Achromobacter Bacteremia in Patients With Cancer

ORIGINAL ARTICLE

Achromobacter Bacteremia in Patients With Cancer Tyler Stutzman, MPH,* Flor Maria Sánchez-Vargas, MD, FACP,* Sowmya Nanjappa, MBBS, MD,†‡ Ana Paula Velez, MD, FACP,§, and John N. Greene, MD, FACP|| Background: Achromobacter species are Gram-negative waterborne bacteria that occasionally cause bacteremia primarily in immunocompromised hosts. Cancer patients have increased risk due to their use of intravascular catheters and immunosuppression from neoplasm, chemotherapy, and prolonged steroids. In this study, we investigated the clinical characteristics of cancer patients with Achromobacter bacteremia and identified risk factors, outcomes, and susceptibility patterns in this selective population. Methods: We retrospectively reviewed all cases of Achromobacter bacteremia occurring from March 2010 to March 2015 at Moffitt Cancer Center. Data collected included age, sex, comorbidities, underlying malignancy, neutropenia status, prior bacteremia, treatment course, and patterns of susceptibilities of the isolates. We also reviewed outcomes such as discharge disposition and death. Results: Eleven patients were identified with positive blood cultures for Achromobacter species. Central venous catheters were infected in 9 patients (82%), and 2 patients had recurrent bacteremia, which resolved after removal of the catheter. Eight (73%) patients had a history of prior bacteremia. Patients were treated with meropenem (n = 4), piperacillin/ tazobactam (n = 3), cefepime, ceftazidime, and trimethoprim-sulfamethoxazole (TMP-SMX). The isolates were susceptible to meropenem (8 of 8 isolates), piperacillin/tazobactam (10 of 10), ceftazidime (7 of 7), and TMP-SMX (8 of 8). Most of isolates were resistant to aminoglycosides and fluoroquinolones. Conclusions: The major predisposing factors for Achromobacter bacteremia were infected intravascular catheters and prior history of bacteremia. Infections can be treated with piperacillin/tazobactam, a carbapenem, or TMP-SMX. Compared with other studies, we observed similar risk factors and morbidity but with a higher rate of intravascular catheter infections. Key Words: Achromobacter, Alcaligenes, bacteremia, cancer, intravenous catheter, antimicrobial susceptibility (Infect Dis Clin Pract 2016;00: 00–00)

A

chromobacter (formerly Alcaligenes) species are motile, oxidase- and catalase-positive, non-fermenting, Gram-negative bacteria commonly found in soil and water. The most common presentation of Achromobacter infection is primary uncomplicated bacteremia. However, Achromobacter can also cause meningitis, urinary tract infections, abscesses, osteomyelitis, corneal ulcers, prosthetic valve endocarditis, peritonitis, and pneumonia.1 Achromobacter bacteremia is a rare but potentially lifethreatening illness. Individuals with immunosuppression, cystic fibrosis,2–4 or underlying malignancy1,5–7 are particularly at risk for developing Achromobacter bacteremia. Other risk factors include

From the *University of South Florida Morsani College of Medicine; Departments of †Internal Medicine, and ‡Oncologic Sciences, H. Lee Moffitt Cancer Center, and §Health Administration, University of South Florida Morsani College of Medicine; and ||Infectious Diseases and Hospital Epidemiologist, Moffitt Cancer Center and Research Institute, Tampa, FL. Correspondence to: John N. Greene, MD, FACP, Infectious Diseases and Hospital Epidemiologist, Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, FOB-3, Tampa, FL 33612-9497. E-mail: [email protected]. The authors have no funding or conflicts of interest to disclose. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1056-9103

chronic renal failure, diabetes mellitus, cardiac disorders, immunosuppression, steroid treatment, and intravascular catheters.1,5–10 Achromobacter infection is often acquired from exposure to contaminated solutions during hospitalization.1 Achromobacter is particularly suited for survival in aqueous environments due to its ability to produce biofilm. Surface disinfection tissue dispensers,11 hospital tap water and disinfectant atomizers,12 ultrasound lubrication gel,13 faucet aerators,6 and chlorhexidine solution9,14 have been documented as point sources for outbreaks within hospitals. Patients with cancer are at risk of Achromobacter infection due to immunosuppression and the use of prophylaxis with fluoroquinolones. Most isolates of Achromobacter are resistant to fluoroquinolones.5 In this study, we sought to identify the clinical characteristics, risk factors, underlying comorbidities, and antimicrobial susceptibility patterns of Achromobacter bacteremia in cancer patients.

