LETTER
We read with interest the article by Albur et al. regarding the interaction between colistin and tigecycline against NDM-1-producing Enterobacteriaceae (1). Colistin and tigecycline have been considered the only therapeutic options for treatment of serious infections caused by carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Because of concerns regarding the low efficacy of each agent as monotherapy, the combination therapy of colistin and tigecycline has increasingly been used to treat serious infections, even though it is difficult to ascertain the combination's clinical efficacy. Albur et al. (1) showed that the addition of tigecycline to colistin does not result in increased antibacterial activity against NDM-1-producing Enterobacteriaceae but instead may cause antagonism at lower concentrations. Moreover, several previous studies regarding in vitro evaluations of antibiotic synergy yielded controversial results (1–5). Recently, we experienced a case of breakthrough bacteremia due to Klebsiella pneumoniae that occurred during the combination therapy of colistin and tigecycline.
A 48-year-old male presented to our hospital with fever and dyspnea. The patient had undergone allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia 1 month prior. On admission, the patient was diagnosed with pneumonia, and antimicrobial therapy with meropenem and vancomycin was initiated and then subsequently switched to cefepime, resulting in improvement. On hospital day 30, the patient complained of increased respiratory secretions and dyspnea. Computed tomography of the chest showed newly developed consolidations in both lower lobes of the lungs, and the patient's sputum cultures produced carbapenem-resistant A. baumannii. Antimicrobial therapy with colistin (150 mg twice daily) and tigecycline (100-mg loading and then 50 mg twice daily) was administered. Despite treatment with the combination therapy for 2 weeks, the patient developed septic shock with acute respiratory failure and was transferred to the intensive care unit. Blood cultures showed presumptive Gram-negative bacilli. Tigecycline was discontinued due to concerns about its low serum levels in bacteremic cases, and meropenem was added to the therapy in combination with colistin. However, 3 days after the administration of meropenem, the patient died of septic shock. Ultimately, K. pneumoniae was identified in his blood cultures. Antimicrobial susceptibility testing, as determined according to the CLSI guidelines, revealed resistance to cefotaxime, cefepime, levofloxacin, and piperacillin-tazobactam. The isolate was phenotypically confirmed as an extended-spectrum-β-lactamase (ESBL) producer and to be resistant to both colistin and tigecycline by additional broth microdilution susceptibility testing. The MICs of various antimicrobial agents for the K. pneumoniae isolate are shown in Table 1. PCR and sequencing analyses confirmed the presence of CTX-M-15-type ESBL.
Table 1.
MICs of various antibiotics for the K. pneumoniae isolate
| Isolate | MIC (μg/ml) ofa: |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| CL | TIG | CTX | CAZ | CPM | P/T | CIP | ETP | IMI | MRP | |
| K. pneumoniae | >64 | 4 | >128 | >128 | >128 | >512/4 | >128 | 0.5 | 0.12 | 0.12 |
CL, colistin; TIG, tigecycline; CTX, cefotaxime; CAZ, ceftazidime; CPM, cefepime; P/T, piperacillin-tazobactam; CIP, ciprofloxacin; ETP, ertapenem; IMI, imipenem; MRP, meropenem.
Although the synergistic effects of tigecycline plus colistin against multidrug-resistant organisms were observed in previous reports (2, 3), the routine use of combination therapy is challenging because in vitro and in vivo results are not always correlated. Moreover, our case suggests that the combination regimen of colistin and tigecycline may induce breakthrough bacteremia by organisms that are resistant to both colistin and tigecycline. Given the possible antagonistic effect and emergence of resistance, physicians should use the combination therapy of colistin and tigecycline with caution for the management of multidrug-resistant Gram-negative bacterial infections.
ACKNOWLEDGMENTS
We thank Min Kyeong Cha for technical support.
This study was supported by Samsung Biomedical Research Institute grant SBRI GL1-B2-031-1.
All authors declare they have no conflicts of interest.
Contributor Information
Jae-Hoon Song, Division of Infectious Diseases.
Jun Ho Jang, Division of Hematology-Oncology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, South Korea.
REFERENCES
- 1. Albur M, Noel A, Bowker K, Macgowan A. 2012. Bactericidal activity of multiple combinations of tigecycline and colistin against NDM-1-producing Enterobacteriaceae. Antimicrob. Agents Chemother. 56:3441–3443 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Bercot B, Poirel L, Dortet L, Nordmann P. 2011. In vitro evaluation of antibiotic synergy for NDM-1-producing Enterobacteriaceae. J. Antimicrob. Chemother. 66:2295–2297 [DOI] [PubMed] [Google Scholar]
- 3. Principe L, D'Arezzo S, Capone A, Petrosillo N, Visca P. 2009. In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii. Ann. Clin. Microbiol. Antimicrob. 8:18 doi:10.1186/1476-0711-8-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Sands M, McCarter Y, Sanchez W. 2007. Synergy testing of multidrug resistant Acinetobacter baumanii against tigecycline and polymyxin using an E-test methodology. Eur. J. Clin. Microbiol. Infect. Dis. 26:521–522 [DOI] [PubMed] [Google Scholar]
- 5. Scheetz MH, et al. 2007. In vitro activities of various antimicrobials alone and in combination with tigecycline against carbapenem-intermediate or -resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 51:1621–1626 [DOI] [PMC free article] [PubMed] [Google Scholar]