Multidrug-resistant Acinetobacter baumannii Pneumonia in Lung Transplant Recipients Madhuri M. Sopirala, MD, Amy Pope-Harman, MD, David R. Nunley, MD, Susan Moffatt-Bruce, MD, PhD, Patrick Ross, MD, PhD, and Stanley I. Martin, MD We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study. J Heart Lung Transplant 2008;27:804 –7. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Patients having undergone lung transplantation (LT) are at an increased risk for pulmonary infection compared with other solid-organ transplant recipients. Despite advances in the field of LT, pneumonia remains a major cause of morbidity and mortality in this population.1 Acinetobacter baumannii (AB) has emerged in recent years as a prominent nosocomial pathogen with multipledrug–resistant mechanisms to broad-spectrum antibiotics.2–5 Recipients of LT (LTRs) may be at an increased risk to develop life-threatening pneumonia with this pathogen. Because of the lack of active drugs, non-traditional antibiotics, such as colestimethate (polymixin E) and polymixin B, and newer anti-microbial agents, such as tigecycline, have been used to treat patients infected with multidrug-resistant (MDR) AB,2,3,6,7 despite the lack of sufficient clinical data and concerns over potential toxicities. There have been reports of non–MDR AB infections in recipients of solid-organ transplants other than LTs8,9; however, there remains a paucity of literature on the subject and there are no known reports of MDR AB pneumonia in LTRs. The objective of this study was to evaluate demographic characteristics, co-morbidities, risk factors, treatment and outcome of MDR AB pneumonia in LTRs.
From the Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University Medical Center, Columbus, Ohio. Submitted October 15, 2007; revised February 1, 2008; accepted March 27, 2008. Reprint requests: Madhuri M. Sopirala, MD, Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University Medical Center, N1129 Doan Hall, 410 West 10th Avenue, Columbus OH 43210. Telephone: 614-293-5667. Fax: 614-293-4556. E-mail:
[email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.03.023
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METHODS Between January 2002 and July 2007, 52 LTs were performed at The Ohio State University Medical Center (OSUMC) in Columbus, Ohio. Six of these patients developed pneumonia with MDR AB, all occurring since July 2005. The rate of MDR AB in the surgical intensive care unit (SICU) in 2005 and 2006 was 0.671 per 1,000 patientdays (PD) and 1.343 per 1,000 PD, respectively; 4 of 6 patients described in this series were diagnosed in 2005 and 2 were diagnosed in 2006 (number of MDR AB cases in the Years 2005 and 2006 among all patients admitted to SICU was 7 and 15, respectively). There is no known problem with health care provider colonization or SICU contamination with this organism at OSUMC. All positive MDR AB cultures have been reviewed for the purpose of this case series and this organism has been so far identified only in the context of infection in LTRs. AB was defined as MDR if the isolate was resistant to at least three classes of antibiotics.10 Upon obtaining approval from the institutional review board, these 6 patients were investigated by retrospective chart review. Characteristics analyzed included age and gender, immunosuppressive therapies, type of transplant (single vs double lung), days since transplant and days since admission, diabetes mellitus, renal failure, acute rejection of the allograft, mechanical ventilation, other infections during the same admission, use of antibiotics prior to diagnosis of MDR AB pneumonia and complications of treatment. Total antibiotic days were defined as total number of days that the patient received antibiotics as inpatient or outpatient or both immediately prior to development of MDR AB pneumonia. Bronchoalveolar lavage (BAL) criteria for true infection were ⬎10,000 cfu/ml of bacteria with purulence in the presence of clinical and radiographic signs suggestive of pneumo-