MATERIALS AND METHODS We retrospectively identified patients who had positive blood cultures for Achromobacter at the H. Lee Moffitt Cancer Center (Tampa, Fla) between March 1, 2010, and March 1, 2015. A standardized questionnaire was created as a template for extracting data from the patient charts. Data recorded were age, sex, comorbidities, underlying malignancy, neutrophil count, prior bacteremia, treatment course, susceptibility patterns of the isolates, discharge condition, and death. All blood culture samples were processed at the H. Lee Moffitt Cancer Center Microbiology Laboratory. The identification of microorganisms was performed using standard microbiological methods. Antimicrobial sensitivities were determined by a standard disk method. The patients' blood was inoculated for aerobic cultures into flasks containing Tryptic Soy Broth (Roche, Brussels, Belgium) with sodium polyanetol sulfonate and using the SeptiCheck slide system for routine subcultures (Roche). The isolates were not associated with an outbreak and represent unrelated episodes of Achromobacter bacteremia.

Definitions Achromobacter bacteremia was defined as a positive blood culture for Achromobacter species. An episode was considered recurrent if positive Achromobacter blood cultures were obtained greater than 2 weeks apart and separated by a sterile blood culture sample. An episode was considered catheter-related if cultures from the catheter site were positive for Achromobacter. Neutropenia was defined as an absolute neutrophil count of less than 500 cells/μL. Systemic inflammatory response syndrome (SIRS) was defined as a positive blood culture accompanied by 2 or more of the following criteria: (1) temperature lower than 36°C (96.8°F) or higher than 38°C (100.4°F); (2) heart rate greater than 90 beats per minute; (3) respiratory rate greater than 20 breaths per minute or PaCO2 less than 4.3 kPa (32 Torr); and (4) leukocyte count less than 4000 cells/μL or greater than 12,000 cells/μL or immature (band) neutrophils greater than 10%. Septic shock was defined as SIRS with systolic blood pressure less than 90 mm Hg or mean arterial pressure less than 70 mm Hg. Mortality was considered to

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TABLE 1. Characteristics of 13 Episodes of Achromobacter Bacteremia

TABLE 1. (Continued) Characteristic

n (%)

Characteristic

Concurrent medical conditions Hypertension Diabetes mellitus Chronic heart failure Atrial fibrillation ESRD Hepatitis B GVHD Rectal fistula

2 (18) 2 (18) 2 (18) 1 (9) 2 (18) 1 (9) 1 (9) 1 (9)

n (%)

Age, mean (SD), y Sex Male Female Length of hospital stay, d Median Range Total no. episodes of bacteremia Achromobacter xylosoxidans Achromobacter denitrificans Treatment Cefepime Meropenem TMP-SMX Ceftazidime Piperacillin/tazobactam Outcomes Discharged To home/rehabilitation To hospice Death Underlying malignancy Hematologic malignancy AML ALL Multiple myeloma Solid organ malignancy Bladder Small bowel Lung carcinoid Pancreas Vulvar Allogeneic HSCT Prior bacteremia Catheterization PICC Port Hickman Mechanical ventilation Primary infection site CVC Gastrointestinal tract Cholangitis Pneumonia Urinary tract Concurrent cancer treatment Steroids Radiation therapy Chemotherapy Neutropenia

52 (16) 7 (64) 4 (36) 32 1–101 13 12 (92) 1 (8) 3 (23) 5 (38) 1 (8) 1 (8) 3 (23) 10 (90) 6 (54) 4 (36) 1 (10) 11 (100) 6 (55) 4 (66) 1 (17) 1 (17) 5 (45) 1 (20) 1 (20) 1 (20) 1 (20) 1 (20) 1 (9) 8 (73) 11 (100) 6 (55) 4 (36) 1 (9) 2 (18) 6 (55) 3 (27) 2 (18) 1 (9) 1 (9) 6 (55) 2 (18) 9 (82) 3 (27) Continued next column

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SD indicates standard deviation; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; HSCT, hematopoietic stem cell transplant; PICC, peripherally inserted central catheter; CVC, central venous catheter; ESRD, end-stage renal disease; GVHD, graft versus host disease.

be related to Achromobacter infection if death occurred within 1 week a blood culture positive for Achromobacter.

RESULTS Between March 2010 and March 2015, a total of 34 blood culture samples were positive for Achromobacter species at the H. Lee Moffitt Cancer Center. The 34 samples were associated with 13 episodes of Achromobacter bacteremia in 11 patients. Twelve episodes were caused by Achromobacter xylosoxidans and 1 episode was caused by Achromobacter denitrificans.

