Susceptible…but Not Responding: When Lab Results Don’t Match the Patient

Patient Case

A patient with Staphylococcus aureus bacteremia is found to have infective endocarditis. Susceptibility testing results demonstrate a methicillin-susceptible isolate, and appropriate therapy is initiated with first-generation cephalosporin. Despite this, results from repeat blood cultures remain persistently positive over several days. The antibiotic selection appears appropriate based on laboratory data, yet the infection is not clearing as expected.

Most clinicians have encountered a similar clinical scenario. Susceptibility results are often treated as definitive, but they are generated under standardized laboratory conditions that do not fully reflect what is happening in the patient. Understanding where those results can mislead us is especially important in bacteremia, where small missteps can have meaningful consequences.

At its core, susceptibility testing is about standardization. The minimum inhibitory concentration (MIC) represents the lowest concentration of an antibiotic that inhibits visible bacterial growth under controlled conditions. Those conditions include a standardized bacterial inoculum, stable drug exposure, and an optimized environment. That consistency is necessary but may not reflect what is happening in a real-life patient.

One of the most important gaps is bacterial burden. The inoculum effect refers to reduced antibiotic activity at higher bacterial densities, something that routine susceptibility testing does not capture.¹ This has been well described with cefazolin in high-inoculum S aureus infections, where in vitro susceptibility does not always translate into reliable clinical efficacy.^2,3 In a recent multicenter retrospective cohort study of serious methicillin-susceptible S aureus (MSSA) infections, cefazolin inoculum effect (CzIE)-positive isolates were associated with a higher rate of microbiologic treatment failure compared with CzIE-negative isolates.⁴

That finding is important, but it also requires careful interpretation. Microbiologic failure is not the same as mortality or overall clinical failure. Recent randomized data from the CloCeBa trial support cefazolin as noninferior to cloxacillin for MSSA bacteremia overall, with fewer serious adverse events.⁵ The ongoing Staphylococcus aureus Network Adaptive Platform trial and related subgroup analyses may help clarify whether select patients, such as those with deep-seated or CzIE-positive infections, should be approached differently.⁶ For now, the practical lesson is not that cefazolin should be avoided broadly. Rather, CzIE should be considered one potential explanation when high-inoculum MSSA infections fail to respond as expected.

Drug exposure is another important variable. Susceptibility testing assumes adequate and sustained antibiotic concentrations, but we know this can vary significantly from patient to patient. Critically ill patients frequently have altered pharmacokinetics (PK), making it difficult to consistently achieve effective antibiotic exposure.⁷ A MIC is only clinically meaningful if the dosing strategy can reach and maintain therapeutic concentrations. When that doesn’t happen, “susceptible” on paper may not translate to effective therapy in practice. In select patients, therapeutic drug monitoring, where available and clinically appropriate, may provide a practical tool to help address PK/pharmacodynamics variability and optimize exposure.

The site of infection adds another layer. Susceptibility testing happens in a controlled medium, not the dynamic physiologic environment of an infected patient. Tissue penetration, biofilm formation, and local host factors all influence antibiotic activity. Endocarditis is a clear example: Organisms embedded within vegetations and biofilm-like structures may be harder to eradicate than planktonic organisms tested in the laboratory. Osteomyelitis and undrained abscesses present similar challenges. In these cases, it is not enough to ask whether the organism is susceptible. We must also ask whether adequate amounts of the drug can reach the site of infection and whether source control has been achieved.

Finally, organism behavior is not fully captured by the MIC. Some bacteria exhibit tolerance or persistence, allowing them to survive antibiotic exposure despite appearing susceptible.⁸ Clinically, this can show up as an initial response followed by incomplete clearance or relapse. These phenomena are not routinely measured, but they help explain why outcomes do not always align with susceptibility reports. Not all susceptible organisms are equally eradicable.

Taken together, these limitations point to a simple but important idea: Susceptibility results are a guide, not a guarantee. Managing bacteremia requires integrating microbiology with the clinical picture. Infection burden, source control, site of infection, and patient-specific factors all influence how antibiotics actually perform.

Practically, this means avoiding the trap of treating the MIC in isolation. In high-inoculum or deep-seated infections, early de-escalation should be approached cautiously when the clinical picture remains uncertain. When a patient is not responding as expected, it is worth stepping back and asking whether the issue is source control, drug exposure, or the chosen agent being the right one despite being labeled “susceptible.” Antibiotic selection should reflect not just what the organism is but where it is and how it is behaving.