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nia. Outcomes such as microbial eradication (ME), clinical resolution (CR) and disposition of the subjects were evaluated. ME was defined as documented eradication of the bacterial isolate by repeat culture from the same site. Those with persistently positive cultures or those with clinical deterioration and no follow-up cultures to demonstrate eradication were considered microbial failures. CR was defined as improvement in clinical condition with neither signs nor symptoms attributable to the treated infection present upon hospital discharge. Subjects who died while on therapy or had persistent signs and symptoms of infection were considered clinical failures. RESULTS The clinical profiles of the 6 LTRs who developed MDR AB pneumonia are summarized in Table 1. Five of the 6 (83%) patients were on mechanical ventilation at the time of diagnosis. Four (67%) were diagnosed with and treated for acute rejection with methylprednisolone Table 1. Demographic and Clinical Features Characteristic Male Median age (years) Type of transplant (%) Single lung Underlying lung disorder (%) COPD Idiopathic pulmonary fibrosis Sarcoidosis Immunosuppressants at time of infection (%) Tacrolimus Sirolimus Mycophenolate mofetil Cyclosporine Prednisone ⱕ10 mg/day ⬎10 mg/day Median days since transplant (range) Median days since admission (range) Non-infectious comorbidities Diabetes mellitus (%) Mechanical ventilation no. (%) GFR ⬍30 ml/min/1.73 m2 Rejection (%) Biopsy-proven (%) Treated for rejection (%) Other infections prior to diagnosis Pneumonia Staphylococcus aureus Pseudomonas aeruginosa Post-operative meningitis Clostridium difficile colitis
All patients (n ⫽ 6) 4 (67%) 63 6 (100%) 3 (50%) 2 (33%) 1 (17%) 4 (67%) 1 (17%) 3 (50%) 2 (33%) 6 (100%) 3 (50%) 3 (50%) 259 (22–1110) 38.5 (10–115) 4 (67%) 5 (83%) 0 4 (67%) 1 (17%) 4 (67%) 4 (67%) 3 (50%) 1 (17%) 2 (33%) 1 (17%) 1 (17%)
COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate.
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boluses (10 mg/kg/day) for 3 days followed by prednisone (1 mg/kg/day). Time from treatment of acute rejection to diagnosis of pneumonia was 11 (median) days (range 10 to 48 days). Five (83%) patients had other infections prior to diagnosis of MDR AB pneumonia. None of the patients had MDR AB grown from BAL, explanted lung or sputum prior to the diagnosis of pneumonia. All patients received antibiotics prior to diagnosis of MDR AB pneumonia. Total antibiotic days ranged from 12 to 115 days (median 59 days). Broad-spectrum anti-microbial agents were used on all patients prior to diagnosis of MDR AB pneumonia. The most commonly used agent was piperacillin/tazobactam (median 7 days, range 4 to 24 days) in 5 cases (83%). The sixth patient received imipenem, another broad-spectrum agent, with a similar anti-microbial coverage profile, for 22 days prior to diagnosis of MDR AB pneumonia. Four of the 6 patients (Patients 1, 2, 4 and 6) had MDR AB resistant to imipenem with a minimum inhibitory concentration (MIC) ⬎8 mg/liter, but all were susceptible to colistin (MIC range 0.5 to 2 mg/liter) and tigecycline (ⱕ2 mg/liter) except Patient 1. Clinical features, diagnoses, treatment and outcomes of these patients are listed in Tables 2 and 3. Patient 1 was treated with inhaled colistin combined with intravenous colistin and achieved both MC and CR. Patient 3 was treated with imipenem alone and achieved both MC and CR. Patient 5 was treated with imipenem combined with inhaled colistin (IC). Patients 2, 4 and 6 were all treated with IC and tigecycline. Patient 4 achieved CR but did not have an MC. Patient 2 achieved MC, but not CR, and died 9 days after diagnosis of MDR AB infection. Patient 6 achieved neither MC nor CR and died 5 days after diagnosis. All patients were started on targeted treatment (defined as antibiotic treatment based on susceptibility pattern) on Day 5 of culture except for Patient 5. He was started on appropriate treatment on Day 8. All patients were on alternative broad-spectrum antibiotics prior to targeted treatment; antibiotics were adjusted upon availability of susceptibilities with the following order of preference with or without IC—imipenem, tigecycline and parenteral colistin (in an attempt to restrict tigecycline and colistin use). None of the patients had adverse effects to any of the antibiotics used. DISCUSSION LTRs are frequently admitted to the hospital, increasing their risk for nosocomial exposure to MDR AB. There is mounting evidence for increased mortality and hospital costs associated with this infection.11–13 We have described the characteristics, clinical course and treatment of 6 LTRs with MDR AB pneumonia.