Patient Characteristics Patient characteristics and risk factors for Achromobacter bacteremia are summarized in Table 1. Of the 11 patients, 7 were male (64%) and 4 were female (36%). The mean patient age was 52 years. Solid tumors were found in 5 patients (45%), and 6 patients (55%) had hematologic malignancies. The most frequent malignancy was acute myeloid leukemia (n = 4, 66%). One patient (9%) received an allogeneic hematopoietic stem cell transplant. Six patients (55%) were receiving corticosteroids. Nine patients (82%) were receiving chemotherapy, and 2 patients (18%) were receiving radiation therapy. Eight patients (73%) had a prior history of bacteremia. In 1 case, the patient had experienced Achromobacter anthropic bacteremia 2 years prior. Two patients (18%) were on mechanical ventilation. Four patients (36%) had a secondary focus of Achromobacter infection: 2 cases of cholangitis, 1 case of urinary tract infection, and 1 case of pneumonia. All patients had intravascular catheters; 4 ports, 6 peripherally inserted central catheter lines, and 1 Hickman. Central venous catheters were infected in 9 patients (82%). Two of these patients experienced recurrent bacteremia, which resolved after removal of the catheter.

Bacteremia Characteristics Characteristics of the episodes of bacteremia are compiled in Table 1. The median length of hospital stay was 25 days (range, 1–101 days). Three episodes occurred in neutropenic patients. All episodes presented with SIRS, and 1 patient presented with septic shock. Three episodes of bacteremia were polymicrobial. The concurrent organisms were Klebsiella (n = 1), Serratia (n = 1), and Candida (n = 1). Five episodes were nosocomial. Five patients were treated with meropenem, 3 with piperacillin/ tazobactam, 3 (23%) with cefepime, 1 with ceftazidime, and 1 © 2016 Wolters Kluwer Health, Inc. All rights reserved.



with trimethoprim-sulfamethoxazole (TMP-SMX). One patient died during the hospital stay, and 4 were discharged to hospice.

Antimicrobial Susceptibilities Antimicrobial susceptibility profiles can be found in Table 2. The isolates were susceptible to carbapenems (meropenem 8/8, imipenem 7/9), ceftazidime 13/13, piperacillin/tazobactam 13/ 13, and TMP-SMX 10/10. Most isolates were resistant to aminoglycosides (gentamicin, amikacin, tobramycin), fluoroquinolones (ciprofloxacin, levofloxacin), cefepime, and ceftriaxone.

DISCUSSION In this single-center retrospective study, we report 11 patients with Achromobacter xylosoxidans bacteremia within a 5-year period. Catheter-related infection (82%) and prior history of bacteremia (73%) were the most common risk factors. In the Aisenberg et al5 case series with 46 patients with cancer and Achromobacter bacteremia, 25% of cases were associated with intravascular catheters. The higher rate of catheter-related infections in our study might reflect differences in the baseline malignancies and the higher use of intravascular catheters in our patients. Other case series had reported rates of catheter-related bacteremia of 19%,1 25%,5 55%,7 and 65%.6 The mortality rate in our study was 9% (1/11). The high rate of infected intravascular catheters and the low attributable mortality in our study is consistent with the reported low rate of mortality with catheter-related Achromobacter bacteremia,1 with mortality rates ranging from 15%5,6 to 47.5%.7 In addition, a death in our study occurred in 1 of the 2 patients with noninfected catheters. Case series published by Duggan et al1 and Gómez-Cerezo 6 et al found Achromobacter bacteremia to be nosocomial in 70% and 96% of cases, respectively. In addition, Shie et al7 and Aisenberg et al5 found that less than a third of cases of Achromobacter bacteremia were nosocomial (27.5% and 33%, respectively). However, a few recent studies have demonstrated increased community-acquired Achromobacter infection. An outbreak of 12 patients with Achromobacter bacteremia was reported in the outpatient setting in oncologic patients associated with central venous catheters. All catheters were removed, and the presence of biofilm was detected by electron microscopy. The outbreak was likely associated with the use of contaminated multidose vials of heparin used for heparin flushes.15 Our study