This is especially important in persistent S aureus bacteremia. Faster blood culture clearance is desirable, but improved microbiologic end points do not always translate into improved patient-centered outcomes. Trials evaluating combination therapy in S aureus bacteremia have shown that reducing microbiologic failure or shortening bacteremia may not consistently improve mortality or overall treatment success and may increase adverse events.^9-11 Therefore, persistent bacteremia should not automatically trigger a reflexive antibiotic change alone. It should trigger a broader clinical reassessment.

Potential management steps may include repeat evaluation for source control, additional imaging, infectious diseases consultation, optimization of antibiotic exposure, transition to an antistaphylococcal penicillin when CzIE is a concern, or, in select salvage situations, consideration of combination therapy. For example, cefazolin plus ertapenem has been described as salvage therapy in persistent MSSA bacteremia, although this remains based on limited data and should not be viewed as routine management.¹² The optimal approach to persistent MSSA bacteremia remains uncertain and should be individualized.

Return to the Patient Case

Given the persistent positivity of the blood culture results, the knowledge that the isolate is MSSA, and that this is a deeper-seated infection (endocarditis) being treated with a first-generation cephalosporin, the team is concerned this strain of MSSA may be producing the β-lactamase associated with the CzIE. The patient’s treatment is changed to an antistaphylococcal penicillin, and blood cultures clear within 48 hours.

This sequence should not be interpreted as proof that cefazolin was ineffective or that switching to an antistaphylococcal penicillin is always the correct answer. Persistent S aureus bacteremia is multifactorial. In some cases, the issue may be antibiotic exposure. In others, it may be source control, an undrained focus, biofilm, or host factors. The key is that persistent bacteremia, despite results indicating susceptible status, should prompt clinicians to reevaluate the full clinical picture.

Susceptibility testing remains essential. It gives us a standardized starting point. But it does not replace clinical judgment. Bridging the gap between laboratory data and patient reality is where stewardship and good clinical decision-making actually happen.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied health care professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References

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2. Miller WR, Seas C, Carvajal LP, et al. The cefazolin inoculum effect is associated with increased mortality in methicillin-susceptible Staphylococcus aureus bacteremia. Open Forum Infect Dis. 2018;5(6):ofy123. doi:10.1093/ofid/ofy123

3. Lee S, Song KH, Jung SI, et al. Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect. 2018;24(2):152-158. doi:10.1016/j.cmi.2017.07.001

4. Jeffs MA, Li N, Ogunkoya O, et al. Cefazolin inoculum effect and cefazolin microbiological treatment failure in serious methicillin-susceptible Staphylococcus aureus infections: a multicenter retrospective cohort study. J Infect Dis. 2026;233(6):e1433-e1442. doi:10.1093/infdis/jiag199

5. Burdet C, Saïdani N, Dupieux C, et al; CloCeBa Study Group. 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

6. Tong SYC, Mora J, Bowen AC, et al; Staphylococcus aureus Network Adaptive Platform (SNAP) Study Group. The Staphylococcus aureus Network Adaptive Platform Trial protocol: new tools for an old foe. Clin Infect Dis. 2022;75(11):2027-2034. doi:10.1093/cid/ciac476

7. Roberts JA, Abdul-Aziz MH, Lipman J, et al; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498-509. doi:10.1016/S1473-3099(14)70036-2

8. Deventer AT, Stevens CE, Stewart A, Hobbs JK. Antibiotic tolerance among clinical isolates: mechanisms, detection, prevalence, and significance. Clin Microbiol Rev. 2024;37(4):e0010624. doi:10.1128/cmr.00106-24

9. Tong SYC, Lye DC, Yahav D, et al; Australasian Society for Infectious Diseases Clinical Research Network. Effect of vancomycin or daptomycin with vs without an antistaphylococcal β-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: a randomized clinical trial. JAMA. 2020;323(6):527-537. doi:10.1001/jama.2020.0103

10. Pujol M, Miró JM, Shaw E, et al; MRSA Bacteremia (BACSARM) Trial Investigators. Daptomycin plus fosfomycin versus daptomycin alone for methicillin-resistant Staphylococcus aureus bacteremia and endocarditis: a randomized clinical trial. Clin Infect Dis. 2021;72(9):1517-1525. doi:10.1093/cid/ciaa1081

11. Grillo S, Pujol M, Miró JM, et al; SAFO Study Group. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat Med. 2023;29(10):2518-2525. doi:10.1038/s41591-023-02569-0

12. Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2020;71(6):1413-1418. doi:10.1093/cid/ciz995