# Molecular basis of the cefazolin inoculum effect

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $233,638

## Abstract

ABSTRACT
 Staphylococcus aureus is one of the most important pathogens responsible for a wide range of
illnesses including life-threatening infections. An important number of these infections are caused by
methicillin-susceptible S. aureus (MSSA) and in many parts of the world (including the US), MSSA infections
are more common than those caused by methicillin-resistant S. aureus (MRSA). Indeed, MSSA represent a
major burden of S. aureus infections and are important contributors to mortality. The treatment of MSSA
infections relies on the use of β-lactams. Indeed, the first line of therapy for severe MSSA infections are the
isoxazolyl penicillins (e.g., nafcillin, oxacillin). However, recent data suggest that clinical outcomes in MSSA
bacteremia are similar in patients treated with nafcillin/oxacillin vs cefazolin, a first generation cephalosporin
with activity against MSSA that appears to be less toxic. Moreover, treatment with nafcillin seem to be
associated with increased costs, more drug reactions (including hepatotoxicity, interstitial nephritis and
neutropenia) and, possibly, higher mortality. Due to these concerns, an important shift in the treatment of
MSSA is occurring whereby clinicians are now using cefazolin as first line of therapy for severe MSSA
infections. An important concern of using cefazolin and other cephalosporins as primary therapy for these
serious infections is the occurrence of the cefazolin inoculum effect (CzIE), defined as a cefazolin minimal
inhibitory concentration of > 16 µg/ml when a high inoculum (107 CFU/ml) is used. The CzIE has been
associated with failures in the treatment of deep-seated MSSA infections and with the production of certain
isotypes of the staphylococcal β-lactamase. However, the molecular basis and the actual clinical impact of
this phenomenon are unknown. Our published and preliminary clinical data indicate that the CzIE is an
important contributor to clinical outcomes of severe MSSA infections. Our Prelim. Data also provide evidence
that the CzIE is mediated, at least in part, by changes in the processing and extracellular release of the β-
lactamase (BlaZ) enzyme and it is influenced by the catalytic activity of the β-lactamase isotype. Our
hypotheses are that, i) the CzIE is primarily mediated by the activity of extracellular β-lactamase released into
the extracellular milieu, ii) the ability to hydrolyze cefazolin effectively depends on the catalytic activity of the
enzyme isotype, and iii) a rapid phenotypic test can be developed to identify isolates with the CzIE and help
clinicians in the treatment of MSSA infections. In two specific aims, we will define the molecular and
biochemical bases of the CzIE exploring the genetic factors influencing this phenomenon and characterizing
novel structural and biochemical isoforms of BlaZ identified via our genomic analyses. We will also aim to
develop a rapid assay to identify MSSA strains with the CzIE. Our findings are likely to influence the man...

## Key facts

- **NIH application ID:** 9832174
- **Project number:** 5R21AI143229-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Cesar Augusto Arias
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $233,638
- **Award type:** 5
- **Project period:** 2018-12-05 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832174

## Citation

> US National Institutes of Health, RePORTER application 9832174, Molecular basis of the cefazolin inoculum effect (5R21AI143229-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9832174. Licensed CC0.

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