Achromobacter Bacteremia

showed a similar rate of nosocomial bacteremia at 38% (n = 5). This is an important distinction because nosocomial Achromobacter bacteremia has been found to have a significantly higher mortality than community-acquired Achromobacter bacteremia.7 Other risk factors significantly associated with increased mortality in episodes of Achromobacter bacteremia include sepsis syndrome and high APACHE II scores.5 All our patients presented with SIRS and one presented with septic shock. Aisenberg et al5 reported a lower frequency of sepsis. Previous studies have found sepsis rates of 22%5 and 37%.6 Prior history of bacteremia was also highly associated with Achromobacter bacteremia. The clinical significance of this factor is difficult to determine as we did not analyze primary infection sites or bacterial species of prior episodes or the time between bacteremia episodes. More data are needed to determine whether prior episodes of bacteremia is an independent risk factor for future episodes or the association is due to a confounding factor such as numerous episodes of neutropenia secondary to multiple chemotherapy regimens over time. Achromobacter bacteremia can be difficult to treat due to its inherent antimicrobial resistance. This infection requires removing the intravascular catheter when infected.1 The consensus from the literature is that Achromobacter is susceptible to antipsuedomonal penicillins, carbapenems, TMP-SMX, tigecycline, and ceftazidime. Resistance to penicillins, most cephalosporins, aminoglycosides, fluoroquinolones, fosfomycin, and aztreonam is common.1,5,7,8,16,17 Our isolates had similar patterns of susceptibilities to those reported in other studies. Cancer patients often have weakened immune systems secondary to high rates of steroid use and chemotherapy. The resistance to fluoroquinolones is noteworthy because standard antimicrobial prophylaxis in cancer patients with prolonged neutropenia is ineffective at preventing Achromobacter bacteremia. Recent research into the mechanisms of resistance of Achromobacter has shown its genome encodes at least 5 different β-lactamases as well as a high number of efflux pump-associated genes.18–20 Strains resistant to carbapenems,17,21 TMP/SMX,6 and pan-resistant strains17,22 have been reported. In addition, Achromobacter has the potential to serve as a reservoir of antimicrobial resistance genes through its ability to horizontally transfer plasmids.23,24 In conclusion, intravenous catheters and a history of prior bacteremia are predisposing factors for infection. Fortunately,

TABLE 2. In Vitro Susceptibility Profiles of 13 Achromobacter Subspecies to 12 Antimicrobials No. Isolates (%) Antimicrobial Agent

Total No. Isolates

Susceptible

Intermediate susceptibility

Resistant

Amikacin Cefepime Ceftazidime Ceftriaxone Ciprofloxacin Gentamicin Imipenem Levofloxacin Meropenem Piperacillin/tazobactam Tobramycin TMP-SMX

13 13 13 10 13 13 9 9 13 13 11 10

2 (15) 3 (23) 13 (100) 0 (0) 3 (23) 1 (8) 7 (78) 2 (22) 13 (100) 13 (100) 0 (0) 10 (100)

0 (0) 6 (46) 0 (0) 1 (10) 4 (31) 3 (23) 2 (22) 6 (67) 0 (0) 0 (0) 5 (45) 0 (0)

11 (85) 4 (31) 0 (0) 9 (90) 6 (46) 9 (69) 0 (0) 1 (11) 0 (0) 0 (0) 6 (55) 0 (0)

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the mortality in these patients remains low. This may be due to the high susceptibility of Achromobacter to TMP/SMX, carbapenems, and antipseudomonal penicillins. Infections can be effectively treated with a single agent from any of the drug classes mentioned previously. Because Achromobacter is resistant to fluoroquinolones, standard antibiotic prophylaxis in cancer patients may not prevent Achromobacter bacteremia. Continued monitoring of Achromobacter susceptibility patterns and effective antimicrobial stewardship programs are important tools to reduce the development of multiple-drug resistant and pan-resistant strains of Achromobacter. REFERENCES

11. Kupfahl C, Walther M, Wendt C, et al. Identical Achromobacter strain in reusable surface disinfection tissue dispensers and a clinical isolate. Infect Control Hosp Epidemiol. 2015;36(11):1362–1364. 12. Hugon E, Marchandin H, Poirée M, et al. Achromobacter bacteraemia outbreak in a paediatric onco-haematology department related to strain with high surviving ability in contaminated disinfectant atomizers. J Hosp Infect. 2015;89(2):116–122. 13. Olshtain-Pops K, Block C, Temper V, et al. An outbreak of Achromobacter xylosoxidans associated with ultrasound gel used during transrectal ultrasound guided prostate biopsy. J Urol. 2011;185(1):144–147. 14. Molina-Cabrillana J, Santana-Reyes C, González-García A, et al. Outbreak of Achromobacter xylosoxidans pseudobacteremia in a neonatal care unit related to contaminated chlorhexidine solution. Eur J Clin Microbiol Infect Dis. 2007;26(6):435–437.

