Infectious Diseases, 2015; Early Online: 1–9

ORIGINAL ARTICLE

Sulbactam treatment for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus–Acinetobacter baumannii complex

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HUANG-SHEN LIN1*, MING-HSUN LEE2*, CHUN-WEN CHENG2, PO-CHANG HSU2, HSIEH-SHONG LEU2, CHING-TAI HUANG2 & JUNG-JR YE2 From the 1Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital at Chia-Yi, Chia-Yi, Taiwan, ROC, and 2Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, ROC

Abstract Background: Multidrug-resistant (MDR) Acinetobacter calcoaceticus–Acinetobacter baumannii (Acb) complex has become an important cause of nosocomial pneumonia. Sulbactam is a β-lactamase inhibitor with antimicrobial activity against MDR Acb complex. Methods: To investigate outcomes of pneumonia involving MDR Acb complex treated with sulbactam or ampicillin/sulbactam for at least 7 days, we conducted a retrospective study of 173 adult patients over a 34 month period. Results: Of 173 patients, 138 (79.8%) received combination therapy, mainly with carbapenems (119/138, 86.2%). The clinical response rate was 67.6% and the 30 day mortality rate was 31.2%. The independent predictors of clinical failure were malignancy, bilateral pneumonia and shorter duration of treatment. In patients with sulbactam-susceptible strains, there was no difference in clinical and microbiological outcome between combination therapy and monotherapy. Compared to the sulbactam-susceptible group, the sulbactam-resistant group had a lower rate of airway eradication, a longer duration of treatment and a higher rate of combination therapy with predominantly carbapenems (p ⬍ 0.05). There was no significant difference between the two groups in clinical resolution and 30 day mortality rates. Conclusions: Sulbactam could be a treatment option for pneumonia involving MDR Acb complex, and combination therapy with carbapenems could be considered for sulbactam-resistant cases.

Keywords: Acinetobacter calcoaceticus–Acinetobacter baumannii complex, multidrug-resistant, pneumonia, sulbactam

Introduction Over the past few years, Acinetobacter baumannii has become an important cause of nosocomial pneumonia, especially the multidrug-resistant (MDR) strains with resistance to most currently available antibiotics, including β-lactams, fluoroquinolones and aminoglycosides [1]. Pneumonia with multidrug-resistant A. baumannii (MDRAB) usually occurs in severely ill patients and is associated with unfavourable outcomes [2–4]. The therapeutic options are limited and the optimal treatment has not been well established [5–10]. Sulbactam is a β-lactamase inhibitor with antimicrobial activity against A. baumannii [11]. It is available

alone or in combination with ampicillin. However, ampicillin does not contribute activity or synergism against A. baumannii [11–13]. In previous studies with small numbers of cases, sulbactam or ampicillin/sulbactam monotherapy had clinical response rates ranging from 67% to 75% in treatment of MDRAB pneumonia [5,7]. Sulbactam in combination with meropenem or cefepime had a synergistic effect against MDRAB in animal and in vitro studies [14–16]. Clinical data on combination therapy containing sulbactam for MDRAB pneumonia are scarce. However, successful treatment with a combination of carbapenem and sulbactam for critically ill patients with MDRAB bacteraemia has been reported [17].

*These two authors contributed equally. Correspondence: Jung-Jr Ye, MD, Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, 5 Fu-Shin Street, Gueishan 333, Taoyuan, Taiwan. Tel: ⫹ 886 3 3281200, ext. 8450. Fax: ⫹ 886 3 3289410. E-mail: [email protected] (Received 7 June 2014 ; accepted 26 November 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.995129

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H.-S. Lin et al.

As A. baumannii and other closely related genomic species are not separated by the phenotypic methods used in general microbiology laboratories, they are often reported as A. calcoaceticus–A. baumannii complex (Acb complex) [18]. In this study, we reviewed a larger number of cases than in previous studies to investigate the characteristics and outcomes of pneumonia involving MDR Acb complex treated with sulbactam or ampicillin/sulbactam.

