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Carbapenem-resistant Acinetobacter baumannii infections among diabetic and non-diabetic patients and possible effective combination treatments

Future Journal of Pharmaceutical Sciences volume 10, Article number: 90 (2024) Cite this article

Abstract

Background

Carbapenems are one of the most noteworthy choices for treating multidrug-resistant Acinetobacter baumannii (A. baumannii). Currently, carbapenem-resistant A. baumannii (CRAB) represents a healthcare problem worldwide, particularly among diabetic patients who are more susceptible to microbial infections. The aim of this study was to investigate the differences in antibiotic susceptibility profiles, the abundance of carbapenem resistance genes across A. baumannii-infected diabetic and non-diabetic patients, and the antimicrobial activity of different antibiotic combinations on highly resistant isolates.

Methods

Data of 99 A. baumannii-infected patients were collected during the period from 2018 to 2022 and categorized according to patients’ diabetes status into either diabetic or non-diabetic group. A total of 45 A. baumannii isolates were collected during 2021 and 2022 from the main hospital laboratory to be reidentified and genetically confirmed. Antibiotic susceptibility, including carbapenems, was determined using disc agar diffusion and broth microdilution methods. The isolates were screened for OXA-23, GES, VIM, and NDM carbapenem-resistant genes. Five antibiotic combinations were assessed using the double-disk synergy and checkerboard methods.

Results

The findings of the current study revealed that multidrug resistance increased gradually, from 56% in 2018 to 95.6% in 2022. Moreover, CRAB increased among diabetics and non-diabetics. Resistance rates of imipenem, meropenem, and doripenem reached 68.8%, 61.8%, and 47.4% in diabetics and 97.9%, 83.3%, and 50% in non-diabetics, respectively. The VIM gene was the most prevalent gene with prevalence rates of 100% and 96.15% in diabetics and non-diabetics, respectively. Moreover, all A. baumannii isolates carried at least two of the selected carbapenem-resistant genes. Across the different used combinations, only the tigecycline-meropenem combination showed synergistic activity in 50% of diabetic and 66.7% of non-diabetic isolates.

Conclusions

An increased carbapenem resistance was observed among A. baumannii-infected individuals, both diabetic and non-diabetic. The MEM/TCG combination was the only one that showed synergistic or additive effects against highly resistant isolates making it a viable alternative treatment option.

Background

Extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) have emerged as a major public health concern worldwide. Infections caused by these organisms could be acquired in both community and hospital settings [1]. These Enterobacterales isolates that produce carbapenemase enzymes are a growing threat to human health worldwide, as they often carry multiple resistance genes that limit treatment options [2]. Also, carbapenem-resistant Acinetobacter baumannii (CRAB) infections pose significant challenges in healthcare settings [3]. Acinetobacter baumannii (A. baumannii) is recognized as one of the most prevalent and dangerous multidrug-resistant (MDR) gram negative pathogens that cause many diseases and nosocomial infections including pneumonia, septicemia, urinary tract infections, skin and wound infections, endocarditis, and meningitis [4,5,6].

The MDR of A. baumannii has been observed in patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), where the global rates of MDR strains have been estimated to be up to 79.9%, ranging from 56.5% in Argentina, 61.8% in Taiwan, and 88.5% in Egypt to 100% in Central America, Pakistan, Lebanon, Qatar, and Croatia [7]. In Egypt, in a nationwide monitoring of healthcare-associated infections (HAI), A. baumannii was reported in 91 intensive care units (ICUs) across 28 Egyptian hospitals, where A. baumannii accounted for 13.7% of ICU-onset infections [8]. Other studies in Egypt have reported that A. baumannii accounted for 10.7% to 28.3% of HAI and 22.1% of VAP cases [9, 10]. Conversely, Meawad et al., observed a slightly lower prevalence, with A. baumannii accounting for 15.9% of VAP cases [11].

The high mortality rates associated with A. baumannii infections ranged from 26% to 68% and often occurred in critically ill patients [11,12,13]. However, separating the attributable mortality cause of such patients has proven to be challenging [14].

Due to their broad antimicrobial spectrum, good safety, and high tolerability profile, carbapenems were the most effective class of β-lactams commonly used to treat severe infections caused by MDR pathogens. Imipenem, meropenem, ertapenem, and doripenem are among those that have been licensed for clinical usage [15]. From 2000 to 2010, global carbapenem use grew by 45%. Not surprisingly, carbapenems are the third most often used antibiotic globally for community-acquired infections in ICUs and the first most regularly used antibiotic for nosocomial infections [16]. They are usually prescribed as the last-line antibiotics for critically ill patients or patients suspected to have resistant bacteria. The CRAB has been identified as a potential threat showing resistance to all antimicrobial drugs including polymyxins which makes treatment of these infections is extremely challenging [17,18,19,20].

