Abstract
We retrospectively reviewed patients with Corynebacterium striatum bacteremia treated with daptomycin. All 11 isolates were initially susceptible to daptomycin, but the emergence of daptomycin nonsusceptibility during treatment and clinical failure occurred in 36% and 45% of patients, respectively.
Keywords: Corynebacterium, daptomycin, resistance, susceptibility, vancomycin
Corynebacterium striatum is a gram-positive, rod-shaped bacterium that colonizes normal human skin and mucosal membranes. It has been increasingly recognized as a significant nosocomial pathogen, particularly in patients who are immunocompromised. Although vancomycin is the most frequently used antibiotic for C striatum infection [1], it is not universally tolerated because of its toxicity. Daptomycin is a cyclic lipopeptide antibiotic with broad-spectrum activity against gram-positive bacteria and is used as an alternative to vancomycin for gram-positive bacterial infections. C striatum has a high susceptibility rate for daptomycin [2, 3], and successful treatment has been reported [4, 5]. However, in recent years, there has been an increasing number of case reports of high-level daptomycin resistance in C striatum associated with daptomycin exposure [6–10]. This phenomenon has also been observed in vitro at a high frequency [11, 12]. The frequency of the emergence of nonsusceptibility in patients who received daptomycin therapy remains unclear. In this retrospective study, we aimed to determine the rate of clinical failure and the emergence of daptomycin nonsusceptibility in patients with C striatum bacteremia.
METHODS
Study Population
This retrospective study was conducted with the medical record data of Kobe University Hospital from 1 January 2012 to 20 February 2024. Kobe University Hospital is a referral hospital in Honshu Island, Japan, with 934 beds. At this hospital, vancomycin is essentially the drug of choice for treating C striatum bacteremia. Daptomycin is an alternative drug that requires preauthorization by infectious disease physicians. We identified all adult patients with positive blood cultures of C striatum during the study period. Patients were included in the study if (1) C striatum was judged to be a true cause of bacteremia, not a contaminant; (2) daptomycin was administered to the patient for at least 1 day as a treatment for C striatum bacteremia; and (3) daptomycin susceptibility of the C striatum isolate was tested. Each case was reviewed by multiple infectious disease physicians to distinguish between true bacteremia and contamination. Demographic information, clinical diagnosis, treatment course, and laboratory data were extracted from the patients' medical records. The study protocol was approved by the Ethics Committee of Kobe University Hospital.
Identification and Susceptibility Testing
Identification of C striatum was performed with either MALDI Biotyper (MBT reference library version 4, 9, or 12; Bruker) or BD BBL Crystal Gram Positive ID System (Becton Dickinson). Susceptibility to daptomycin was tested with either Etest (bioMérieux) or the broth microdilution method with dry-plate Eiken. Susceptibility testing for daptomycin was routinely reported after September 2023; before that, it was reported and stored in the medical records at the physician's request.
Outcomes
We determined the emergence of daptomycin nonsusceptibility as the primary outcome. Emergence of nonsusceptibility was defined as the initial isolate being susceptible and any isolate from a specimen obtained during treatment or within 30 days after treatment cessation being nonsusceptible to daptomycin. Susceptibility was determined by the breakpoint in document M45 of the Clinical and Laboratory Standards Institute [13]. As the institute defines only the breakpoint for susceptibility, we used the term “nonsusceptible” for minimum inhibitory concentration (MIC) values >1 μg/mL. We also evaluated the rate of clinical failure as a secondary outcome, which was defined as the deterioration or nonimprovement of symptoms, vital signs, or laboratory data that could not be explained by the progression of diseases other than C striatum infection occurring during or after daptomycin treatment. Clinical failure was judged by the agreement of at least 2 infectious disease physicians.
Statistical Analysis
Descriptive statistics were used to report the patient characteristics and outcomes of the study. The nonsusceptibility rate was defined as the number of patients who developed daptomycin nonsusceptibility divided by the number of all included patients. The clinical failure rate was defined as the number of patients with clinical failure divided by the total number of included patients.
RESULTS
C striatum was identified in 122 adult patients during the study period. Susceptibility to daptomycin was tested in 18 patients. The initial isolates from these patients were susceptible to daptomycin, except for 1 isolate with prior daptomycin administration. Of these, 11 patients were administered daptomycin as a treatment of C striatum bacteremia, with 7 receiving daptomycin for >7 days. All 11 cases were confirmed as true bacteremia through a chart review by the infectious disease physicians. Details of these patients are summarized in Table 1. Nonsusceptibility emerged in 4 of the 11 patients (36%), and clinical failure occurred in 5 of the 11 patients (45%). Among the patients with clinical failure, 4 had been treated with daptomycin for >7 days, while 1 had received daptomycin for only a single day. Patients with clinical failure were diagnosed with either febrile neutropenia or infective endocarditis. Patient 5 developed persistent C striatum bacteremia during antibiotic treatment for infective endocarditis caused by Enterococcus faecalis. The patient finally underwent valve replacement surgery, and culture of the valve tissue revealed C striatum. Patients 10 and 11 were clinically diagnosed with catheter-related bloodstream infections. Indwelling catheters were retained in patient 10 but removed in patient 11. Patient 11 had an artificial aortic graft, but no signs of graft infection were observed. Patients 3, 4, and 6 had ureteral stents that were replaced for treatment in all patients.
