Carbapenem-resistant Acinetobacter baumannii in patients with burn injury: A systematic review and meta-analysis

burns 45 (2019) 1495 –1508

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Review

Carbapenem-resistant Acinetobacter baumannii in patients with burn injury: A systematic review and meta-analysis William Gustavo Lima a,c, *, Geisa Cristina Silva Alves b, Cristina Sanches b , Simone Odília Antunes Fernandes c , Magna Cristina de Paiva a a

Laboratório de Diagnóstico Laboratorial e Microbiologia Clínica, Campus Centro-Oeste/Dona Lindu, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil b Laboratório de Farmácia Hospitalar, Campus Centro-Oeste/Dona Lindu, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil c Laboratório de Radioisótopos, Departamento de Análises Clínicas, Faculdade de farmácia, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

article info

abstract

Article history:

Purpose: Inthis study, we aimed reviewed the data about the patterns of antimicrobial susceptibility

Accepted 3 July 2019

and resistance determinants among carbapenem-resistant Acinetobacter baumannii (CRAB) from patients with burn injury. Methods: A systematic review was conducted using the PRISMA statement in PUBMED/ MEDLINE, Scopus, Scientific Electronic Library Online (SciELO), Biblioteca Virtual de Saúde (BVS)

Keywords:

and Cochrane Library. The data referring to enzymatic resistance mechanisms were

Acinetobacter baumannii

evaluated by meta-analyses according to random effect.

Multi-drug resistance

Results: 17 articles that evaluated 1226 CRAB recovered from patients with burn injury were

Healthcare-associated infections

included in study. The majority of studies are from Iran (12/17; 70.6%), published in 2016 (6/17;

Burn units

35.3%) and showed prospective design (15/17; 88.2%). The samples were obtained mainly

Minocycline

from burn wounds (14/17; 82.3%) and more than half of the studies did not identify if the

Colistin

isolates originated from infected or colonized patients (10/17; 58.8%). Second the metaanalyses, OXA-type carbapenemase was the main mechanism involved in low susceptibility to carbapenems (53.2%; 95% CI = 60, 80.0%, I2 = 86.0%), followed by metallo-b-lactamases (MBL) (30.2%; 95% CI = 11, 42.0%, I2 = 93.0%), and Klebsiella pneumoniae carbapenemase (KPC) (16.6%; 95% CI = 5, 63.0%, I2 = 88.0%). The majority of strains harbored blaOXA-23-like (12/17; 70.6%) or blaOXA-24/40-like (12/17; 35.3%) genes. The studies included showed that minocycline (69.5%) and colistin (99.9%) susceptibility remains high and is not impacted by carbapenem resistance in these isolates.

* Corresponding author at: Laboratório de Diagnóstico Laboratorial e Microbiologia Clínica, Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Rua Sebastião Gonçalves Coelho, 400. Divinópolis, Minas Gerais, 35501-293, Brazil. E-mail address: [email protected] (W.G. Lima). https://doi.org/10.1016/j.burns.2019.07.006 0305-4179/Published by Elsevier Ltd.

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Conclusions: The results summarized in this review indicate the importance of a high-quality surveillance program to design suitable and effective interventions to control CRAB infection in burn units worldwide. Published by Elsevier Ltd.

Contents 1. 2.

3.

4. 5.

1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search strategies . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion and exclusion criteria . . . . . . . . 2.2. 2.3. Study selection . . . . . . . . . . . . . . . . . . . . . . Data analysis . . . . . . . . . . . . . . . . . . . . . . . . 2.4. 2.5. Quality assessment . . . . . . . . . . . . . . . . . . . Additional analyses . . . . . . . . . . . . . . . . . . . 2.6. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Literature search and quality of studies . . 3.1. Main characteristics of included studies . 3.2. Antimicrobial resistance profile . . . . . . . . 3.3. Mechanisms of carbapenem resistance . . 3.4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Acinetobacter genus comprises many closely related species, including those belonging to the Acinetobacter calcoaceticusbaumannii complex (e.g., A. baumannii, A. nosocomialis, A. pittii, and A. calcoaceticus), which are frequently misidentified using the traditional techniques employed in clinical microbiology [1]. A. baumannii, a ubiquitous, non-glucose-fermenting, Gram-negative, oxidase negative, aerobic, pleomorphic, and non-motile coccobacillus (typically 1.0–1.5 mm by 1.5– 2.5 mm in size), is recognized as the most clinically relevant species in this microbial complex, as it has been frequently identified in healthcare-associated infections [2,3]. Initially described as an opportunistic bacterium of low pathogenicity, A. baumannii has emerged as an important pathogen in critical care settings during the last decade, being involved in diseases such as pneumonia (mechanical ventilator-associated pneumonia in particular), osteomyelitis, peritonitis, endocarditis, septicemia, meningitis, and wound, skin, soft tissue, urinary tract, ear, and eye infections [4,5]. Herein, several studies have showed that patients with burn injury are particularly susceptible to A. baumannii infection during hospitalization. This bacterium has been reported to be the second most common cause of nosocomial infections in patients with burn injury [5,6]. Furthermore, outbreaks caused by A. baumannii are common in intensive-care (ICU) and burn units [7].