(meropenem or imipenem), fluoroquinolones (ciprofloxacin or levofloxacin), amikacin, cephalosporins (ceftazidime or cefepime), piperacillin, piperacillin–tazobactam and aztreonam. Delayed treatment was defined as more than 3 days between the detection of airway MDR Acb complex isolates and the first dose of sulbactam or ampicillin/sulbactam. Demography and comorbidity

Materials and methods

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Study design and patients This retrospective observational study was conducted at the Chang Gung Memorial Hospital (CGMH)Linkou, a 3715-bed university-affiliated tertiary-care medical centre in Taiwan. The study was approved by the research ethics committee (institutional review board) of CGMH-Linkou (number 100-0294B). From September 2004 to July 2007, all hospitalized patients above 18 years of age who received sulbactam or ampicillin/sulbactam treatment for pneumonia involving MDR Acb complex were enrolled. Pneumonia was diagnosed if the patient had a radiographic infiltrate that was new or progressive, along with at least two of the following clinical characteristics: new onset of fever (ⱖ 38°C) or hypothermia (⬍ 35.5°C), leucocytosis (leucocyte count ⬎ 12 000 cells/mm3) or leucopenia (leucocyte count ⬍ 4000 cells/mm3), decline in oxygenation (oxygen saturation ⬍ 90%) and increasing amount of purulent sputum [19]. Pneumonia involving MDR Acb complex was defined as clinical evidence of pneumonia and MDR Acb complex isolated from sputum or tracheal aspirate 1 week before to 3 days after the first dose of sulbactam or ampicillin/sulbactam. Tracheal aspirate and sputum specimens were cultured if they had at least 25 neutrophils and fewer than 10 epithelial cells per low-power field on Gram’s staining. Growth was assessed semi-quantitatively. The aetiological pathogen of pneumonia was determined if the tracheal aspirate or sputum culture had at least moderate growth, i.e. growth confined to the primary streaking line and more than five colonies in the secondary streaking zone [20]. Polymicrobial pneumonia was defined as one or more additional bacterial species concurrently isolated from the respiratory tract during sulbactam or ampicillin/sulbactam treatment. All eligible patients received intravenous sulbactam 1 g or ampicillin/sulbactam 3 g (at a rate of 2:1) every 6 or 8 h for at least 7 days. Dosing intervals were adjusted according to the serum creatinine levels. Combination therapy was defined as simultaneous use of another class of antibiotics for at least 3 days. These antibiotics included carbapenems

Data on age, gender, surgical procedures and comorbid illness were obtained from the inpatient medical records. Comorbid illnesses included liver cirrhosis or hepatic dysfunction with a serum total bilirubin level over 2.5 mg/dl, renal disease with requirement for dialysis, chronic pulmonary disease, heart disease, diabetes mellitus, immune compromise and haematological or solid organ malignancy. Immune compromise was defined by at least one of the following conditions: use of prednisone or equivalent over 20 mg per day for at least 2 weeks during hospitalization, organ transplant recipient, human immunodeficiency virus infection or acquired immunodeficiency syndrome, neutropenia, use of immunosuppressive agents and concurrent haematological malignancy.

Clinical conditions and outcomes Use of a ventilator, vital signs and infections other than pneumonia during sulbactam or ampicillin/sulbactam treatment were recorded. Defervescence was defined as normal body temperature for at least 3 days at the end of treatment. Severity of illness was assessed by a modified Acute Physiology and Chronic Health Evaluation (APACHE) II score [21], which was recorded within 48 h before or after the first dose of sulbactam or ampicillin/sulbactam. The 30 day mortality was defined as death occurring within 30 days after sulbactam or ampicillin/sulbactam use. The chest radiographs were evaluated by at least two investigators. A series of chest radiographs was evaluated during treatment. Clinical resolution of pneumonia at the end of treatment was defined as (1) decreased pulmonary infiltrate, and (2) survival with stationary findings on chest radiographs and defervescence. Thus, patients with persistent fever or death during treatment would be defined as clinical failure if infiltrates were stationary. Progressing infiltrates were defined as clinical failure.

Microbiology Identification of Acb complex was based on Gram’s staining and conventional biochemical tests [18].

