTHOR AFFILIATIONS See aliation list on p. 5.
ABSTRACT
Background Deep-seated Staphylococcus aureus infections are dicult to treat and
require appropriate antibiotic regimens for clinical success. Recent studies have shown
that continuous infusion (CI) of β-lactam antibiotics is associated with reduced mortality,
though optimal dosages remain to be determined. Here, we present a case in which
high-dose cefazolin, at 10 g daily CI, was used to safely and successfully clear methicillin-
susceptible S. aureus (MSSA) pneumonia.
Case Summary A 33-year-old male was admitted to the medical intensive care unit
with suspected MSSA community-acquired pneumonia. Over the course of a 43-day
hospital stay, the patient’s pneumonia relapsed twice following two 5- to 7-day courses
of cefazolin 8 g daily CI. Clearance of the pneumonia was achieved after a 14-day course
of cefazolin 10 g daily CI, and the patient was discharged.
Conclusion Here, we describe a patient with incomplete clearance of MSSA pneumonia
despite two 5- to 7-day courses of cefazolin 8 g daily CI. Following a 14-day course of
cefazolin 10 g daily CI, the patient’s fever and leukocytosis rapidly resolved without direct
evidence of drug-related toxicity. This case report provides evidence for the safe and
eective use of high-dose cefazolin CI in the clearance of persistent MSSA pneumonia.
KEYWORDS beta-lactams, continuous infusion, CABP, MSSA
Methicillin-susceptible Staphylococcus aureus (MSSA) pneumonia often manifests
as a deep-seated infection that is notoriously challenging to treat, requires a
prolonged treatment duration, and is associated with higher rates of treatment failure.
Cefazolin, a rst-generation cephalosporin, has been shown to be safe and eective in
treating many bacterial infections, including MSSA pneumonia. The standard recommen
ded cefazolin dosing for this indication is 2 g administered intravenously every 8 h (q8h),
totaling 6 g daily, for a minimum duration of 5 to 7 days per the Infectious Diseases
Society of America and American Thoracic Society guidelines (1).
Recent high-prole studies evaluating the traditional dosing canon for β-lactams
indicate that prolonged or continuous infusion (CI) administration may produce similar
outcomes compared to the standard intermittent dosing, despite not being routinely
performed (2–4). Under certain disease states, it may be more benecial to administer
β-lactams via CI as opposed to traditional intermittent infusion, but the published data is
insucient.
Furthermore, while the ANCEF (brand name cefazolin for injection) package insert
states that “in rare instances, doses up to 12 g of cefazolin per day have been used,”
there is a paucity of data detailing the safety and ecacy of high-dose cefazolin (i.e., 10+
grams/day). Several retrospective studies have reported dosing of cefazolin up to 12 g
May 2025 Volume 1 Issue 3 10.1128/asmcr.00114-24 1
Editor Carey-Ann D. Burnham, Pattern Bioscience,
Austin, Texas, USA
Address correspondence to Dan F. Smelter,
smelterd@uthscsa.edu.
The authors declare no conict of interest.
See the funding table on p. 5.
Received 16 December 2024
Accepted 16 March 2025
Published 31 March 2025
Copyright © 2025 Smelter et al. This is an open-
access article distributed under the terms of the
Creative Commons Attribution 4.0 International
license.

daily, but none report greater than 8 g daily for the entire treatment duration (5–7). To
our knowledge, this is the rst report to show 10 g daily CI for 2 weeks, with nearly 4
weeks total of cefazolin therapy at ≥8 g daily, without any indication of adverse events
or unsafe ndings. Here, we present a case in which high-dose cefazolin, at 10 g daily CI,
was used to safely and eectively clear persistent MSSA pneumonia.