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Carbapenem antibiotics such as imipenem, meropenem, doripenem, but not ertapenem, are considered last-resort treatments for multi-drug resistant (MDR) A. baumannii infection [5,8]. However, since 1991, when the first carbapenem-resistant A. baumannii (CRAB) was recognized, a considerable increase in the number of these strains has been documented worldwide [9,10]. In Greece, for example, imipenem resistance rates increased from 90.3% in 2010 to 94.5% in 2015, while meropenem resistance rates increased from 82.6% in 2010 to 94.8% in 2015 [11]. Reddy et al. [12] showed that in North American hospitals, carbapenem resistance rates in A. baumannii have also risen, ranging from 1.0% in 2003 to 58.0% in 2008. The efficacy of carbapenems may be drastically compromised in A. baumannii by overexpression of efflux pumps (e.g., AdeABC) [13], penicillin-binding protein alterations [14], loss of outer membrane protein (e.g., CarO) [15], and to the ability of this bacterium to produce carbapenem-hydrolysing b-lactamases (carbapenemases). To date, three types of carbapenemases have been reported in A. baumannii, namely Ambler class A b-lactamases (e.g., GES-14 and KPC-1), Ambler class B metallo-b-lactamases (e.g., IMP, VIM, SIM-1, and NDM) and Ambler class D oxacillinases (OXAs) [16]. According to reports from different countries, OXA-type is the main determinant of resistance to carbapenems in A. baumannii. It has been described in seven different families in this species: intrinsic, chromosomally located and also found in plasmid OXA-51-like [17]; and the acquired OXA-23-like, OXA-40-like (formally

burns 45 (2019) 1495 –1508

OXA-24-like), OXA-48-like, OXA-58-like, OXA-143-like, and OXA-235-like [18,19]. The presence of insertion sequences (IS) immediately upstream of blaOXA genes is known to induce the overexpression of OXA-51, OXA-23, or OXA-58, and to generate carbapenem resistance at a high level in A. baumannii [17]. In burn units, it is estimated that more than 75.0% of deaths are associated with infections, surpassing the mortality rates of osmotic shock and hypovolemia [20]. Although burn wounds are sterile immediately after injury, they are with frequency colonized by bacteria present in burn units, in particular with CRAB [21,22]. To design suitable and effective interventions to control CRAB infection in burn units worldwide, it is important to understand the current status of resistance to carbapenems in patients and identify gaps in our knowledge. In this context, we reviewed the data in reference to patterns of antimicrobial susceptibility and resistance determinants among CRAB infections in patients with burn injury, aiming to determine changing trends in A. baumannii populations and to provide helpful information to better direct clinical practices.

2.

Methods

A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23]. In order the evaluate the susceptibility patterns and the main antimicrobial resistance determinants of CRAB in patients with burn injury, we used the strategy PEOS, as follows: “Population”, patients of both sexes and all age ranges; “Exposition”, critically burns patients; “Outcomes”, susceptibility patterns and antimicrobial resistance determinants of CRAB isolated from patients; “Study design”, Cross-section analytical studies or prospective/retrospective cohorts.

2.1.

studies presented at scientific meetings or published in scientific journals that did not present original material were excluded. Additional exclusion criteria applied in selection of studies were: (i) studies with only susceptibility profiles or antimicrobial resistance determinants; (ii) epidemiological surveillance studies that included other microorganisms in addition to A. baumannii and did not specifically identify the results for these microorganisms; (iii) works that did not identify the Acinetobacter spp. isolates at the species level. Publications in English, Spanish, French, Italian, or Portuguese were included, with no restriction on publication date.

2.3.

Study selection

For the study selection, two independent investigators (W.G.L. and G.C.S.A.) identified and removed all duplicate records [25]. Titles, abstracts, and keywords were analysed to identify relevant studies in accordance with the inclusion criteria. Finally, the articles pre-selected were subjected to a full text evaluation in order to assess whether they should be included in the study. Any discrepancy was resolved by discussion with a third investigator (M.C.P.) to reach a consensus regarding inclusion or exclusion in the study. Kappa coefficient was used to analyse the degree of agreement between the two evaluators in this step. This test was performed with 95% confidence intervals [26].

2.4.

Data analysis

All the data of interest were summarized in tables for further critical analysis and interpretation. For the antimicrobial resistance data, the median resistance (MR) and interquartile range (IQR) of resistance for each antimicrobial tested was calculated from the collected data.

Search strategies 2.5.

A systematic search from PUBMED/MEDLINE, Scopus, Scientific Electronic Library Online (SciELO), Biblioteca Virtual de Saúde (BVS) and Cochrane Library was performed (up to May 7, 2018) using the following Medical Subject Heading (MeSH) terms and key words: (“Acinetobacter baumannii” OR “Acinetobacter” OR “Acinetobacter infections”) AND (“Burn units” OR “Burn Centers” OR “Burns” OR “Burns patients”) AND (“Carbapenem-resistant” OR “Carbapenem-nonsusceptible” OR “Extensively drug-resistant” OR “Pandrug-resistant” OR “Carbapenems” OR “Carbapenem Antibiotics” OR “Imipenem” OR “Imipenem-cilastatin” OR “Doripenem” OR “Meropenem” OR “Ertapenem”). The details of the search strategies for each database are summarized in the Supplementary files. In addition, the reference list of all included studies and relevant reviews regarding this topic were also screened to identify potential eligible studies [24]. Finally, we have used Web of Science to search who cited the included articles, aimed to make that others eligible articles were identified.

2.2.

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Inclusion and exclusion criteria

Studies in humans aimed at assessing the susceptibility patterns and antimicrobial resistance determinants in CRAB isolates from critical patients with burn injury were included in the review. Reviews, notes, emails, editorials, letters, and

Quality assessment

The assessment of risk of bias of studies selected was assessed independently by two researchers (W.G.L. and G.C.S.A.), using the methodological quality score proposed by Downs and Black [27]. This tool is composed of 27 ‘yes’-or-‘no’ questions across five sections (Study quality, External validity, Study bias, Confounding and selection bias, and Power of the study) that allows the evaluation of quality of randomized controlled trials and nonrandomized studies. To this review, 8 items referring to experimental studies were excluded. Studies with more methodological rigor were determined to be those with scores >15 points and classified as >75.0% in the methodological evaluation.

2.6.