The leading cause of resistance of CRAB is carbapenem-hydrolyzing class D β-lactamases, which are composed of five families of genes encoding oxacillinase (OXA) that correlate to OXA-23-like, OXA-24/40-like, OXA-58-like, OXA-143-like, and OXA-235-like enzymes [21]. Metallo-β-lactamases (MBLs) were also identified as a less common potential cause of this resistance than the OXA-type carbapenemases. However, MBLs have a substantially stronger hydrolytic activity against carbapenems. In A. baumannii, four MBLs were identified: Imipenemase (IMP), Verona integron-encoded MBL (VIM), Seoul Imipenemase (SIM), and the New Delhi MBL (NDM) [22]. Carbapenem resistance can also be induced by other processes, such as the formation of additional carbapenemases, alteration or loss of porins, or changes in the penicillin-binding proteins [23, 24].

Another growing public health problem, particularly in the Middle East, is the rise in the number of diabetic patients [25]. Diabetes has been found to be a substantial risk factor of acquisition of severe A. baumannii HAI [26,27,28]. The emergence of CRAB isolates, along with the increasing incidence of diabetes creates a worrying scenario from the fast-expanding number of difficult-to-treat infections.

As a result of lack of robust clinical data supporting the treatment of A. baumannii with a single antibacterial agent and the fact that these patients are usually very ill with severe comorbidities and have the possibility that initially active antibiotics may develop resistance, the Infectious Diseases Society of America (IDSA) recommends using at least two active agents whenever possible [29]. The aim of the current study was to investigate the effect of patients’ demographics (such as sex and gender) and comorbidities (especially diabetes status) on A. baumannii infection. Additionally, the study aimed to determine the susceptibility of A. baumannii to different antibiotic regimens including carbapenems, detect carbapenem resistance genes, and compare the in vitro efficacy of different antibiotic combinations on CRAB isolates obtained from diabetic and non-diabetic patients.

Materials and methods

Data and isolates collection

Retrospective study

All patients with isolated A. baumannii infections admitted to the Critical Care Medicine Department at Cairo University Hospitals, Cairo, Egypt, during the period from January 2018 to December 2019 were included in the study. Data were collected from patients’ medical records and electronic files on the hospital system. Patients were categorized into two groups: diabetic and non-diabetic patients. Data from antimicrobial susceptibility testing for A. baumannii cultures were also collected in both groups. Pediatrics, pregnant women, and cancer patients were excluded.

Prospective study

Isolates of A. baumannii were collected from patients admitted to the Critical Care Medicine Department at Cairo University Hospitals, Cairo, Egypt from February 2021 to November 2022. Isolates were obtained from various clinical specimens including blood, bronchoalveolar lavage (BAL), chest tubes, pus, pleural fluids, sputum, urine, and wounds. Patients infected with A. baumannii were stratified based on their diabetes status into diabetic and non-diabetic groups. These isolates were collected, reidentified and genetically confirmed. Pediatrics, pregnant women, and cancer patients were excluded from this study.

The study was carried out after receiving ethical approval from Cairo University’s Research Ethics Committee with ethical approval number: MI 2798.

Antibiotic susceptibility test

For determination of the antibiotic susceptibility profile of A. baumannii isolates during the retrospective study period, patients’ electronic medical files were used to collect the required data. Thirteen antibiotics were investigated using the disc diffusion and broth microdilution methods including amikacin (AK), cefepime (FEP), cefoperazone/sulbactam (CFS), cefotaxime (CTX), ceftriaxone (CRO), ciprofloxacin (CIP), gentamicin (GEN), levofloxacin (LEV), tetracycline (TE), tigecycline (TGC), piperacillin/tazobactam (TPZ), imipenem (IPM), and meropenem (MEM). Notably, the sensitivity of polymixins and doripenem was not reported in the patients’ data.