1. Duggan JM, Goldstein SJ, Chenoweth CE, et al. Achromobacter xylosoxidans bacteremia: report of 4 cases and review of the literature. Clin Infect Dis. 1996;23(3):569–576.

15. Kim MJ, Bancroft E, Lehnkering E, et al. Alcaligenes xylosoxidans bloodstream infections in outpatient oncology office. Emerg Infect Dis. 2208;14:1046–1052.

2. De Baets F, Schelstraete P, Van Daele S, et al. Achromobacter xylosoxidans in cystic fibrosis: prevalence and clinical relevance. J Cyst Fibros. 2007; 6(1):75–78.

16. Legrand C, Anaissie E. Bacteremia due to Achromobacter xylosoxidans in patients with cancer. Clin Infect Dis. 1992;14(2):479–484.

3. Razvi S, Quittell L, Sewall A, et al. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest. 2009;136(6): 1554–1560. 4. Ridderberg W, Bendstrup KE, Olesen HV, et al. Marked increase in incidence of Achromobacter xylosoxidans infections caused by sporadic acquisition from the environment. J Cyst Fibros. 2011;10(6): 466–469. 5. Aisenberg G, Rolston KV, Safdar A. Bacteremia caused by Achromobacter and Alcaligenes species in 46 patients with cancer (1989-2003). Cancer. 2004;101(9):2134–2140. 6. Gómez-Cerezo J, Suárez I, Ríos JJ, et al. Achromobacter xylosoxidans bacteremia: a 10-year analysis of 54 cases. Eur J Clin Microbiol Infect Dis. 2003;22(6):360–363. 7. Shie SS, Huang CT, Leu HS. Characteristics of Achromobacter xylosoxidans bacteremia in northern Taiwan. J Microbiol Immunol Infect. 2005;38(4):277–282. 8. Atalay S, Ece G, Samlioğlu P, et al. Clinical and microbiological evaluation of eight patients with isolated Achromobacter xylosoxidans. Scand J Infect Dis. 2012;44(10):798–801. 9. Tena D, Carranza R, Barberá JR, et al. Outbreak of long-term intravascular catheter-related bacteremia due to Achromobacter xylosoxidans subspecies xylosoxidans in a hemodialysis unit. Eur J Clin Microbiol Infect Dis. 2005;24(11):727–732. 10. Turgutalp K, Kiykim A, Ersoz G, et al. Fatal catheter-related bacteremia due to Alcaligenes (Achromobacter) xylosoxidans in a hemodialysis patient. Int Urol Nephrol. 2012;44(4):1281–1283.

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17. Abbott IJ, Peleg AY. Stenotrophomonas, Achromobacter, and nonmelioid Burkholderia species: antimicrobial resistance and therapeutic strategies. Semin Respir Crit Care Med. 2015;36(1):99–110. 18. Bador J, Amoureux L, Blanc E, et al. Innate aminoglycoside resistance of Achromobacter xylosoxidans is due to AxyXY-OprZ, an RND-type multidrug efflux pump. Antimicrob Agents Chemother. 2013;57(1): 603–605. 19. Bador J, Amoureux L, Duez JM, et al. First description of an RND-type multidrug efflux pump in Achromobacter xylosoxidans, AxyABM. Antimicrob Agents Chemother. 2011;55(10):4912–4914. 20. Hu Y, Zhu Y, Ma Y, et al. Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans. Antimicrob Agents Chemother. 2015;59(2):1152–1161. 21. Trancassini M, Iebba V, Citerà N, et al. Outbreak of Achromobacter xylosoxidans in an Italian cystic fibrosis center: genome variability, biofilm production, antibiotic resistance, and motility in isolated strains. Front Microbiol. 2014;5:138. 22. Lobo LJ, Tulu Z, Aris RM, et al. Pan-resistant Achromobacter xylosoxidans and Stenotrophomonas maltophilia infection in cystic fibrosis does not reduce survival after lung transplantation. Transplantation. 2015;99(10): 2196–2202. 23. Traglia GM, Almuzara M, Merkier AK, et al. Achromobacter xylosoxidans: an emerging pathogen carrying different elements involved in horizontal genetic transfer. Curr Microbiol. 2012;65(6):673–678. 24. Yamamoto M, Nagao M, Hotta G, et al. Molecular characterization of IMP-type metallo-β-lactamases among multidrug-resistant Achromobacter xylosoxidans. J Antimicrob Chemother. 2012;67(9):2110–2113.

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