Additional analyses

The prevalence profile of enzymatic resistance mechanisms found in the included studies (OXAs, MBLs, and KPC) was evaluated by meta-analyses. Resistant determinant references were grouped in Excel according to: study, year, isolated samples and percentage of isolates according to each resistance mechanism. Next, the data were evaluated for metaanalysis according to random effect, confidence interval 1 (95.0% CI) through RStudio Software, using the meta package and metaprop command.

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3.

Results

3.1.

Literature search and quality of studies

A total of 485 articles were identified in initial research, including 232 on Scopus, 123 on Biblioteca Virtual de Saúde, 120 on PubMed/MEDLINE, 9 on SciELO and 1 on Cochrane Library (Fig. 1). After exclusion of records repeated and selection in accordance with inclusion criteria, 20 relevant studies were included. From these articles, 5 were excluded in accordance with the criteria described in Fig. 1, and 15 that met the eligibility criteria were selected for extraction of variables of interest. The reference lists of included articles were analyses, and 2 new works were also selected, resulting in a total of 17 papers [28–44]. The degree of agreement between two authors was considered substantial second kappa test (0.6150) [26]. With respect to methodological quality, 70.5% (n = 12) articles had scores >15 points with a response rate ratio >75.0%; thus, they were considered to have high methodological quality. The remaining 29.4% (n = 5) were considered to be well-designed studies, but they did not detail the distribution of the main confounding factors, as well as the losses. No studies were excluded due to methodological quality.

3.2.

Main characteristics of included studies

A total of 1226 CRAB isolates obtained from patients with burn injury between August 2003 and May 2015 were analysed in the selected studies (Table 1). All included studies recovered one isolate per patient. Most studies were published in 2016 (6/17; 35.3%) [28,35,39,41,42,44] and 2015 (5/17; 29.4%) [29,34,37,38,43], and the majority were conducted in Iran (12/ 17; 70.6%) [28,29,31–38,43,44], followed by China (3/17; 17.6%) [39,41,42], France (1/17; 5.9%) [40] and Poland (1/17; 5.9%) [30]. Only one study involved at least two healthcare centres (5.9%) [32], and prospective design (15/17; 88.2%) [28,32–38,40–42,44] was more common than retrospective (2/17; 11.8%) [39,43]. The samples were obtained mainly from burn wounds (14/17; 82.3%) [6,18,28,29,32–34,36–39,42–44], blood (6/17; 35.3%) [30,33,39,41–43], body fluids (5/17; 29.4%) [34,39–41,43], and tracheal aspirates (2/17; 11.8%) [34,40]. More than half of the studies did not identify if the isolates originated from infected or colonized patients (10/17; 58.8%) [28–31,33–36,38,39,42,44], 6 studies included only CRAB from infected sites (35.3%) [32,34,37,40,42,43], and one employed isolates from both infected and colonized patients (5.9%) [33]. Among the included studies, 4 different methods for susceptibility testing were used, including disk diffusion (15/17; 88.2%) [28,29, 31–35,38,43,44], E-test (5/17; 33.3%) [32–34,37,43], broth microdilution (4/17; 17.6%) [30,36,38,44], and agar dilution (1/17; 5.9%)

Fig. 1 – Flowchart of the selected articles for the systematic review according to the PRISMA criteria [23,25].

Table 1 – : Summary of studies evaluating the susceptibility profile and resistance determinates of carbapenem-resistant Acinetobacter baumannii (CRAB) isolated from burn patients. Referenceb

Type, setting and region of study

Microbiological aspects of CRABs

Size (CRAB isolates number)a , collect period and origin of samples

Dates of resistance to carbapenems 1

MICs (mg L )

Determinants of resistance (%)

Dates of resistance to others antibiotics Method and criteriac employed

 Prospective  Single center  Rangueil hospital, Toulouse, France  Range age of participants: 20 to 91 years

 6 isolatesf  August 2003–March 2004  Skin, tracheal aspirate and urine.

 IPM: 32  MEM: >64

 Plasmids with blaOXA-58 (100%)

 Disc diffusion assayd and agar dilution techniquee  CLSI, 2003

Mahdian et al. [43]A

 Retrospective  Single center  Shahid Motahari Hospital, Tehran, Iran

 27 isolatesf  2011 Wounds, blood and urine

–

 Disc diffusion assayd and E-test method (POLB and CST)e  CLSI, 2013

Azimi et al. [29]B

 Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran  Range age of participants: 9 months to 72 years

 65 isolatesh  April–July 2013  Wounds

–

 ISAba1 element in blaOXA-51 (100%)  blaOXA-23 (48.1%)  blaOXA-24/40 (3.7%)  blaOXA-23/ blaOXA-24/40 (48.1%)  blaOXA-23 (64.6%)  blaVIM (3.1%)  blaKPC/blaOXA-23 (9,2%)  blaOXA-23/blaVIM (9.2%)

Azimi et al. [28]C

 Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran  Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran  Range age of participants: 7– 65 years

 50 isolatesh  Wounds

–

 60 isolatesh  June–October 2013  Wounds

 IPM: 16–128

Gholami et al. [38]

Mohammadi et al. [44]

 blaOXA-23/blaKPC (10%)  blaVIM (4%)  blaOXA-23/blaVIM (10%)  blaOXA-23 (67%)  adeA (100%)  adeB (100%)  adeC (85%)

