International Journal of Antimicrobial Agents 43 (2014) 378–382
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short Communication
Colistin-based treatment for extensively drug-resistant Acinetobacter baumannii pneumonia夽 Thana Khawcharoenporn a,∗ , Nattapol Pruetpongpun a , Pimsiri Tiamsak b , Sasinuch Rutchanawech a , Linda M. Mundy c , Anucha Apisarnthanarak a a
Division of Infectious Diseases, Faculty of Medicine, Thammasat University, Pathumthani, Thailand Thammasat University, Pathumthani, Thailand c GlaxoSmithKline, Collegeville, PA, USA b
a r t i c l e
i n f o
Article history: Received 16 October 2013 Accepted 22 January 2014 Keywords: Extensively drug-resistant Acinetobacter baumannii Pneumonia Outcomes Treatment Colistin
a b s t r a c t Data for treatment and outcomes of extensively drug-resistant Acinetobacter baumannii (XDR-AB) pneumonia are limited. A retrospective cohort study of 236 adult patients with XDR-AB pneumonia was conducted between January 2009 and December 2012. The median age of subjects was 70 years (range 17–95 years), 53% were male, 55% had ventilator-associated pneumonia and 42% had been admitted to the intensive care unit. All XDR-AB isolates were susceptible only to tigecycline and colistin; 52 (22%) of the 236 subjects did not receive an agent active against XDR-AB, with an associated 28-day survival of 0%. Colistin-based two-drug combination treatment was prescribed to 166 subjects (70%); regimens included (i) colistin and high-dose sulbactam (n = 93); (ii) colistin and tigecycline (n = 43); and (iii) colistin and high-dose prolonged infusion of a carbapenem (n = 30). The 28-day survival rate and mean length of hospital stay were not statistically different between these three regimens (65%, 53% and 60% and 39, 39 and 38 days, respectively). Predictors of mortality included Acute Physiology and Chronic Health Evaluation (APACHE) II score [adjusted odds ratio (aOR) = 1.11; P < 0.001 for each point increase], duration from infection onset to receipt of active regimen (aOR = 1.01; P = 0.002 for each hour delay), underlying malignancy (aOR = 3.46; P = 0.01) and chronic kidney disease (aOR = 2.85; P = 0.03). These findings suggest that the three colistin-based two-drug combination regimens may be treatment options for XDR-AB pneumonia. Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
1. Introduction Extensively drug-resistant Acinetobacter baumannii (XDR-AB) has emerged globally as a pathogen causing healthcare-associated pneumonia [1]. Previous studies have reported mortality rates of up to 65% with XDR-AB pneumonia in a variety of treated populations [2–5]. Treatment of XDR-AB pneumonia is challenging as clinical isolates are usually susceptible only to colistin [4,5]. Colistin monotherapy for pneumonia has been associated with 38–57% clinical response rates and 45–69% microbiological response rates [2–4]. A case series demonstrated a 57% clinical response rate and
86% microbiological response rate when nebulised colistin was used [6]. These poor response rates have contributed to the practice of colistin use in combination with other available antibiotics with potential synergy such as tigecycline, rifampicin, sulbactam and carbapenems [7–9]. Combined colistin and rifampicin was used successfully in 57% of patients, whilst the clinical response rates of colistin combined with the other antibiotics have not been reported for XDR-AB pneumonia [4]. This study was conducted to assess the treatment patterns and outcomes of XDR-AB pneumonia defined as either hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). 2. Methods
夽 Parts of this study were presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10–13 September 2013, Denver, CO [poster K-175]. ∗ Corresponding author. Tel.: +66 2 926 9794; fax: +66 2 926 9793. E-mail address: [email protected] (T. Khawcharoenporn).