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Table 2. Clinical Features
Age (years) Albumina Patient gender Diagnoses (g/dl) 1 65/M Pneumonia, 1.7 sepsis, C difficile colitis 2 65/F Pneumonia, hip 1.7 fracture 3 66/M Pneumonia, 3.5 allograft rejection 4 44/F Pneumonia 1.9
5
63/M
6
56/M
Meningitis, allograft rejection Pneumonia, sepsis, acute cholecystitis
Augmented immunosuppressionb Radiographic evidence (days since last (graft or dose to MDR native lung) AB pneumonia) No Yes (graft)
Total days of intubation Hospital day (reperfusion Body injury if of first site(s) immediately Days positive of MDR postsince MDR AB AB transplant) transplant culture 54 44 1,110 Sputum, blood
Yes (48)
Yes (graft)
115
67
420
Sputum
Yes (10)
Yes (graft)
10
2 (no)
30
BAL
No
Yes (graft)
23
24 (no)
98
2.8
Yes (12)
Yes (graft)
79
53 (no)
956
Sputum, lung aspirate Sputum, BAL
1.4
Yes (10)
Yes (native lung)
22
20 (no)
22
Bile, BAL, blood
MDR AB, multidrug resistant A baumannii; BAL, bronchoalveolar lavage. a Albumin level at the time of diagnosis of pneumonia. b During current hospitalization.
Broad-spectrum anti-microbial agent use prior to infection stands out as the most likely risk factor for MDR AB. Piperacillin/tazobactam is the most commonly used broad-spectrum agent at OSUMC and hence appears to be implicated in our study. This likely can be generalized to other anti-microbial agents that have a similar spectrum to that of piperacillin/tazobactam. Prolonged hospitalization and serum albumin ⬍2.5 g/dl also appear to be potential risk factors in this study. Being in the ICU and requiring mechanical ventilation appears to be associated with these infections in this and other studies.14,15 All 6 patients were single LTRs (49 of 52 LTs since 2002 at OSUMC were single LTs).
Intravenous colistin with adjunctive inhaled colistin was used in Patient 1 in whom the MDR AB was resistant to all antibiotics except colistin. In other patients, imipenem or tigecycline was used if the organism was susceptible, with adjunctive inhaled colistin in most cases. There is some evidence in the literature of benefit with adjunctive aerosolized polymyxin therapy in patients with pneumonia caused by MDR gram-negative organisms.16 Patient 5 had late onset of targeted therapy (at 8 days as opposed to 5 days in other patients). Patients 1 and 3 received systemic directed treatment and achieved both MC and CR.
Table 3. Hospital Course Patient 1 2 3 4 5 6
Body site(s) of MDR A baumannii Sputum, blood Sputum BAL (graft) Sputum, lung aspirate (graft) Sputum, BAL (graft) Bile, BAL (native), blood
Treatment Colistina Colistinb tigecycline Imipenem Colistinb tigecycline Imipenem, colistinb Colistinb tigecycline
Microbiologic cure (if yes, site cultured) Yes (sputum) Yes (BAL) Yes (BAL) No No No
MDR, multidrug resistant; A baumannii, Acinetobacter baumannii; BAL, bronchoalveolar lavage. a Inhaled and parenteral. b Inhaled.