 Disc diffusion assayd  CLSI, 2011

 Disc diffusion assayd  CLSI, 2013

 Disc diffusion assayd and broth microdilution methode  CLSI, 2012

AMP, AMP + CLA, AMP + SUL, SUL, TIC, TIC + CLA, PIP, PIP + TZB, CAZ, CTX, FEP, CPR, AZT (100%); RIF (0%), SUL (0%) and CST (0%) GEN, TCY, PIP + TZB (96.3%); AMP + SUL (66%); POLB (0%) and CST (0%) CTX, CAZ, FEP, PIP + TZB, PIP, TIC, TIC + CLA, TM, SXT, CIP (100%); AMK (95.4%); TOB (89.2%); GEN (84.6%); TCY (38.5%); CST (0%) CTX, CAZ, TIC, TIC-CLA, PIP, PIPTAZ, TM, SXT (100%); CST (0%) CTX, CAZ, CRO, CIP, FEP, PIP, PIPTZB and CLZ (100%); GEN (94%); AMK (81%); TCY (76%); CST (0%)

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Héritier et al. [40]

Resistance profile (%)

–

(continued on next page)

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1500

Table 1 (continued) Referenceb

Type, setting and region of study

Microbiological aspects of CRABs

Size (CRAB isolates number)a , collect period and origin of samples

Dates of resistance to carbapenems 1

MICs (mg L )  Prospective  D100 isolatesh  Single center  August 2013–March 2014  Shahid Motahari Hospital,  Wounds Tehran, Iran  Range age of participants: 1– 90 years

Determinants of resistance (%)

Dates of resistance to others antibiotics Method and criteriac employed  Disc diffusion assayd and Microdilution broth methode  CLSI, 2012

 blaOXA-23 (70%)  blaOXA-24/40 (20%)

 Disc diffusion assayd and E-test methode  CLSI, 2011

 blaOXA-23 (93%)  ISAba1 element in blaOXA-51 (5%)

 Disc diffusion assayd  CLSI, 2012

Shoja et al. [33]

 Prospective  Single center  Taleghani Hospital, Ahvaz, Iran

 D40 isolatesg or f  August 2011–August 2012  Wounds, skill biopsy and blood samples

Huang et al. [41,42]E

 Retrospective  Single center  Southwest Hospital Burn Institute, Chongqing, China

 F80 isolatesf  January 2012–December 2014 Blood (all patients shown bloodstream infection)

Gong et al. [39]G

 Prospective  Single center  Southwest Hospital Burn Institute, Chongqing, China

 62 isolatesh  July–December 2013  Wound secretions, sputum, blood, catheter and pus

–

 blaVIM (70.9%)  blaOXA-23 (83.9%)

 Disc diffusion assayd  CLSI

Owlia et al. [6]H

 Prospective  Single center  Shahid Motahari Hospital,

 f,c126 isolatesh  August 2010–February 2011  Wound

–

 MBL-positive in phenotypic test (33.3%)

 Disc diffusion assayd  CLSI

 IPM: 0.38–256  MEM: 0.19-32

CTX, CAZ, CRO, CIP, FEP, PIP-TAZ (100%); PIP (99%); SXT (95%); GEN (93%); AMK (90); TCY (82%); CST (0%) AZT (100%); CIP (97.5%); CAZ, FEP, PIP, PIP-TZB, CRO, RIF (92.5%); TOB, GEN, AMK (87.5%); TCY (70%); TGC (45%); AMP-SUL (27.5%); CST (2.5%); POLB (0%) LVX, TCY, SXT, NET, PIP, CAZ, FEP, AMP + SUL, PIP + TZB, GEN, CIP, AMK (>90%); CPZ + SUL (77%); MNO (30%) PIP, AMP + SUL, PIP+AZB, CAZ, CTX, FEP, AMK, SXT (100%); TOB, CIP, TCY (98.4%); GEN, NET (98.3%); CPZ + SUL (96.7%); LVX (91.9%); MNO (27.1%); POLB (0%) CAZ, AZT, TM (98%), PIP (97%), PIP-TZB (96%),

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blaOXA-23 (100%, been that 80% have ISAba1 element)  blaOXA-24/40 (74%) ISAba1 element in blaOXA-51-like (65%)

Resistance profile (%)

Table 1 (continued) Referenceb

Type, setting and region of study

Size (CRAB isolates number)a , collect period and origin of samples

Microbiological aspects of CRABs

Dates of resistance to carbapenems 1

MICs (mg L )

Determinants of resistance (%)

Dates of resistance to others antibiotics Method and criteriac employed

Tehran, Iran  Range age of participants: 1– 73 years

 Prospective  Single center  Southwest Hospital Burn Institute, Chongqing, China

 248 isolatesh  January 2012–December 2014  Wound, sputa, catheters, blood, purulent secretions, tissues, and urines.

–

 blaOXA-23 (65.4%)

 Disc diffusion assayd  CLSI, 2015

Tarashi et al. [35]

 Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran

 189 isolatesh  January 2012–May 2015

–

 blaVIM-1 (18.18%)  blaIMP-1 (5.3%)

 Disc diffusion assayd  CLSI, 2013

Salimizand et al. [34]

 Prospective  Single center  Imam Reza hospital, Mashhad, Iran  Range age of participants: 1– 83 years  Prospective  Multicenter  Two different hospitals in Tehran, Iran

–  30 isolatesf  October–December 2012  Wound swab, body fluids and tracheal aspirates

 blaOXA-23 with ISAba1 element (100%)  blaOXA-24/40 (73%)

 Disc diffusion assayd and E-test method (IPM and MEM)e  CLSI, 2012

 43 isolatesf  November–June 2011  Wounds

 IPM: >32  MEM: >32  ERT: 6–>32  DOR: >32

 Disc diffusion assayd and E-test methode  CLSI, 2009

 69 isolatesf  January 2012–May 2013  Wounds

 IPM: 8 to128  MEM: 8–256

 blaOXA-23 (23.2%)  blaOXA-23 with ISAba1 element (23.2%)  blaOXA-40 (27.9%)  blaOXA-23/blaOXA-24/40 (46.5%)  blaOXA-23 with ISAba1 element/ blaOXA-24/40 (27.9%)  Absence of CarO (7%)  blaOXA-23 (65%)  blaOXA-23/blaOXA-24/40 (9%)  blaOXA-23/blaOXA-58 (3%)  ISAba1 was detected