2.1. Study setting The study was conducted at Thammasat University Hospital (TUH) (Pathumthani, Thailand), which serves patient populations
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.016 0924-8579/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
T. Khawcharoenporn et al. / International Journal of Antimicrobial Agents 43 (2014) 378–382
from Pathumthani and nearby provinces in central Thailand. The study population included adult patients diagnosed with XDR-AB pneumonia from 1 January 2009 to 31 December 2012 at TUH. This study was approved by the Faculty of Medicine, Thammasat University Ethics Committee. 2.2. Study design and case definitions Eligible patients were identified by review of expectorated, induced or suctioned sputum or bronchoalveolar lavage culture results during the study period. Cases with mixed isolated microorganisms were excluded. XDR-AB was resistant to most classes of antibiotics except for two or less classes. Antibiotic susceptibility testing was performed using the Kirby–Bauer disk diffusion method with interpretation according to Clinical and Laboratory Standards Institute (CLSI) criteria. The disk diffusion breakpoints for tigecycline were ≥16 mm and ≤12 mm for susceptible and resistant, respectively, as previously reported [10]. The diagnosis of pneumonia was based on radiographic evidence of a new or progressive infiltrate, along with clinical findings of new onset of fever, purulent sputum, leukocytosis or decline in oxygenation [11]. HAP was defined as pneumonia occurring ≥48 h after hospital admission, whilst VAP was a type of HAP that developed more than 48–72 h after endotracheal intubation [11]. In this study, subjects were categorised by HAP versus VAP at the onset of infection. Subjects who died within 48 h after the onset of infection (n = 10) were excluded. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured at the onset of infection. 2.3. Antibiotic regimens for extensively drug-resistant Acinetobacter baumannii pneumonia Antibiotic regimens prescribed after the diagnosis of XDR-AB pneumonia were at the discretion of treating physicians. An XDRAB-active regimen was a regimen that contained at least one antibiotic to which A. baumannii was susceptible. The antibiotics and dosage for normal renal function prescribed at TUH for XDR-AB pneumonia were standardised based on the protocol of the Division of Infectious Diseases, including: (i) inhaled colistin (40 mg of colistin diluted in 2 mL of sterile normal saline delivered via a mask or ventilator nebuliser every 6 h); (ii) intravenous (i.v.) colistin (300 mg loading followed by 150 mg i.v. every 12 h); (iii) tigecycline (100 mg i.v. as a loading dose followed by 50 mg i.v. every 12 h); (iv) high-dose sulbactam (6 g/day of i.v. sulbactam in the form of cefoperazone/sulbactam or ampicillin/sulbactam); and (v) high-dose prolonged i.v. infusion of carbapenems (imipenem 1 g i.v. over 3 h every 8 h, meropenem 1 g i.v. over 3 h every 8 h or doripenem 1 g i.v. over 4 h every 8 h). The dosage of colistin was adjusted according to a previous colistin dosing study [12]. The formulation of colistin was colistin methanesulfonate (1 mg equals 12 500 international units). The duration of all treatment regimens was 14 days. 2.4. Outcomes measurement Evaluation of efficacy was based on 28-day survival. Other outcomes of interest included microbiological cure at the end of therapy, defined as a follow-up sputum or bronchoalveolar lavage specimen without growth of XDR-AB at 14 days, and length of hospital stay. Adverse drug reactions were assessed as clinical signs and symptoms and via laboratory findings. Acute kidney injury (AKI) was defined according to the Kidney Disease—Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. Evidence of neurotoxicity from colistin was obtained from the review of physicians’ notes.
379
2.5. Statistical analysis All analyses were performed using SPSS v.15.0 (SPSS Inc., Chicago, IL). Categorical variables were compared using the Pearson’s 2 test or Fisher’s exact test as appropriate. Continuous variables were compared using the Mann–Whitney U-test. P-values of
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short Communication
Colistin-based treatment for extensively drug-resistant Acinetobacter baumannii pneumonia夽 Thana Khawcharoenporn a,∗ , Nattapol Pruetpongpun a , Pimsiri Tiamsak b , Sasinuch Rutchanawech a , Linda M. Mundy c , Anucha Apisarnthanarak a a
Division of Infectious Diseases, Faculty of Medicine, Thammasat University, Pathumthani, Thailand Thammasat University, Pathumthani, Thailand c GlaxoSmithKline, Collegeville, PA, USA b
a r t i c l e
i n f o
Article history: Received 16 October 2013 Accepted 22 January 2014 Keywords: Extensively drug-resistant Acinetobacter baumannii Pneumonia Outcomes Treatment Colistin
a b s t r a c t Data for treatment and outcomes of extensively drug-resistant Acinetobacter baumannii (XDR-AB) pneumonia are limited. A retrospective cohort study of 236 adult patients with XDR-AB pneumonia was conducted between January 2009 and December 2012. The median age of subjects was 70 years (range 17–95 years), 53% were male, 55% had ventilator-associated pneumonia and 42% had been admitted to the intensive care unit. All XDR-AB isolates were susceptible only to tigecycline and colistin; 52 (22%) of the 236 subjects did not receive an agent active against XDR-AB, with an associated 28-day survival of 0%. Colistin-based two-drug combination treatment was prescribed to 166 subjects (70%); regimens included (i) colistin and high-dose sulbactam (n = 93); (ii) colistin and tigecycline (n = 43); and (iii) colistin and high-dose prolonged infusion of a carbapenem (n = 30). The 28-day survival rate and mean length of hospital stay were not statistically different between these three regimens (65%, 53% and 60% and 39, 39 and 38 days, respectively). Predictors of mortality included Acute Physiology and Chronic Health Evaluation (APACHE) II score [adjusted odds ratio (aOR) = 1.11; P < 0.001 for each point increase], duration from infection onset to receipt of active regimen (aOR = 1.01; P = 0.002 for each hour delay), underlying malignancy (aOR = 3.46; P = 0.01) and chronic kidney disease (aOR = 2.85; P = 0.03). These findings suggest that the three colistin-based two-drug combination regimens may be treatment options for XDR-AB pneumonia. Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
1. Introduction Extensively drug-resistant Acinetobacter baumannii (XDR-AB) has emerged globally as a pathogen causing healthcare-associated pneumonia [1]. Previous studies have reported mortality rates of up to 65% with XDR-AB pneumonia in a variety of treated populations [2–5]. Treatment of XDR-AB pneumonia is challenging as clinical isolates are usually susceptible only to colistin [4,5]. Colistin monotherapy for pneumonia has been associated with 38–57% clinical response rates and 45–69% microbiological response rates [2–4]. A case series demonstrated a 57% clinical response rate and
86% microbiological response rate when nebulised colistin was used [6]. These poor response rates have contributed to the practice of colistin use in combination with other available antibiotics with potential synergy such as tigecycline, rifampicin, sulbactam and carbapenems [7–9]. Combined colistin and rifampicin was used successfully in 57% of patients, whilst the clinical response rates of colistin combined with the other antibiotics have not been reported for XDR-AB pneumonia [4]. This study was conducted to assess the treatment patterns and outcomes of XDR-AB pneumonia defined as either hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). 2. Methods
夽 Parts of this study were presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10–13 September 2013, Denver, CO [poster K-175]. ∗ Corresponding author. Tel.: +66 2 926 9794; fax: +66 2 926 9793. E-mail address: [email protected] (T. Khawcharoenporn).