CASE PRESENTATION
A 33-year-old male with a past medical history signicant for obesity, sleep apnea,
methamphetamine use, and a recent tooth infection presented to the emergency
department (ED) via emergency medical services at 4:00 a.m. for multiple episodes of
severe apnea after a family member found the patient unresponsive in his sleep (day 1
of admission, Fig. 1). Initial vital signs were remarkable for tachypnea, tachycardia at 119
beats per minute, PaO2 saturation of 57%, blood pressure of 96/58 mmHg, body mass
index of 37.5 kg/m2, and temperature 98.6°F. Upon presentation to the ED, he appeared
somnolent and not oriented with appreciable xed, constricted pupils. Following two
rounds of 0.4 mg naloxone and sternal rub, he showed modest improvement and
dilation of pupils; however, clinical lab analysis of a urine sample later identied only
amphetamine metabolites. Lungs were clear to auscultation bilaterally, and the patient
denied any chest pain or shortness of breath. Although the patient had recently been
diagnosed with sleep apnea, he reported not tolerating CPAP use at home. The patient
initially responded well to CPAP/BiPAP with PaO2 reaching normal levels but then
demonstrated a decline in mental status until he became unresponsive with PaO2
desaturation down to 60% and suspected hypoxic seizure, requiring intubation. Chest
X-ray (CXR) at presentation demonstrated low lung volumes, right middle lobe and
bilateral infrahilar opacities, and air bronchograms concerning for pneumonia with likely
left pleural eusion (see Fig. 2A). The patient was started on empiric ceftriaxone (1 g
q24h) and azithromycin (500 mg q24h) for community-acquired bacterial pneumonia
coverage and admitted to the medical intensive care unit (MICU). Blood and urine
cultures collected at presentation were negative for growth. At the time of intubation,
tracheal cultures were positive for MSSA with oxacillin susceptibility≤0.25mg/L.
Notable details for the 43-day hospital course and pertinent laboratory values are
provided in Fig. 1. Briey, the patient was sedated and appeared stable for the rest
of the rst day of admission (D1), but overnight into D2 became febrile (101.7°F) and
hypotensive (94/45 mmHg), requiring pressors. Pulmonary exam revealed coarse breath
sounds. Antimicrobial therapy was changed to vancomycin (2 g loading dose and 1 g
q8h) and cefepime (2 g q8h) on D2 for ventilator-associated pneumonia (VAP) coverage.
Vancomycin dosing was determined using the Cockroft-Gault equation to estimate
glomerular ltration rate using serum creatinine. Over the next 3 days, the medical
team ruled out aspiration pneumonia and, with pharmacy consult, determined that the
vancomycin regimen produced subtherapeutic levels even with daily increases in dosing
(highest measured trough concentration was 8.5 mg/L, with a goal of 10–20mg/L). On
D4, the antimicrobial regimen was re-evaluated following the reassessment of initial
indications of pneumonia; cefepime was discontinued and replaced with cefazolin 8 g
daily CI (with one cefazolin 2 g loading dose given as IV push over 2 to 5 min and one
vancomycin 1.5 g dose). D5 blood cultures continued to be negative.
On D9, cefazolin was discontinued after a 7-day antimicrobial course (5 days cefazolin
8 g daily CI), despite temperature remaining elevated (100.4°F). The medical team noted
“no sign of active infection” on D10 and marked “leukocytosis” and “septic shock” as
resolved in notes. The patient’s white blood cell (WBC) count became elevated again
on D11 and by D12 was febrile (100.4°F) and required aggressive suction for pulmonary
secretions. Cefepime (2 g q8h) therapy was initiated empirically and on D13 was changed
to cefazolin 8 g daily CI. As long-term intubation was expected, a tracheostomy was
attempted on D14. However, copious secretions and mucous plugs obscured the view,
and the patient suered a brief cardiopulmonary arrest. A successful tracheostomy was
performed on D16, and a bronchoalveolar lavage returned negative for pathogenic
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microorganisms (10,000 CFU/mL usual respiratory ora, 1+ epithelial cells, 1+ WBCs). The
patient’s fever and leukocytosis persisted through D18 when cefazolin treatment was
discontinued at the completion of the second set of 7 days of antimicrobial therapy.