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Sulbactam for pneumonia involving MDR Acb complex In brief, the isolates were identified as species of the genus Acinetobacter based on the following properties: aerobic, Gram-negative, non-motile coccobacillary rods with a non-fermentative, catalase-positive and oxidase-negative reaction. Acinetobacter species with glucose-oxidizing non-haemolytic characteristics were classified as Acb complex. Antimicrobial susceptibility was determined and interpreted according to the criteria of Clinical and Laboratory Standards Institute by the disk diffusion method [22]. Susceptibility to sulbactam was determined using a disk diffusion method with Müeller–Hinton agar (BD Microbiology Systems, Cockeysville, MD, USA) with a disk containing 10 μg/10 μg of ampicillin/sulbactam. Inhibitory zone sizes of ⱖ 15 mm, 14–12 mm and ⱕ 11 mm were interpreted as susceptible, intermediately resistant and resistant, respectively. An isolate with full or intermediate resistance to amikacin, gentamicin, cefepime, ceftazidime, aztreonam, piperacillin, piperacillin–tazobactam, ciprofloxacin, imipenem and meropenem was defined as MDR Acb complex [23]. Cultures were collected from 1 week before the first dose of sulbactam or ampicillin/sulbactam to the discharge of patients. Pathogens, sites of growth and susceptibility testing were recorded. Microbial eradication of MDR Acb complex was defined as no growth of Acb complex or susceptibility change from MDR strains to susceptible strains in Acb complex in follow-up respiratory tract cultures before and 7 days after cessation of sulbactam or ampicillin/ sulbactam treatment. Relapse was defined as new isolation of MDR Acb complex from the respiratory tract cultures within 2 weeks after initial eradication. Initial bacteraemia was defined as bacteraemia at the beginning of sulbactam or ampicillin/sulbactam treatment, which meant at least one positive blood culture from 1 week before to 3 days after the first dose of sulbactam or ampicillin/sulbactam. Statistical analysis All statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (version 15.0; SPSS, Chicago, IL, USA). Univariate and multivariate analyses were performed to identify the risk factors for clinical failure. In patients with and without clinical resolution, categorical variables were compared using the chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were tested for normality of distributions by the Kolmogorov–Smirnov test, and then compared by Student’s t test or the Mann-Whitney U test, as appropriate. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated. Variables with a p value of less than 0.1 in univariate analysis or the variables of interest were included in logistic regres-

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sion models for multivariate analysis. All tests were two tailed, and a p value of less than 0.05 was considered significant. Comparisons were made between patients with sulbactam-susceptible and sulbactam-resistant MDR Acb complex. In patients with sulbactam-susceptible strains, comparisons were made between patients with monotherapy and combination therapy.

Results Demography, comorbidities and clinical conditions In total, 173 patients with pneumonia involving MDR Acb complex were identified. Forty-five were treated with sulbactam, 125 with ampicillin/sulbactam, and three with sulbactam and ampicillin/sulbactam in turn. Twenty-seven (15.6%) had positive sputum cultures for MDR Acb complex, and 146 (84.4%) had positive tracheal aspirate cultures. Demographics, clinical features, treatment and outcomes are summarized in Table I. The mean age was 68.4 years, with a male predominance (72.3%). Diabetes mellitus was the most common comorbidity (35.8%). Ventilator use was common (82.7%), and the mean APACHE II score was 17.7. In total, 134 patients (77.5%) had bilateral pneumonia and 121 (69.9%) had polymicrobial pneumonia. Among the 173 initial airway isolates, 65 (37.6%) were sulbactam susceptible and 44 (25.4%) were sulbactam resistant (Table I). Treatment and outcomes The mean duration of treatment was 15.9 days. Altogether, 138 patients (79.8%) had combination therapy. Carbapenems were most commonly coadministered (119/138, 86.2%). Forty-eight patients (27.7%) had a delayed start of sulbactam or ampicillin/sulbactam. At the end of treatment, 100 patients (69.0%) had airway eradication of MDR Acb complex without relapse, including 88 (60.7%) with airway eradication of Acb complex among the 145 patients with subsequent follow-up respiratory tract cultures. Clinical resolution of pneumonia was seen in 117 patients (67.6%). Thirty-three patients (19.1%) died during treatment, and the 30 day mortality rate was 31.2% (Table I). Predictors for clinical failure In univariate analysis, patients with clinical failure had higher rates of bilateral pneumonia and ventilator use, higher APACHE II scores, and shorter sulbactam or ampicillin/sulbactam treatment compared to patients with clinical resolution (p ⬍ 0.05).