2.1. Study setting The study was conducted at Thammasat University Hospital (TUH) (Pathumthani, Thailand), which serves patient populations
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.016 0924-8579/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
T. Khawcharoenporn et al. / International Journal of Antimicrobial Agents 43 (2014) 378–382
from Pathumthani and nearby provinces in central Thailand. The study population included adult patients diagnosed with XDR-AB pneumonia from 1 January 2009 to 31 December 2012 at TUH. This study was approved by the Faculty of Medicine, Thammasat University Ethics Committee. 2.2. Study design and case definitions Eligible patients were identified by review of expectorated, induced or suctioned sputum or bronchoalveolar lavage culture results during the study period. Cases with mixed isolated microorganisms were excluded. XDR-AB was resistant to most classes of antibiotics except for two or less classes. Antibiotic susceptibility testing was performed using the Kirby–Bauer disk diffusion method with interpretation according to Clinical and Laboratory Standards Institute (CLSI) criteria. The disk diffusion breakpoints for tigecycline were ≥16 mm and ≤12 mm for susceptible and resistant, respectively, as previously reported [10]. The diagnosis of pneumonia was based on radiographic evidence of a new or progressive infiltrate, along with clinical findings of new onset of fever, purulent sputum, leukocytosis or decline in oxygenation [11]. HAP was defined as pneumonia occurring ≥48 h after hospital admission, whilst VAP was a type of HAP that developed more than 48–72 h after endotracheal intubation [11]. In this study, subjects were categorised by HAP versus VAP at the onset of infection. Subjects who died within 48 h after the onset of infection (n = 10) were excluded. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured at the onset of infection. 2.3. Antibiotic regimens for extensively drug-resistant Acinetobacter baumannii pneumonia Antibiotic regimens prescribed after the diagnosis of XDR-AB pneumonia were at the discretion of treating physicians. An XDRAB-active regimen was a regimen that contained at least one antibiotic to which A. baumannii was susceptible. The antibiotics and dosage for normal renal function prescribed at TUH for XDR-AB pneumonia were standardised based on the protocol of the Division of Infectious Diseases, including: (i) inhaled colistin (40 mg of colistin diluted in 2 mL of sterile normal saline delivered via a mask or ventilator nebuliser every 6 h); (ii) intravenous (i.v.) colistin (300 mg loading followed by 150 mg i.v. every 12 h); (iii) tigecycline (100 mg i.v. as a loading dose followed by 50 mg i.v. every 12 h); (iv) high-dose sulbactam (6 g/day of i.v. sulbactam in the form of cefoperazone/sulbactam or ampicillin/sulbactam); and (v) high-dose prolonged i.v. infusion of carbapenems (imipenem 1 g i.v. over 3 h every 8 h, meropenem 1 g i.v. over 3 h every 8 h or doripenem 1 g i.v. over 4 h every 8 h). The dosage of colistin was adjusted according to a previous colistin dosing study [12]. The formulation of colistin was colistin methanesulfonate (1 mg equals 12 500 international units). The duration of all treatment regimens was 14 days. 2.4. Outcomes measurement Evaluation of efficacy was based on 28-day survival. Other outcomes of interest included microbiological cure at the end of therapy, defined as a follow-up sputum or bronchoalveolar lavage specimen without growth of XDR-AB at 14 days, and length of hospital stay. Adverse drug reactions were assessed as clinical signs and symptoms and via laboratory findings. Acute kidney injury (AKI) was defined according to the Kidney Disease—Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. Evidence of neurotoxicity from colistin was obtained from the review of physicians’ notes.
379
2.5. Statistical analysis All analyses were performed using SPSS v.15.0 (SPSS Inc., Chicago, IL). Categorical variables were compared using the Pearson’s 2 test or Fisher’s exact test as appropriate. Continuous variables were compared using the Mann–Whitney U-test. P-values of