Pajand et al. [32]J

Farshadzadeh et al. [37]K  Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran

 E-test methode  CLSI, 2014

CTX, CIP (95%), TIC, TIC-CLA (94%), AMK (93%), KAN (92%), GEN (62%), TOB (58%), CST (0%) CIP, FEP, CTX, PIP, PIP + TZB (100%); CPZ + SUL (74.6%); MNO (33.5%) and POLB (0%) CLZ, CTX, FEP, CIP, CRO, PIP + TZB, CAZ, PIP (100%); TCY, AMK (94.7%); GEN (94.2%); CST (0%) CAZ, CTX, PIP + TZB, AMP + SUL (100%); CIP (93%); AMK (90%); GEN (83%); TOB (66%); CST (0%) CAZ, FEP, PIP + TZB, CIP (100%); AMK (95%); TOB (84%); TGC (42%)

burns 45 (2019) 1495 –1508

Huang et al. [41,42]

Resistance profile (%)

PIP, SXT (99%); FEP, RIF (97%); PIP + TZB, CAZ (96%); CIP, LVX

(continued on next page)

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1502

Table 1 (continued) Referenceb

Type, setting and region of study

Microbiological aspects of CRABs

Size (CRAB isolates number)a , collect period and origin of samples

Dates of resistance to carbapenems 1

MICs (mg L )

Determinants of resistance (%) upstream of blaOXA and blaOXA51 (26%)

Nowak et al. [18]

 32 isolatesh  2005–2010  Wounds, blood and other specimens  28 isolatesh  April–July 2012  Wounds

(42%)

–

 blaOXA 23 (87.5%)  blaOXA-24/40 (6.25%)

 IPM: 4–128

 MBL-positive in phenotypic test (16.4%)  blaSPM (3.5%)

Method and criteriac employed

Resistance profile (%)

(95%); GEN (93%); AMK (86%); TOB (66%); AMP-SUL (65%); TCY (39%); MNO (31%); TGC (13%); CST (0%)  Cards AST-N022 and AST-N091 in GEN, CIP (100%); Vitek 2 Compact systeme FEP (94%); CAZ  CLSI, 2008 (91%); AMK (85%); CST (0%)  Disc diffusion assayd and AZT, CIP, CAZ, Microdilution broth methode CTX, FEP, CRO  CLSI, 2012 (100%); GEN (96.85%)

MBL: Metallo-b-lactamase; AMP: Ampicillin; CLA: Clavulanic acid; SUL: Sulbactam; TIC:Ticarcillin; PIP: Piperacillin; TZB: Tazobactam; CRO: Ceftriaxone; CAZ: Ceftazidime; CTX: Cefotaxime; FEP: Cefepime; CPR: Cefpirome; AZT: Aztreonam; IPM: Imipenem; MEM: Meropenem; RIF: Rifampicin; COL: Colistin; GEN: Gentamicin; TCY: Tetracycline; AMK: Amikacin; DOX: Doxycyclin; TGC: Tigecyclin; CIP: Ciprofloxacin; LVX: levofloxacin; STX: Trimethoprim-sulfamethoxazole; TOB: Tobramycin; TM: Trimethoprim; CLZ: Co-trimoxazole; PABN: Phenylalanine-arginine B-naphthylamide; CPZ: cefoperazone. MNO: minocycline; NET: Netilmicin; AZB: Azobactam, KAN: Kanamycin. A blaTEM (40.7%) and blaPER (100%) were also detected in some isolates. B One isolate was extended-spectrum beta-lactamase (ESBL)-positive in phenotypic test. C Some isolates were also founded to carrier AmpC beta-lactamase. D Between the isolates included in these studies 3 are carbapenem-sensitivity Acinetobacter baumannii (CSAB). E AmpC (86%), ISAba1-AmpC (73%), blaPER (73%) and blaSIM (52%) were also detected in some isolates. F Between the isolates included in these studies 4 are CSAB. G blaPER (40.3%) and blaAmpC (80.6%) were also detected in some isolates. H 21.4% of isolates were ESBL-positive in phenotypic test. I* Among the isolates included in these studies 19 are CSAB. J ampC gene and ISAba1 element were amplified in some isolates. K blaPER 1 was detected in 54% of isolates in this study. L blaCTXM-15 and ESBL-positive in phenotypic test were found in 3 and 6 isolates, respectively. a All studies included only one isolate per patient. b The complete reference of all the included articles is showed in supplementary files. c European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria was utilized for the breakpoint of tigecycline and rifampicin in all studies that employed these antibiotics. d Qualitative assay (antimicrobial resistance determination). e Quantitative assay (minimum inhibitory concentration determination). f Isolates from infected sites. g Isolates from colonized sites. h The study did not determine whether isolates were obtained from infected or colonized sites.

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Vala et al. [36]

 Prospective  Single center  Rydygier’s Hospital, Krakow, Poland  Prospective  Single center  Shahid Motahari Hospital, Tehran, Iran

23

Dates of resistance to others antibiotics

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[40]. With the exception of tigecycline and rifampicin, for which resistance was interpreted by EUCAST guidelines, all antibiotics followed the CLSI cut-offs for resistance (Table 1). Detection of the gene blaOXA-51 (11/17; 64.7%) [28,29,44,30,32,33,35,36,38,41,42], which is intrinsic in A. baumannii [17], was the main characteristic employed for identification of isolates recovered (Table S1, Supplementary files). A combination of molecular and biochemical methods was used by 82.0% of studies (14/17) [28,29,41–44,30,33–35,37–40], and the simultaneous use of blaOXA-51 and oxidase/triple sugar iron (TSI) tests was the most frequent association (6/14; 42.8%) [28,29,33,35,38,44].