Table 1.
Clinical Characteristics and Outcomes of the Patients
| No. | Age, y | Sex | Background Disease | Clinical Diagnosis | Clinical Failure | Duration of DAP, d | Initial Dose of DAP, mg/kg | Initial MIC, μg/mLa | Subsequent Culture | Subsequent MIC, μg/mL | Emergence of NS | Interval to Become NS, d |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 76 | F | Acute myeloid leukemia | FN | Yes | 24 | 5.8 | ≤0.5 | Positive | >4 | Yes | 39 |
| 2 | 57 | F | Acute myeloid leukemia | FN | Yes | 15 | 5.9 | ≤0.5 | Positive | >4 | Yes | 27 |
| 3 | 56 | F | Uterine cancer | cUTI | No | 11 | 6.7 | ≤0.5 | Negative | … | No | … |
| 4 | 63 | F | Uterine cancer | cUTI | No | 7 | 6.7 | ≤0.5 | Not performed | … | No | … |
| 5 | 76 | M | IEb | IE | Yes | 7 | 5.9 | ≤0.5 | Positive | >4 | Yes | 4 |
| 6 | 81 | M | Bladder cancer | cUTI | No | 23 | 10.3 | ≤0.5 | Negative | … | No | … |
| 7 | 67 | M | Non-Hodgkin lymphoma | FN | Yes | 1 | 5.6 | ≤0.25 | Positive | ≤0.25 | No | … |
| 8 | 56 | F | Acute myeloid leukemia | FN | No | 4 | 6.4 | ≤0.25 | Negative | … | No | … |
| 9 | 73 | M | Acute myeloid leukemia | FN | No | 3 | 6.0 | ≤0.25 | Negative | … | No | … |
| 10 | 65 | M | Liver transplantation | CRBSI | No | 4 | 6.3 | ≤0.25 | Negative | … | No | … |
| 11 | 82 | F | Aortic dissection | CRBSI, IE | Yes | 12 | 6.0 | ≤0.25 | Positive | >4 | Yes | 3 |
Abbreviations: CRBSI, catheter-related bloodstream infection; cUTI, complicated urinary tract infection; DAP, daptomycin; F, female; FN, febrile neutropenia; IE, infective endocarditis; M, male; MIC, minimum inhibitory concentration; NS, nonsusceptibility.
aAll MICs were measured with dry-plate Eiken.
bIE caused by Enterococcus faecalis.
The initial dose of daptomycin was 5.6 to 10.3 mg/kg (median, 6.0 mg/kg). None of the patients had a body mass index >30. The duration between the initial blood culture and subsequent culture, in which nonsusceptibility was confirmed, ranged from 3 to 39 days.
DISCUSSION
In this retrospective study, we confirmed that C striatum frequently became nonsusceptible to daptomycin during treatment, leading to clinical failure. Nonsusceptibility developed in as little as 3 days, which is consistent with previous in vitro observations that C striatum isolates can develop high-level resistance after brief exposure to daptomycin [11, 12]. To the best of our knowledge, this is the first study to evaluate the incidence of this phenomenon in the clinical setting. In the present study, nonsusceptibility cases were diagnosed with febrile neutropenia or endocarditis. In the literature, nonsusceptibility cases have also been reported in left ventricular assist device infections [7–9], intra-abdominal abscesses [10], and prosthetic joint infections [14], suggesting that daptomycin should be avoided, especially for complicated infections.
In our study population, the dose of daptomycin was at least 5.6 mg/kg. Although higher doses of daptomycin are associated with favorable outcomes for staphylococci and enterococci [15], it is unclear whether this applies to C striatum. It can express high-level daptomycin resistance through mutations in phosphatidylglycerol synthase (pgsA2), resulting in the loss of phosphatidylglycerol, a target molecule of daptomycin, from the membrane [16]. With this mechanism, the daptomycin MIC exceeds 256 μg/mL, a level that is unlikely to be overcome by a dose increase [17]. In our study as well as in previous in vitro studies, daptomycin resistance rapidly developed at a high frequency. It is more likely that preexisting pgsA2 mutants were selected through daptomycin exposure rather than all the resistant strains having newly acquired mutations in pgsA2. The present study has several limitations. First, it was conducted at a single institution, which limits the external validity of our results. Second, because of the nature of rare infections, the number of patients enrolled in this study was small. Third, we could not confirm the emergence of high-level resistance because the MIC values for nonsusceptible isolates were above the measurement range of the broth microdilution plate. Nevertheless, considering the consistency of our findings with previous in vitro observations and case reports, treatment failure and the emergence of nonsusceptibility to daptomycin during treatment should be regarded as a common phenomenon, and daptomycin may not be a good treatment for treating C striatum bacteremia.