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H.-S. Lin et al.

Table I. Characteristics of 173 patients with pneumonia involving multidrug-resistant Acinetobacter calcoaceticus–Acinetobacter baumannii complex (MDR Acb complex) treated with sulbactam (SB) or ampicillin/sulbactam (AMP/SB).

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Characteristics Demographic parameters Age (years), mean ⫾ SD Male/female Concomitant diseases Hepatic dysfunction Requirement for dialysis Chronic pulmonary disease Cardiac disease Diabetes mellitus Immune compromise Malignancy Surgery Clinical conditions APACHE II score, mean ⫾ SD Ventilator use Bilateral pneumonia Polymicrobial pneumonia With methicillin-resistant Staphylococcus aureus With Pseudomonas aeruginosa With Stenotrophomonas maltophilia With Klebsiella spp.b With Escherichia coli Concomitant infections With urinary tract infection With soft tissue and wound infection With catheter-related infection With intra-abdominal infection With invasive fungal infectionc Initial bacteraemia With MDR Acb complex bacteraemia Sulbactam susceptibility of initial airway MDR Acb complex isolates Susceptible Intermediate Resistant SB or AMP/SB treatment Duration (days) mean ⫾ SD Combination therapy With carbapenems With cephalosporins With fluoroquinolones With aminoglycosides With piperacillin With aztreonam Delayed treatment Concurrent use of glycopeptides Microbiology outcomes Airway eradication of MDR Acb complex without relapse (n ⫽ 145) Airway eradication of Acinetobacterbaumannii (n ⫽ 145)

Valuea 68.4 ⫾ 15.0 125/48 15 18 45 15 62 26 43 38

(8.7) (10.4) (26.0) (8.7) (35.8) (15.0) (24.9) (22.0)

17.7 ⫾ 6.5 143 (82.7) 134 (77.5) 121 (69.9) 54 (31.2) 48 (27.7) 27 (15.6) 13 (7.5) 6 (3.5) 71 (41.0) 34 (19.7) 18 (10.4) 15 (8.7) 8 (4.6) 5 (2.9) 11(6.4) 3 (1.7)

65 (37.6) 64 (37.0) 44 (25.4) 15.9 ⫾ 8.2 138 (79.8) 119 (68.8) 15 (8.7) 6 (3.5) 3 (1.7) 2 (1.2) 1 (0.6) 48 (27.7) 58 (33.5) 100 (69.0) 88 (60.7) (Continued)

In multivariate analysis, the independent predictors for clinical failure were malignancy, bilateral pneumonia and shorter sulbactam or ampicillin/sulbactam treatment (Table II). In multivariate analyses excluding treatment

Table I. (Continued) Characteristics Clinical outcomes Clinical resolution of pneumonia Mortality during treatment Defervescence Imaging study for pneumonia Improvement Stationary Deterioration 30 day mortality

Valuea 117 (67.6) 33 (19.1) 150 (86.7) 77 54 42 54

(44.5) (31.2) (24.3) (31.2)

APACHE II, Acute Physiology and Chronic Health Evaluation II. aData are shown as number (%) of subjects and n ⫽ 173 unless otherwise indicated. bTwelve patients had coinfection with K. pneumoniae, including eight with extended-spectrum β-lactamase-producing strain, and one had K. ozaenae. cFour patients had candidaemia and one had possible invasive aspergillosis diagnosed with a positive serum galactomannan test.

duration, or including sulbactam-resistant or sulbactam-non-susceptible MDR Acb complex, the independent predictors were also only malignancy and bilateral pneumonia.

Sulbactam-susceptible group versus sulbactam-resistant group Sixty-five patients had initial airway isolates susceptible to sulbactam, while 44 had sulbactamresistant isolates. There were no significant differences between these patients with regard to demographic parameters, concomitant diseases and clinical conditions. Compared to the sulbactam-susceptible group, the sulbactam-resistant group had a lower rate of airway eradication, a longer duration of treatment and a higher rate of combination therapy, with predominantly carbapenems (p ⬍ 0.05). There was no significant difference between the two groups in clinical resolution and 30 day mortality rates (Table III).