By D20, the patient reached a high fever (103.1°F) and was noted to have thick airway
secretions. Vancomycin (2.5 g loading dose, then 1 g q6h) and piperacillin/tazobactam
(4.5 g q8h) were initiated for VAP coverage on D21. When respiratory cultures identied
MSSA, antimicrobial therapy was changed to high-dose cefazolin 10 g daily CI for 14
days on D23. The patient’s fever and leukocytosis improved steadily, with persistent thick
oral and tracheal secretions for the rst week that improved during the second week of
cefazolin 10 g daily CI. Serum creatinine remained within the normal range or slightly
below (0.7–1.3 mg/dL reference range) throughout the duration of high-dose cefazolin
therapy. CXR on D35 showed improvement in aeration and resolution of pulmonary
edema, parenchymal opacities, and areas of consolidation (see Fig. 2B). The patient’s
FIG 1 Summary of hospital course. Timeline detailing clinical events, cultures, and antimicrobial therapy throughout the 43-day hospital stay with temperature,
white blood cell (WBC) count, and serum creatinine with normal value range shaded. Serum creatinine is included as an analog for renal function. CXR, chest
X-ray; CI, continuous infusion; CRO, ceftriaxone (1 g q24h push); AZM, azithromycin (500 mg q24h); FEP, cefepime (2 g q8h push); TZP, piperacillin/tazobactam
(4.5 g q8h over 4 h); VAN, vancomycin; CFZ, cefazolin. IV push administered over 2 to 5 min. *Note: Last VAN dose 8 h after CFZ start on D4.
Case Report ASM Case Reports
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condition improved such that his tracheostomy tube was capped on D40, and he was
stable on room air until discharge to home care on D43.
DISCUSSION
Here, we describe a patient with MSSA pneumonia of unclear etiology with incomplete
clearance after two week-long courses of cefazolin 8 g daily CI. Success was achieved
following a 14-day course of cefazolin 10 g daily CI: the patient’s condition improved
with rapid and lasting resolution of fever and leukocytosis without evidence of toxicity
or adverse eects, providing evidence for the use of both high-dose cefazolin and CI
β-lactam therapy.
For more than ve decades, cefazolin has been successfully used to treat bacte
rial pneumonias, particularly those caused by MSSA (8). However, deep-seated and
complicated staphylococcal infections are still associated with high morbidity and
mortality, having 30-day mortality rates near 30% (9, 10). Cefazolin is often the preferred
antibiotic for treating infections caused by MSSA as it has a favorable dosing regimen
and a robust safety prole compared to similar anti-staphylococcal penicillins (ASPs) such
as nafcillin or oxacillin (11). Recent studies have found cefazolin to be associated with
lower mortality rates, less nephrotoxicity, and reduced clinical failure or discontinuation
due to adverse events when compared to ASPs (12–14).
One concern with cefazolin use is the potentially reduced penetrance into compart
ments of the body such as the cerebrospinal uid when treating meningitis (5, 15) or, as
in our patient’s case, penetrance into the lungs. To our knowledge, there is no available
data on the penetration of cefazolin into the lung epithelial lining uid. However, pleural
uid measurements of cefazolin indicate that standard intermittent dosing achieves
concentrations sucient for therapeutic ecacy (16). If penetration of the antibiotic
is a concern, an increase in dosage will likely lead to increased drug concentration at
the site of interest, including the lungs or cerebrospinal uid, especially in the setting
of inammation. Furthermore, through increasing the antibiotic dose and/or dosing
frequency, it is likely easier to achieve maximal time above the minimum inhibitory
concentration (T > MIC), particularly for infection sources within highly vascularized
tissues.
Recent major reports and a large clinical trial (BLING III) have focused on CI versus
intermittent infusions of β-lactam antibiotics, and the data suggest that CI is associated
with reduced mortality compared to intermittent infusion, likely due to maximizing
FIG 2 Chest X-rays from admission and post-antimicrobial therapy. (A) AP CXR showing enlarged cardiomediastinal silhouette with low lung volumes, associated
right middle lobe, and bilateral infrahilar opacities (black arrows) with air bronchograms (white triangles), uid in minor ssure, and likely left pleural eusion
(white arrows) (day of admission). (B) AP CXR showing improved aeration of bilateral lungs and interval resolution of pulmonary edema and parenchymal
opacities, without areas of focal consolidation (day 35 of hospitalization).