3.3.

Antimicrobial resistance profile

Overall resistance to cephalosporins such as ceftazidime (MR 100%, IQR 98.0%–100%), ceftriaxone (MR 100%, IQR 96.3%–100%), cefotaxime (100% in all studies include), and cefepime (MR 100%, IQR 97.8%–100%) was high. Moreover, the majority of CRAB isolates were non-susceptible to ciprofloxacin (MR 100%, IQR 95.0%–100%) and levofloxacin (MR 91.9%, IQR 91.4%–93.4%), as well as to gentamycin (MR 93.5%, IQR 86.1%–96.6%), netilmicin (MR 94.6%), amikacin (MR 88.7%, IQR 86.4%– 94.9%), and tobramycin (MR 88.3%, IQR 66.0%–89.2%). Antibiotics frequently employed in hospitals also showed low efficacy against the isolates, as was the case for piperacillin (MR 100%, IQR 97.5%–100%), ticarcillin (100% in all studies include), and ampicillin (MR 96.3%, IQR 80.6%–98.1%). Only the combinations of ampicillin (MR 95.6%, IQR 59.2%–100%) or cefoperazone (MR 77.0%, IQR 75.8%–86.8%) with sulbactam showed better efficacy compared to the drug administered on its own. Moderate resistance was found to tigecycline (MR 42.0%, IQR 27.5%–43.5%) and minocycline (MR 30.5%, IQR 27.8%– 32.9%). Colistin and polymyxin B showed the lowest resistance rate. Correspondingly, only 1 of the 1226 CRAB tested was resistant to colistin.

3.4.

Mechanisms of carbapenem resistance

Regarding the resistance determinants found in the CRAB isolates, Table 1 and Fig. 2 shows that OXA-type carbapenemase was the main mechanism involved in low susceptibility to b-lactams (53.2%; 95% CI = 60, 80.0%, I2 = 86.0%), followed by metallo-b-lactamases (MBL) (30.2%; 95% CI = 11, 42.0%, I2 = 93.0%), and Klebsiella pneumoniae carbapenemase (KPC) (16.6%; 95% CI = 5, 63.0%, I2 = 88.0%). AdeABC overexpression (efflux pump) [38] and reduction in porin content (CarO) [32] were reported in a single study each. Among the OXA-producing A. baumannii, the gene blaOXA-23-like was the most important, being reported in 12 studies [28,29,44,30,32–34,37,39,42,43] with a frequency (Fq) ranging from 65.4% to 100% of isolates. Others acquired OXA-type carbapenemases were identified at studies a lower frequency, with blaOXA-24/40-like (Fq 3.7%–100%) [30,32–34,37,44] and blaOXA-58-like (Fq 3.0%-100%) [37,40] found in 7 and 2 studies, respectively. The frequency of ISAba1 element upstream to OXA-genes ranged from 5.0% to 100% of isolates with the blaOXA-51-like gene, and from 23.2% to 100% in A. baumannii with the blaOXA-23-like gene. Six studies reported MBL production [28,29,31,35,36,39]. integron-encoded metallo-b-lactamase (VIM) Verona

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[28,29,35,39] was the most frequent MBL, being reported in >70.0% of isolates in one study. In addition, the genes blaIMP-1 (Fq 5.3%) [35] and blaSPM (Fq 3.5%) [36], which encode the MBLs Imipenem-resistant Pseudomonas (IMP)-type 1 (IMP-1) and São Paulo Meropenemase (SPM), respectively, were each found in one study. KPC-1 was the least common of the carbapenemases identified from CRAB isolates, being reported by only 2 groups [28,29]. Co-existence of 2 carbapenemases were more common, being identified the followed combinations: 2 OXAtype carbapenemases - blaOXA-23/blaOXA-24/40 (Fq. 9.0%–48.1%) [32,34,43]; blaOXA-23/blaOXA-58 (3.0%) [37]; one OXA-type carbapenemase with KPC - blaOXA-23/blaKPC (Fq. 9.2%–10.0%) [28,29]; and one OXA-type carbapenemase with MBL - blaOXA-23/blaVIM (Fq. 9.2%–10.0%) [28,29].

4.

Discussion

In the present review, we highlight that the OXA-type carbapenemase was the main mechanism involved in low susceptibility to carbapenems (53.2%; 95% CI = 60, 80.0%, I2 = 86.0%) in A. baumannii from patients with burn injury, been that the majority of strains harboured blaOXA-23-like (12/17; 70.6%). The resistance rates to b-lactams, quinolones, and aminoglycosides between the CRAB isolates were considerable high. However, the studies included showed that minocycline and colistin have preserved their antimicrobial activity, suggesting the use of these antibiotics against infections by CRAB in patients into burn units. After the search and selection of articles, 17 studies that evaluated 1226 CRAB isolates recovered between 2010 and 2015 from patients with burn injury were reviewed. This was a period of considerable increases in the rate of resistance to carbapenems among A. baumannii worldwide. In the last 5 years, for example, the number of articles published on clinical CRAB infections has increased by almost 85.0%, going from 1919 between 2006–2011 to 3532 articles in period of 2012– 2017 [45]. This phenomenon suggests the advance of carbapenem resistance among A. baumannii in diverse environments, including burn units. More than 80% of the studies were conducted in Asian hospitals, with emphasis on Iran where 12 of the manuscripts originated. In fact, several CRAB cases have been reported in hospitals of Middle Eastern countries such as Iran, United Arab Emirates, Bahrain, Saudi Arabia, Palestine, and Lebanon [5]. However, the high concentration of studies involving CRAB in patients with burn injury in the Middle East makes the population profile traced to this microorganism a reflection of regional variations and not a worldwide trend. Another important limitation is that most of the selected studies were conducted in a single hospital and patient demographic data are neglected, making it even more difficult to extrapolate these data to the burn population outside these centres. The disk diffusion method was the most frequently used to evaluate the profile of susceptibility to different antibiotics, including carbapenems. However, a few studies evaluated the MIC of b-lactams by quantitative techniques such as E-test, microdilution in broth, or macrodilution in agar. Quantification of the effective concentration is important to define the degree of resistance of isolates to the antibiotics in question

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Fig. 2 – Florest plot of prevalence profile of enzymatic resistance mechanisms found in the included studies (OXAs, MBLs, and KPC). CI, confidence interval; Heterogeneity (I2); Heterogeneity's pvalue (p).