Monotherapy versus combination therapy in patients with sulbactam-susceptible isolates Among 65 patients with sulbactam-susceptible isolates, 22 had monotherapy with sulbactam or ampicillin/sulbactam, and 43 had combination therapy. Those treated with monotherapy had a higher rate of cardiac disease and a lower rate of surgery (p ⬍ 0.05) than those with combination therapy. There was no significant difference in demographic parameters, clinical conditions, disease severity, treatment duration and outcomes between the two groups (Table IV).

Sulbactam for pneumonia involving MDR Acb complex

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Table II. Univariate and multivariate analyses of the predictors for clinical failure of pneumonia involving multidrug-resistant Acinetobacter calcoaceticus–Acinetobacter baumannii complex (MDR Acb complex) treated with sulbactam (SB) or ampicillin/sulbactam (AMP/SB).

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Variables Demographic parameters Age, years Male gender Concomitant diseases Hepatic dysfunction Requirement for dialysis Chronic pulmonary disease Cardiac disease Diabetes mellitus Immune compromise Malignancy Surgery Clinical conditions APACHE II score Ventilator use Bilateral pneumonia Polymicrobial pneumonia MRSA Pseudomonas aeruginosa Stenotrophomonas maltophilia Klebsiella spp. Escherichia coli Concomitant infections Urinary tract infection Soft tissue and wound infection Catheter-related infection Intra-abdominal infection Invasive fungal infection Initial bacteraemia Microbiology Initial airway MDR Acb complex isolate with SB resistance Initial airway MDR Acb complex isolate without SB susceptibility Airway eradication of MDR Acb complex without relapsec SB or AMP/SB treatment Duration (days) Combination therapy With carbapenems With cephalosporins With fluoroquinolones With aminoglycosides With piperacillin With aztreonam Delayed treatment Concurrent use of glycopeptides

Clinical failurea

Clinical resolutiona

Univariate

(n ⫽ 56)

(n ⫽ 117)

p

68.5 (14.3) 39 (69.6)

68.3 (15.4) 86 (73.5)

0.988 0.596

3 5 15 4 22 10 19 9

(5.4) (8.9) (26.8) (7.1) (39.3) (17.9) (33.9) (16.1)

12 13 30 11 40 16 24 29

(10.3) (11.1) (25.6) (9.4) (34.2) (13.7) (20.5) (24.8)

0.391 0.660 0.872 0.776 0.513 0.471 0.056 0.195

19.4 51 50 36 18 14 13 5 1 23 13 3 5 2 1 5

(5.9) (91.1) (89.3) (64.3) (32.1) (25.0) (23.2) (8.9) (1.8) (41.1) (23.2) (5.4) (8.9) (3.6) (1.8) (8.9)

16.9 92 84 85 36 34 14 8 5 48 21 15 10 6 4 6

(6.7) (78.6) (71.8) (72.6) (30.8) (29.1) (12.0) (6.8) (4.3) (41.0) (17.9) (12.8) (8.5) (5.1) (3.4) (5.1)

0.018 0.043 0.010 0.262 0.855 0.577 0.056 0.759 0.665 0.995 0.415 0.132 1.000 1.000 1.000 0.338

13 (23.2)

31 (26.5)

0.643

33 (58.9)

75 (64.1)

0.511

30 (75.0)

70 (66.7)

0.332

13.6 44 38 5 2 0 1 0 11 20

(6.6) (78.6) (67.9) (8.9) (3.6) (0.0) (1.8) (0.0) (19.6) (35.7)

17.0 94 81 10 4 3 1 1 37 38

(8.7) (80.3) (69.2) (8.5) (3.4) (2.6) (0.9) (0.9) (31.6) (32.5)

0.001 0.786 0.855 1.000 1.000 0.552 0.544 1.000 0.100 0.673

Multivariateb p

Adjusted OR (95% CI)

0.014

2.778 (1.226–6.294)

0.224 0.217 0.039

1.037 (0.978–1.100) 1.992 (0.667–5.994) 2.855 (1.055–7.731)

0.063

2.515 (0.950–6.661)

0.020

0.933 (0.880–0.989)

OR, odd ratio; CI, confidence interval; APACHE II, Acute Physiology and Chronic Health Evaluation II; MRSA, methicillin-resistant Staphylococcus aureus. aCategorical data are shown as number (%) of subjects; continuous data are shown as mean (SD). bAll variables included in the final multivariable model are shown. c145 patients had available data and 105 had clinical resolution.