Clinical resolution Yes No Yes Yes Yes No
Outcome (hospital day) Survived Died (124) Survived Survived Survived Died (27)
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Patients 2, 4 and 6 also received directed systemic therapy and failed microbiologically, clinically or both. Patient 5 had a delay in appropriate directed antimicrobial therapy and had a poor outcome. Treating the infection early in the LTR’s clinical course with appropriate antibiotics is likely an important factor in achieving MC and CR. The true efficacy of non-traditional agents such as colistin and tigecycline in the treatment of MDR AB infections remains unclear. In this study, aerosolized colistin was adminstered at 75 mg every 12 hours, whereas parenteral therapy was given at 5 mg/kg/day divided into two doses. Optimization of dosing is unknown and, although combination therapy may be more effective as suggested by in vitro studies, in vivo comparative data are not available.17,18 In conclusion, physicians caring for LTRs with significant underlying morbidity in an ICU setting need to be aware of the possibility of pneumonia due to MDR AB and the challenges in treating this still poorly understood infectious process. In LTRs, pre-operative colonization with gram-negative rods was found to be a risk factor for post-transplant pneumonia in a recent study.19 None of the patients in this series had colonization with MDR AB prior to developing pneumonia. In LTRs, early recognition of the pathogen, rapid initiation of targeted therapy, and consideration of empiric treatment with intravenous imipenem, colistin and tigecycline with aerosolized colistin as adjunctive therapy (based on the hospital’s antibiogram) in cases with a high suspicion of pneumonia due to MDR AB may have a positive impact on clinical outcome. REFERENCES 1. Aguilar-Guisado M, Givalda J, Ussetti P, et al. Pneumonia after lung transplantation in the RESITRA cohort: a multicenter prospective study. Am J Transplant 2007;7:1989 –96. 2. Manikal VM, Landman D, Saurina G, et al. Endemic carbapenemresistant Acinetobacter species in Brooklyn, New York: citywide prevalence, interinstitutional spread, and relation to antibiotic usage. Clin Infect Dis 2000;31:101– 6. 3. Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999;28:1008 –11. 4. Urban C, Mariano N, Rahal JJ, et al. Polymyxin B–resistant Acinetobacter baumannii clinical isolate susceptible to recom-
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5. 6. 7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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binant BPI and Cecropin P1. Antimicrob Agents Chemother 2001;45:994 –5. Tygacil package insert. Wyeth Pharmaceuticals, Inc. Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis 2005;41(suppl 5):S303–14. Schafer JJ, Goff DA, Stevenson KB, Mangino JE. Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumannii. Pharmacotherapy 2007;27:980 –7. George RS, Birks EJ, Haj-Yahia S, et al. Acinetobacter mediastinitis in a heart transplant patient. Ann Thorac Surg 2006;82: 715– 6. Wade J, Rolando N, Williams R. The significance of aerobic gram-negative bacilli in clinical specimens following orthotopic liver transplantation. Liver Transplant Surg 1998;4:51–7. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Sixteenth informational supplement. Approved standard M100-S16, 2006; CLSI. Falagas ME, Rafailidis PI. Attributable mortality of Acinetobacter baumannii: no longer a controversial issue. Crit Care 2007;11: 134. Metan G, Alp E, Aygen B, Sumerkan B. Acinetobacter baumannii meningitis in post-neurosurgical patients: clinical outcome and impact of carbapenem resistance. J Antimicrob Chemother 2007; 60:197–9. Niederman MS. Impact of antibiotic resistance on clinical outcomes and the cost of care. Crit Care Med 2001;29(suppl): N114 –20. Cisneros-Herreros JM, Garnacho-Montero J, Pachon-Ibanez ME. Nosocomial pneumonia due to Acinetobacter baumannii. Enferm Infecc Microbiol Clin 2005;23(suppl 3):46 –51. Ruiz CM, Guerrero PJ, Romero PC. Etiology of ventilator-associated pneumonia in a university hospital. Association with comorbidity, previous use of antibiotics and mortality. Rev Chilena Infectol 2007;24:131– 6. Pereira GH, Muller PR, Levin AS. Salvage treatment of pneumonia and initial treatment of tracheobronchitis caused by multidrugresistant gram-negative bacilli with inhaled polymyxin B. Diagn Microbiol Infect Dis 2007;58:235– 40. Sopirala M, Mangino J, Bannerman T, Pancholi P. Antimicrobial synergy testing for multi-drug-resistant Acinetobacter baumannii. Paper presented at the program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Chicago, IL, September 2007. Timurkaynak F, Can F, Azap OK, et al. In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int J Antimicrob Agents 2006;27:224 – 8. Mattner F, Fischer S, Weissbrodt H, et al. Post-operative nosocomial infections after lung and heart transplantation. J Heart Lung Transplant 2007;26:241–9.