[47,48]. In addition, some studies point out that qualitative methods such as disk diffusion involve low detection of resistance to carbapenems. Shoja et al. [33] found that imipenem disks could not detect 25% of resistant isolates designated by E-test, suggesting that the use of disks for antimicrobial susceptibility testing could lead to false positives of carbapenems susceptibility. As antimicrobial efficacy is dependent on in vitro susceptibility of the isolated strains [48], the low performance of disk diffusion method for identifying carbapenem resistance might guide clinicians in the wrong choice of antimicrobial, which could lead to therapeutic failure. In patient burn sites, it is difficult to distinguish between colonization and infection with A. baumannii [33]. Often bacterial load (>105 bacteria/g tissue), presence of clinical signs, antibiotic treatment, and indications of invasive infections are investigated in patients to distinguish between colonization and infection [46]. Correspondingly, many of the studies did not report whether the included microorganisms originated from

infected or colonized patients, reflecting the challenges in differentiating these two phenomena in clinical practice. Despite this, resistance to carbapenems in A. baumannii has been pointed out as a major problem in patients with burn injury, involving a variety of resistance mechanisms. According to the results of this review, the main determinant of resistance in CRAB isolated from patients with burn injury was the presence of OXA-type carbapenemases, which showed a global prevalence of 53.2% in the meta-analysis. In fact, many reviews point out that class D carbapenemases (OXAs) are most frequently involved in carbapenem resistance in A. baumannii [2,3,5]. Although all specimens of A. baumannii possess the blaOXA-51-like gene, it is only expressed at levels compatible with carbapenem resistance after insertion sequence acquisition, specifically the ISAba1 element [49]. In this review, 3 studies reported this element upstream of the blaOXA51-like gene, revealing its importance among patients with burn injury. The presence of ISAba1 was also reported in isolates bearing the blaOXA-23-like gene, which is responsible for

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inducing high level of resistance to carbapenems (MIC > 32 mg mL 1). OXA-23-like was the most frequent carbapenemase in patients with burn injury, thus corroborating several studies that showed high frequency of these enzymes among other populations of hospitalized patients [41,42]. Moreover, OXA23 is the primary antimicrobial resistance determinant found in A. baumannii isolated from various environments into the hospital such as air, water, and inanimate surfaces [22,50]. Detection of OXA-24/40 and OXA-58 was lower than that of OXA-23; however, these enzymes are important in patients with burn injury. Recently, molecular studies have showed that A. baumannii cells use outer membrane vesicle (OMVs)mediated transfer for dissemination of OXA-24/40 and OXA-58 [51,52]. In this system, bacterium export vesicles from the outer membrane contain lipids, periplasmic proteins, DNA, and RNA, which are captured and incorporated by several bacterium, including species of other genera [53]. Thus, the overexpression of OXA-24/40 and OXA-58 by A. baumannii protects other bacteria, allowing the unexpected survival of carbapenem-susceptible species in, for example, polymicrobial infections [19]. MBLs, an important group of carbapenemases, are not frequently reported in A. baumannii isolates; reports of these genes are more abundant and diverse in other non-glucosefermenting bacteria, such as Pseudomonas aeruginosa [54]. Here, we have confirmed this pattern, and MBLs were identified in only some CRAB isolates from burn units, showing an overall prevalence of 30.2% (Fig. 2). In a similar manner, KPC-type carbapenemases are rarely found in Acinetobacter spp. [18], which explains the low prevalence of this resistance determinant in the studies included. The isolation of Acinetobacter plasmids has been shown to be a difficult task, and thus may be a limiting factor in experimental assays [19]. In fact, only one of the included studies was able to identify the localization of genes that encode carbapenemases, but it is known that many of the blaOXA genes and some MBLs determinants are plasmidic. This suggests that conjugation has an important role in the dissemination of carbapenemases between different A. baumannii exemplars. Nonetheless, the interspecies dissemination of carbapenemases appears to be limited in these bacterium, and several studies showed failure of the conjugation of blaOXA-23 [55], blaOXA-24/40 [56], blaGES [57], and blaVIM-1 [58] genes from A. baumannii to Escherichia coli. In addition to enzymatic mechanisms, CRAB isolates from patients with burn injury were also shown to carry genes involved in overexpression of efflux pumps. Gholami et al. [38] showed that >80.0% of CRAB isolates from burn wounds in a hospital of Theran overexpress AdeABC efflux pumps, which conferred moderate to high resistance to imipenem (MIC 16– 128 mg/mL). The chromosomally encoded AdeABC is a tripartite system comprised by AdeA (membrane fusion protein), AdeB (inner membrane protein channel with twelve transmembrane segments), and AdeC (outer membrane protein channel). AdeABC belongs to the resistant-nodulation-cell division (RND)-type family and confers resistance to aminoglycosides, fluoroquinolones, erythromycin, tetracycline, trimethoprim, and chloramphenicol [59]. Other non-enzymatic resistance mechanism to carbapenems founded in A. baumannii are the mutations in porins that allow the antibiotic to enter the bacterial cell [32,60]. The most characterised porin