Contributor Information
Shunkichi Ikegaki, Division of Infectious Disease Therapeutics, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Goh Ohji, Division of Infectious Disease Therapeutics, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Kei Furui Ebisawa, Division of Infectious Disease Therapeutics, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Mitsutaka Tsujimura, Division of Infectious Disease Therapeutics, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Kenichiro Ohnuma, Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Kentaro Iwata, Division of Infectious Disease Therapeutics, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Notes
Acknowledgments . We used Grammarly (https://www.grammarly.com) and Paperpal (https://paperpal.com) to edit our manuscript with regard to grammar and English usage.
Author contributions. S. I. contributed to the study design, data analysis, interpretation of the results, and writing of the manuscript. G. O. and K. F. E. contributed to the design of the study and data analysis and reviewed the manuscript. M. T. contributed to data analysis and reviewed the manuscript. K. O. contributed to the acquisition and extraction of data, interpretation of results, and review of the manuscript. K. I. contributed to study design and manuscript review. All authors approved the final version of the manuscript.
Patient consent statement. The study protocol was approved by the Ethics Committee of Kobe University Hospital.
References
- 1. Milosavljevic MN, Milosavljevic JZ, Kocovic AG, et al. Antimicrobial treatment of Corynebacterium striatum invasive infections: a systematic review. Rev Inst Med Trop Sao Paulo 2021; 63:e49. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Abe M, Kimura M, Maruyama H, et al. Clinical characteristics and drug susceptibility patterns of Corynebacterium species in bacteremic patients with hematological disorders. Eur J Clin Microbiol Infect Dis 2021; 40:2095–104. [DOI] [PubMed] [Google Scholar]
- 3. Alibi S, Ferjani A, Boukadida J, et al. Occurrence of Corynebacterium striatum as an emerging antibiotic-resistant nosocomial pathogen in a Tunisian hospital. Sci Rep 2017; 7:9704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Serpa Pinto L, Dias Frias A, Franca M. Corynebacterium striatum cardiac device-related infective endocarditis: the first case report in a patient with a cardiac resynchronization therapy defibrillator device and review of the literature. J Med Cases 2021; 12:61–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Hollnagel K, Willen J, Ellis M, Soleimanifard Y, Booth R, Nandi S. Chronic Corynebacterium striatum septic arthritis in a patient referred for total knee arthroplasty. Case Rep Orthop 2020; 2020:1392182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Tran TT, Jaijakul S, Lewis CT, et al. Native valve endocarditis caused by Corynebacterium striatum with heterogeneous high-level daptomycin resistance: collateral damage from daptomycin therapy? Antimicrob Agents Chemother 2012; 56:3461–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. McElvania TeKippe E, Thomas BS, Ewald GA, Lawrence SJ, Burnham CAD. Rapid emergence of daptomycin resistance in clinical isolates of Corynebacterium striatum… a cautionary tale. Eur J Clin Microbiol Infect Dis 2014; 33:2199–205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Werth BJ, Hahn WO, Butler-Wu SM, Rakita RM. Emergence of high-level daptomycin resistance in Corynebacterium striatum in two patients with left ventricular assist device infections. Microb Drug Resist 2016; 22:233–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Ajmal S, Saleh OA, Beam E. Development of high-grade daptomycin resistance in a patient being treated for Corynebacterium striatum infection. Antimicrob Agents Chemother 2017; 61:e00705-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hagiya H, Kimura K, Okuno H, et al. Bacteremia due to high-level daptomycin-resistant Corynebacterium striatum: a case report with genetic investigation. J Infect Chemother 2019; 25:906–8. [DOI] [PubMed] [Google Scholar]
- 11. McMullen AR, Anderson N, Wallace MA, Shupe A, Burnham CAD. When good bugs go bad: epidemiology and antimicrobial resistance profiles of Corynebacterium striatum, an emerging multidrug-resistant, opportunistic pathogen. Antimicrob Agents Chemother 2017; 61:e01111-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Mitchell KF, McElvania E, Wallace MA, et al. Evaluating the rapid emergence of daptomycin resistance in Corynebacterium: a multicenter study. J Clin Microbiol 2021; 59:e02052-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Clinical and Laboratory Standards Institute . Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidious bacteria. 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute, 2016. [DOI] [PubMed] [Google Scholar]
- 14. Streifel AC, Varley CD, Ham Y, Sikka MK, Lewis JS. The challenge of antibiotic selection in prosthetic joint infections due to Corynebacterium striatum: a case report. BMC Infect Dis 2022; 22:290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Samura M, Takada K, Hirose N, et al. Comparison of the efficacy and safety of standard- and high-dose daptomycin: a systematic review and meta-analysis. Br J Clin Pharmacol 2023; 89:1291–303. [DOI] [PubMed] [Google Scholar]
- 16. Goldner NK, Bulow C, Cho K, et al. Mechanism of high-level daptomycin resistance in Corynebacterium striatum. mSphere 2018; 3:e00371-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003; 47:1318–23. [DOI] [PMC free article] [PubMed] [Google Scholar]