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T > MIC (3, 4, 17). β-lactam antibiotics are known for having short half-lives, which
require frequent dosing to maintain serum concentrations over the bacterial MIC. This is
something that can be overcome through the use of CI or prolonged dosing regimens.
Many institutions do not currently use CI dosing for antibiotics, and incorporating it as
an institution policy likely faces challenges. Deciding when CI or intermittent infusion is
appropriate for the patient requires further studies, particularly if CI allows for increased
total daily drug dosage (such as 10+ grams/day cefazolin) without the risk associated
with high peak serum concentrations that come with intermittent infusion. However, CI
regimens increase the healthcare burden and workload for nursing and pharmacy sta,
and the extended duration of infusion can introduce new risks such as drug stability.
This report demonstrates nearly 4 weeks total of high-dose cefazolin CI therapy
without directly attributable toxicity due to the drug. Throughout the high-dose
cefazolin therapy, the patient’s serum creatinine stayed within the normal range, and
there was no indication of hypoprothrombinemia (INR never went above 1.6) (7, 18).
Conclusion
High-dose cefazolin (10 g daily), given as a CI, was able to clear community-acquired
MSSA pneumonia while not exhibiting any signs of toxicity or adverse eects, highlight
ing the wide therapeutic index of this rst-generation cephalosporin. The recurrence of
pneumonia twice throughout the patient’s hospital course, before receiving the higher
dose of cefazolin CI, suggests incomplete clearance of the infection that may have been
averted with a longer duration of therapy or higher initial dosing of cefazolin. Clinicians
should consider consultation with the infectious diseases team when patients have
complex and severe infections caused by S. aureus.
ACKNOWLEDGMENTS
No funding was received for this study. A.A.S. is supported by South Texas Medi
cal Scientist Training Program NIH NIGMS/T32GM113896 and T32GM145432. D.F.S. is
supported by NIA P30AG044271 RL5 Mentored Career Development Award. C.R.F. is
partially supported by NCATS UM1TR004538 and co-directs two Translational Science
Training T32 programs NCATS T32TR004544 and T32TR004545. The views expressed in
this article are those of the authors and do not necessarily represent the views of the
National Institutes of Health or the authors’ aliated institutions.
AUTHOR AFFILIATIONS
1Joe R. and Teresa Lozano Long School of Medicine, The University of Texas Health at San
Antonio, San Antonio, Texas, USA
2College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
AUTHOR ORCIDs
Annie A. Smelter http://orcid.org/0009-0003-9586-6228
Christopher R. Frei http://orcid.org/0000-0002-0692-4787
Dan F. Smelter http://orcid.org/0000-0001-9181-0786
FUNDING
Funder Grant(s) Author(s)
National Institute of General Medical
Sciences
T32GM113896,
T32GM145432
Annie A. Smelter
National Institute on Aging P30AG044271 Dan F. Smelter
National Center for Advancing
Translational Sciences
UM1TR004538,
T32TR004544,
T32TR004545
Christopher R. Frei
Case Report ASM Case Reports
May 2025 Volume 1 Issue 3 10.1128/asmcr.00114-24 5

AUTHOR CONTRIBUTIONS
Annie A. Smelter, Formal analysis, Investigation, Methodology, Writing – original draft,
Writing – review and editing | Christopher R. Frei, Methodology, Project administration,
Writing – review and editing | Dan F. Smelter, Conceptualization, Methodology, Project
administration, Supervision, Writing – review and editing
DATA AVAILABILITY
Data are available upon request.
ETHICS APPROVAL
This study was approved by the institutional review board (STUDY00000994) of the
University of Texas Health at San Antonio with a waiver of informed consent. Informed
consent was waived by the IRB due to the retrospective nature of the study and the
absence of identiable patient information.
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