Discussion Compared to previous studies of sulbactam or ampicillin/sulbactam treatment for pneumonia involving MDRAB [5–7,11], our study had a larger number of cases.

Although Corbella et al. reported a high clinical response rate (93%) to sulbactam treatment for nonlife-threatening nosocomial infections caused by MDRAB [11], some studies did not support monotherapy of sulbactam or ampicillin/sulbactam for

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H.-S. Lin et al. Table III. Comparison between the episodes with sulbactam (SB)-susceptible multidrug-resistant Acinetobacter calcoaceticus–Acinetobacter baumannii complex (MDR Acb complex) as initial airway isolates and the episodes with SB-resistant MDR Acb complex isolates.

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Variables Demographic parameters Age (years) Male gender Concomitant diseases Hepatic dysfunction Requirement for dialysis Chronic pulmonary disease Cardiac disease Diabetes mellitus Immune compromise Malignancy Surgery Clinical conditions APACHE II score Ventilator use Bilateral pneumonia Polymicrobial pneumonia With MRSA With Pseudomonas aeruginosa With Stenotrophomonas maltophilia With Klebsiella spp. With Escherichia coli Multisite infection With urinary tract infection With soft tissue and wound infection With catheter-related infection With intra-abdominal infection With invasive fungal infection Initial bacteraemia SB or AMP/SB treatment Duration Combination therapy With carbapenems With cephalosporins With fluoroquinolones Delayed treatment Outcomes Airway eradication of MDR Acb complex without relapseb Clinical resolution of pneumonia 30 day mortality

SB-susceptible groupa

SB-resistant groupa

(n ⫽ 65)

(n ⫽ 44)

p

65.4 (16.8) 33 (75.0)

0.606 0.892

67.7 (14.3) 48 (73.8) 7 8 14 7 23 6 12 9

(10.8) (12.3) (21.5) (10.8) (35.4) (9.2) (18.5) (13.8)

3 3 10 2 16 8 13 12

(6.8) (6.8) (22.7) (4.5) (36.4) (18.2) (29.5) (27.3)

0.737 0.520 0.883 0.308 0.917 0.171 0.177 0.081

17.6 54 51 46 18 21 12 4 3 25 17 4 4 3 0 3

(6.0) (83.1) (78.5) (70.8) (27.7) (32.3) (18.5) (6.2) (4.6) (38.5) (26.2) (6.2) (6.2) (4.6) (0.0) (4.6)

17.6 35 30 34 15 10 10 3 1 20 7 3 6 4 3 4

(7.2) (79.5) (68.2) (77.3) (34.1) (23.9) (23.9) (6.8) (2.3) (45.5) (15.9) (6.8) (13.6) (9.1) (6.8) (9.1)

0.962 0.640 0.228 0.451 0.476 0.277 0.586 1.000 0.646 0.467 0.205 1.000 0.310 0.437 0.063 0.437

13.6 43 33 6 5 18

(6.0) (66.2) (50.8) (9.2) (7.7) (27.7)

19.3 41 39 4 0 11

(11.4) (93.2) (88.6) (9.1) (0.0) (25.0)

0.002 0.001 ⬍ 0.001 1.000 0.080 0.755

43 (84.3)

24 (58.5)

0.006

42 (64.6) 24 (36.9)

31 (70.5) 10 (22.7)

0.525 0.117

APACHE II, Acute Physiology and Chronic Health Evaluation II; MRSA, methicillin-resistant Staphylococcus aureus; AMP/SB, ampicillin/sulbactam. aCategorical data are shown as number (%) of subjects; continuous data are shown as mean (SD). b92 patients had available data and 51 were in the susceptible group.

serious MDRAB infections [7]. Levin et al. reported a cure rate of 67.5% in 40 cases with MDRAB infections treated with ampicillin/sulbactam. Of the 40 cases, 12 had MDRAB pneumonia, with a clinical response rate of 75%. The patients with successful outcomes had a significantly lower APACHE II score than those with treatment failure (median 12.4 vs 19.6; p ⫽ 0.015) [7].