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among A. baumannii is the carbapenem-associated outer membrane protein (CarO), a heat modifiable 29 kDa polypeptide comprised of 247 amino acid residues that form a specific monomeric porin channel essential to permeability of several molecules, such as carbapenems and basic amino acids (e.g., arginine) [60]. According to Pajand et al. [32], decrease in the expression of CarO resulted in a high MIC for imipenem (>32 mg/mL), meropenem (>32 mg/mL), ertapenem (6–32 mg/ mL), and doripenem (>32 mg/mL) in A. baumannii. Many of the included studies, in addition to carbapenem resistance mechanisms, also reported the presence of resistance determinants to other classes of antibiotics. It was identified a high incidence of resistance to cephalosporins, aminoglycosides, fluoroquinolones, and others b-lactams in CRAB isolates. The presence of genes encoding broad-spectrum b-lactamases (e.g., blaTEM,blaPER, blaSIM, and blaCTX-M-15), which confers resistance to extended spectrum cephalosporin, was reported in more than half of the studies. Coproduction of mechanisms that confer resistance to several classes of antimicrobials is often found in microorganisms isolated from patients with burn injury, since exposure to broad-spectrum antimicrobial agents and combination treatment with different antibiotics is common in these patients [61]. A notable finding of this review was the susceptibility rate to minocycline. In contrast to high resistance of other classes of antibiotics, this drug showed reasonable susceptibility to 1 CRAB isolates. Minocycline (Minocin ) is a second-generation tetracycline that was voluntarily withdrawn from the US market in 2005 due to decreasing use [62,63]. However, with the increase in MDR infections, intravenous treatment with minocycline was reintroduced in 2009. After the cessation of clinical use of these drugs, the rate of resistance decreased from 56.5% (2003–2005) to 30.5% (2009–2012) [62]. Corroborating the promising use of minocycline against CRAB, Pogue and collaborators [63] showed that the intravenous minocycline infusion at 100 mg or 200 mg twice daily for 4–13 days produced clinical and microbiological cures in critically ill patients infected with these microorganisms. Furthermore, in contrast to the resistance rates to antimicrobials such as colistin, carbapenems, and tigecycline that continue to increase every year, resistance to minocycline has been shown to be stable, thus reducing the possibility of therapeutic failure of this antibiotic caused by resistance [62]. Colistin, in turn, was the most susceptible antibiotic reported in the CRAB isolates. Although the Eurofins Surveillance Network demonstrated that resistance to colistin among Acinetobacter spp. has more than doubled in recent years (2.8% in 2006–2008 and 6.9% in 2009–2012), this rate to be considerably lower in patients with burn injury [64]. Therefore, colistin remains to be a viable therapeutic option for patients with burn injury infected with CRAB. Colistin is available as a prodrug in the form of colistin methanesulfonate (CMS) for clinical practice, and is formulated for intravenous, intramuscular, intraventricular, intrathecal, and inhalation use. This antibiotic is characterized by a concentration-dependent activity and narrow therapeutic window, and its nephrotoxic and neurotoxic effects are well known [64]. In patients with burn injury, total body surface area (TBSA) affects colistin pharmacokinetics and the higher distribution volume of drug in these patients may be associated with lower colistin plasma

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concentration. Thus, in order to optimize colistin treatment in patients with burn injury, higher doses are used, which increases the risk of toxicity [65]. However, a recent study revealed that higher CMS doses were not found to be associated with increased nephrotoxicity in patients with burn injury [66]. In addition, the administration of aerosolized colistin in patients with ventilator-associated pneumonia caused by CRAB has shown high cure rates [67]. Although the volume status and organ functions of these patients may affect colistin safety and efficacy, the studies available have shown that colistin is a safe and preferable therapeutic option for patients with burn injury infected with CRAB [64]. This review has some limitations. Data regarding characteristic of patients, antimicrobial use, and profile of heath units are limited in the included articles, which complicates the determination of the roles of these factors on the susceptibility profile of CRABs in burn units. The exclusion of Chinese and Arabic language reports causes a bias in this review, since many studies originating from the Middle East and China might have been missed. In addition, the heterogeneity (I2 = 86–93%) of included articles was too high. Carbapenem-resistance determination was performed by the disk diffusion method in several studies, however the low specificity of this technique in identifying CRAB may have reduced the number of isolates included in these studies. Additionally, MIC for carbapenems was mainly absent. Lastly, resistance mechanisms obtained by different laboratory methodologies (phenotypic tests and molecular assays) were combined for the purposes of this review. However, as the majority of studies used molecular biology methods, the impact of variation in the frequency of resistance determinants on the validity of the final results is thought to be minimal.

5.

Conclusions

In summary, this review highlights four important findings related to CRAB in burn units. First, most countries do not target CRAB in surveillance studies, thus limiting the availability of information that is needed to trace the microorganism population profile in patients with burn injury. Second, the use of low sensitivity methods for identification of carbapenem-resistant isolates, such as disk diffusion, was common in the studies, have undoubtedly contributed to underreporting cases of CRAB infections. Third, the presence of ISAba1 upstream OXA-23-like was frequent in patients with burn injury, and it was associated with high levels of resistance to carbapenems. Last, the studies included showed that minocycline and colistin susceptibility remains high and is not impacted by carbapenem resistance in these isolates. These results indicate the importance of a high-quality surveillance program in burn units that includes monitoring of CRAB infections, molecular typing of microorganisms, and characterization of antibiotic efficacy.

Author contributions All authors contributed to the development, analysis and drafting of this article.

Funding None.

Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest All authors report that they do not have any conflicts of interest.

Acknowledgements W.G.L. is grateful to Coordenação de Aperfeiçoamento de Pessoal do Nível Superior (CAPES) for a Ph.D. fellowship.

Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.burns.2019. 07.006.

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