The threat of carbapenem-resistant gram-negative bacteria in a Middle East region

Abstract

Data on the status of carbapenem-resistant microorganisms in the Middle East countries are scarce. The aim of this review was to collect available data regarding resistance to carbapenems in a Middle East region. Available data regarding carbapenem-resistant isolates were considered for evaluation in this review. Biomedical electronic databases were systematically searched to find related articles. The key terms used were "carbapenem-resistant, resistant gram-negative bacilli, Enterobacteriaceae, fermenting and non-fermenting gram-negative bacilli, Pseudomonas, Acinetobacter, Klebsiella and Iran". After primary screening, 275 relevant articles were selected to be assessed thoroughly. Resistance rate to carbapenems was reported between 1% and 86% during years 2006-2018. Most of the carbapenem-resistant microorganisms were isolated from burn patients. Modified Hodge test was a commonly used phenotypic test. Only in few studies, genotypic assays were considered. Pattern of antibiotic use can affect emergence of resistant microorganisms. Rational use of drugs, and specifically, antibiotics is a challenging issue in developing countries. Mean number of drugs per prescription in these countries was higher than the World Health Organization standards. Overuse of antibiotics, especially injectable ones, and easy access to antibiotics without prescription is a warning alarm for future antibiotic resistance in developing countries. Establishing antimicrobial stewardship's programs is new in the hospitals. Unfortunately, rules and regulatory issues to restrict antibiotic access in community pharmacies and prescription by general physicians are limited.

Keywords: antibiotics; carbapenem; gram-negative bacteria; resistant.

Figure 1

Screening methods for carbapenem-resistant microorganisms. Notes: ¹MHT was the most used phenotypic method in Iranian studies. MHT originally detects KPC, but if zinc sulfate is added to MHT culture media, it can detect MBL. It is based on carbapenemase inhibition by betalactamase inhibitors. CDT consists of two disks: a carbapenem and the other combination of a carbapenem and a betalactamase inhibitor. If the disk with inhibitor shows a bigger inhibition zone, the result is considered positive. DDST consists of carbapenem discs at a variable distance to inhibitor discs. The observation of synergy between disks is noted as a positive result. These phenotypic methods can detect different Ambler classes. CIM is a newer phenotypic method that was introduced in 2015 by van der Zwaluw. A carbapenem disk is inserted in culture media of suspected strain. Then it is transferred to another culture media with known control strain. If the suspected strain contains carbapenemase enzyme, the carbapenem disk has been degraded and the control strain in second culture will grow. Some other phenotypic methods like spectrometric assays are also used and have higher sensitivity and specificity, but they are costly and time consuming. Abbreviations: CDT, combination disk test; CIM, carbapenem inactivation method; DDST, double disk synergy test; ESBL, extended spectrum β-lactamase; KPC, Klebsiella-producing carbapenemase; MBL, metallo-β-lactamase; MHT, modified Hodge test; MIC, minimum inhibitory concentration; PCR, polymerase chain reaction.

Figure 2

Consort flowchart of study. Abbreviation: ESBL, extended spectrum β-lactamase.

Figure 3

Carbapenem-resistance rates in different areas of Iran (according to the disk diffusion method). Notes: The data were extracted from the latest available studies. Multicenter studies from different cities were not considered for mapping due to pooled data. The studies in the special populations (ie, pediatrics or cystic fibrosis) and outpatients were excluded. *Reported resistance rates from Fars province were conflicting (13.7% in 2017 and 96% in 2016). ^§Data for Isfahan province were obtained from both Kashan (a city around Isfahan) and Isfahan itself, although the sample size for Isfahan was very small. ^¶Data for Khorasan area were extracted from a study in 2015 with 36 strains. ^€Intermediate and absolute resistance rates were 25% and 2%, respectively. ^¥Data in these provinces were for 2010–2014 studies.

Figure 4

Carbapenem-resistant rates in different areas of Iran (according to the phenotypic and genotypic methods). Notes: The data were extracted from the latest available studies. Multicenter studies from different cities were not considered for mapping due to pooled data. The studies in the special populations (ie, pediatrics or cystic fibrosis) and outpatients were excluded. Some genes like blaSPM and blaSHV are mostly known as genes that encode ESBL enzymes, but they were included in this map, because these genes were assessed along with carbapenemase genes, and also overexpression of these genes concomitant with harboring efflux pump may be responsible for resistance to carbapenems. ^*Data for these five provinces were extracted from 2011 to 2014 articles, so new data are needed. ^€Data were extracted from a 2015 study with 36 samples; another study in 2013 confirmed the presence of the genes of resistance in 4% of strains. ^¥Data from Tehran province were conflicting; genes encoding resistance were detected in 15%–50% of isolates through 2015–2016. ^¶Data from Kashan (a city in Isfahan province) showed presence of resistance genes in 80% of isolates in 2015. ^§In Mazandaran and West Azerbaijan, these genes were reported, but rates of resistance were not included because the studies included different cities from different provinces. ① blaOXA-23 ② blaOXA-24 ③ blaOXA-58 ④ blaOXA-40 ⑤ blaOXA-48 ⑥ blaOXA-10 ⑦ blaOXA-143 ⑧ blaIMP ⑨ blaVIM ⑩ blaSPM ⑪ blaGES ⑫ blaPER ⑬ blaNDM ⑭ blaKPC ⑮ blaTEM ⑯ blaSHV ⑰ blaADC ⑱ blaSIM ⑲ blaGIM. Abbreviations: ESBL, extended spectrum β-lactamase; KPC, Klebsiella-producing carbapenemase; MBL, metallo-β-lactamase.