Other studies suggested that a high-dose regimen might be an alternative choice [5]. Betrosian et al. reported 27 cases with late-onset ventilator-associated pneumonia (VAP) caused by MDRAB, who were treated with high-dose ampicillin/sulbactam (daily dose of 18 g/9 g or 24 g/12 g). The mean treatment duration was 8 days and the median APACHE II score was 15. The overall clinical improvement rate

Sulbactam for pneumonia involving MDR Acb complex

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Table IV. Comparison between sulbactam (SB) or ampicillin/sulbactam (AMP/SB) monotherapy and combination therapy for the episodes with SB-susceptible multidrug-resistant Acinetobacter calcoaceticus– Acinetobacter baumannii complex (MDR Acb complex) as the initial airway isolates.

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Variables Demographic parameters Age (years) Male gender Concomitant diseases Hepatic dysfunction Requirement for dialysis Chronic pulmonary disease Cardiac disease Diabetes mellitus Immune compromise Malignancy Surgery Clinical conditions APACHE II score Ventilator use Bilateral pneumonia Polymicrobial pneumonia With MRSA With Pseudomonas aeruginosa With Stenotrophomonas maltophilia With Klebsiella spp. With Escherichia coli Multisite infection With urinary tract infection With soft tissue and wound infection With catheter-related infection With intra-abdominal infection Initial bacteraemia SB or AMP/SB treatment Duration Delayed treatment Outcomes Airway eradication of MDR Acb complex without relapseb Clinical resolution of pneumonia 30 day mortality

Monotherapya

Combinationa

(n ⫽ 22)

(n ⫽ 43)

p

66.9 (14.3) 19 (86.4)

68.1 (14.4) 29 (67.4)

0.751 0.100

2 3 7 5 6 0 5 0

(9.1) (13.6) (31.8) (22.7) (27.3) (0.0) (22.7) (0.0)

5 5 7 2 17 6 7 9

(11.6) (11.6) (16.3) (4.7) (39.5) (14.0) (16.3) (20.9)

1.000 1.000 0.204 0.039 0.328 0.088 0.521 0.023

16.4 20 18 17 9 6 5 0 1 9 6 1 2 0 1

(5.8) (90.9) (81.8) (77.3) (40.9) (27.3) (22.7) (0.0) (4.5) (40.9) (27.3) (4.5) (9.1) (0.0) (4.5)

18.2 34 33 29 9 15 7 4 2 16 11 3 2 3 2

(6.1) (79.1) (76.7) (67.4) (20.9) (34.9) (16.3) (9.3) (4.7) (37.2) (25.6) (7.0) (4.7) (7.0) (4.7)

0.255 0.308 0.757 0.410 0.089 0.535 0.521 0.291 1.000 0.772 0.883 1.000 0.599 0.545 1.000

12.5 (4.7) 5 (22.7)

14.2 (6.5) 13 (30.2)

0.292 0.522

17 (89.5)

26 (81.3)

0.694

14 (63.6) 8 (36.4)

28 (65.1) 16 (37.2)

0.906 0.947

APACHE II, Acute Physiology and Chronic Health Evaluation II; MRSA, methicillin-resistant Staphylococcus aureus. aCategorical data are shown as number (%) of subjects; continuous data are shown as mean (SD). b51 patients had available data and 19 were in the monotherapy group.

was 66.7%. There was no significant difference in microbiological and clinical outcomes in patients receiving these two regimens [5]. To the best of our knowledge, this study is the largest case series showing the clinical efficacy of a standard-dose therapeutic regimen of sulbactam or ampicillin/sulbactam for pneumonia involving MDR Acb complex in critically ill patients. The 30 day mortality rate of 31.2% and clinical resolution rate of 67.6% in this study were similar to those in previous reports [5,7].We calculated a ‘modified APACHE II score’ for all patients. Low scores may have been underestimated and the high scores of critically ill patients may have been relatively overestimated.

Even with possible overestimation, the APACHE II score still was not an independent risk factor for clinical failure, but other parameters for severe pneumonia, such as bilateral pneumonia, were. Short duration of treatment was independently associated with clinical failure, but the difference in treatment duration between cases with clinical failure and clinical response was small (13.6 days vs 17 days). Short treatment duration may be a risk factor for clinical failure. On the other hand, fewer days of sulbactam use in patients with clinical failure may reflect the fact that these cases did not respond to treatment or died and, as a consequence, treatment was stopped earlier.

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For patients with sulbactam-susceptible MDR Acb complex, combination therapy seemed not to be superior to monotherapy with regard to microbiological and clinical outcomes. For patients with sulbactam-resistant MDR Acb complex, the overall clinical outcomes did not differ from those with sulbactam-susceptible isolates despite a significantly lower microbiological eradication rate. Almost 90% of the patients with sulbactam-resistant isolates had combination therapy with carbapenems, which may be why resistance or non-susceptibility to sulbactam was not an independent predictor for clinical failure in multivariate analyses. As only a few patients with sulbactam-resistant isolates had monotherapy with sulbactam or ampicillin/sulbactam, we could not evaluate the effect of monotherapy on infections with sulbactam-resistant strains. In earlier in vitro and animal studies [14,15], the synergistic effect against MDRAB suggested that combination of sulbactam and carbapenems could be a potential treatment option for MDRAB infections, but clinical data are scarce. Lee et al. reported favourable clinical outcomes with carbapenem/sulbactam combination therapy in four critically ill patients with bacteraemia caused by MDRAB isolates resistant to commonly available antibiotics, including carbapenems and sulbactam. The in vitro study using isolates from these patients showed that the combination had a synergistic effect with enhanced antibacterial activity [17]. Our study is the largest case series of sulbactam/carbapenem combination therapy for pneumonia involving MDR Acb complex, especially the sulbactam-resistant strains, which have increased in recent years [24–26]. Because carbapenems were the most frequently coadministered agents in our study, it is difficult to evaluate the efficacy of sulbactam combined with other antibiotics for pneumonia involving MDR Acb complex. In an early study, Wood et al. reported 14 patients with Acinetobacter VAP treated with ampicillin/sulbactam, including two with imipenem-susceptible Acinetobacter isolates, and 12 with isolates resistant or intermediate to imipenem. These ampicillin/sulbactam-treated patients had a clinical success rate of 93%, similar to that of 63 patients receiving imipenem for VAP with imipenem-susceptible Acinetobacter isolates. The ampicillin/sulbactam-treated group had combination therapy with amikacin more often but clinical outcomes did not differ between patients with monotherapy and combination therapy, either within each treatment group or in the entire population [6]. There are some limitations in this study. First, the respiratory specimens were taken in clinical practice, and they may not have been from deep in the lungs. Growth of aetiological pathogens was assessed

semi-quantitatively if the specimens were qualified for culture. We cannot absolutely distinguish airway MDR Acb complex infections from colonization. However, our definition for pneumonia was practical, and our conclusion, based on clinically relevant data and management, could provide important information for clinical practice. Secondly, polymicrobial pneumonia and concomitant infections were common, and the clinical impact of other aetiological pathogens or extrapulmonary infections was not evaluated comprehensively. Thirdly, we studied MDR Acb complex rather than MDRAB. Although previous studies reported that about 90% of Acb complex with multidrug or carbapenem resistance was the genomic specie of A. baumannii, comparison with studies on A. baumannii isolates is not straightforward [27]. Finally, during the period between 2004 and 2007, colistin and tigecycline were not available in our hospital. After 2007, most cases with MDR Acb complex infection treated with sulbactam also received colistin or tigecycline, and it is difficult to define the effect of each drug with these cases. We studied the cases from the period in which sulbactam was the only choice for MDR Acb complex in our hospital to evaluate the effect of sulbactam; however, the data are now rather old. In conclusion, sulbactam could be a treatment option for pneumonia involving MDR Acb complex, and combination therapy with carbapenems could be considered for sulbactam-resistant cases. To establish the optimal regimens for pneumonia involving MDR Acb complex, it is essential to conduct more studies for comparison of sulbactam/carbapenem combination therapy with other combination regimens or monotherapy, such as high-dose sulbactam, colistin or tigecycline. Declaration of interest: There were no conflicts of interest. No funding was received.

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