During prospective study, antimicrobial susceptibility for A. baumannii isolates was carried out by Kirby Bauer method using the following six antibiotic discs: TE (30 µg, Himedia), LEV (5 µg, Bioanalysis), AK (30 µg, Bioanalysis), CRO (30 µg, Bioanalysis), TPZ (100/10 µg, Himedia), and FEP (30 µg, Himedia) [30, 31]. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method for colistin (CT, 1 million IU/vial, Teva UK). For the study of carbapenem resistance patterns, antimicrobial susceptibility of IPM (10 µg, Bioanalysis), MEM (10 µg, Bioanalysis), and doripenem (DOR, 10 µg, Himedia) discs were carried out using the disk diffusion method [30, 31]. The antibiotic susceptibility was determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines from 2018 and 2021 [30, 31].

Bacterial identification

Isolates of A. baumannii collected during the prospective study were identified using biochemical tests and confirmed genetically by detection of the OXA-51 gene using conventional polymerase chain reaction (PCR) [32]. For PCR, bacterial DNA was extracted using a QIAamp DNA minikit (Qiagen, Germany) according to the manufacturer’s instructions, followed by PCR using OXA-51 gene specific primers mentioned in Table 1. The PCR program settings were: 94 °C for 3 min, followed by 30 cycles of 94 °C for 30 s, 56 °C for 30 s, 72 °C for 1 min, and a final extension at 72 °C for 10 min. All identified isolates were stored as glycerol stock at – 80 °C until further use.

Table 1 Gene primers with sequences, amplicon size and annealing temperatures (TA) used for PCR amplification
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Molecular screening of carbapenem-resistant genes among the A. baumannii isolates

Different genes related to CRAB were selected. The selected genes were oxacillinase enzyme OXA-23 gene, two Metallo β lactamase genes, VIM, and NDM, and class A carbapenemase GES gene. Conventional PCR reactions were performed to detect the selected genes using isolates’ DNA and genes’ specific primers mentioned in Table 1.

Antibiotic combination assessment

Two methods were applied in this study to determine the effect of five combinations of two antibiotics against MDR A. baumannii. The double-disk synergy test was used for all combinations while the checkerboard method was used for the TGC and MEM combination.

Double-disk synergy test

Double-disk synergy test was performed for the isolates that were resistant to at least two of the applied antibiotics. Mueller–Hinton agar (Merck, Germany) was inoculated with a saline suspension of fresh culture of the isolated microorganism adjusted to 0.5 McFarland turbidity standard. Combinations of all possible pairs of antibiotics were tested by placing antibiotic discs at 20 mm from each other (center to center). After 18 h of incubation, a synergistic effect among two antibiotics can be detected by formation of an inhibition zone between their discs [37].

The selected antibiotic combinations were as follows: a Double-Carbapenem Therapy (DCT): Dor- IMP, β-Lactam with an aminoglycoside: AK-FEP and AK-CRO, and β-Lactam/β-Lactamase inhibitor plus an aminoglycoside: TPZ-AK.

Checkerboard method for assessment of TGC and MEM combination activity

According to CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, the TGC susceptibility can only be detected by broth microdilution [38]. Thus, the checkerboard assay was carried out to determine effect of the TGC and MEM against MDR A. baumannii. The antibiotic concentrations used were 4 to 8 times the MICs. Briefly, in a sterile 96 microtiter plate, TGC was added in vertical lines and MEM in horizontal lines, in a series of twofold dilutions. The final inoculum of the bacterial suspensions was added in each well to be around 5 × 105 CFU/ml. The plate was incubated at 35 ± 2 °C for 18 ± 2 h [39].

The MIC of each antibiotic alone and in combination was detected, and to determine the antibiotic combination effect, the fractional inhibitory concentration (FIC) was calculated as follows:

ΣFIC = FIC A + FIC B, where FIC A and FIC B were calculated using the following formula:

$${\text{FIC A}} = \left( {\text{MIC of drug A in combination}} \right)/\left( {\text{MIC of drug A alone}} \right).$$
$${\text{FIC B}} = \left( {\text{MIC of drug B in combination}} \right)/\left( {\text{MIC of drug B alone}} \right).$$

The ΣFIC was interpreted as follows: ΣFIC ≤ 0.5 means synergistic; 0.5 < ΣFIC < 2 means additive; and ΣFIC ≥ 2 means antagonistic [40].

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 20. For the statistical analysis carried out to compare the trend of antimicrobial resistance rate, the incidence of MDR, β-lactamases, and MBLs A. baumannii based on diabetes status, Chi-square test or Fisher’s exact test and descriptive statistics (cross tab and frequency) were utilized. All continuous data were expressed as mean ± SD and were compared using Student’s t test as per the non-significant Shapiro–Wilk test. Statistical significance was defined as a P value less than 0.05. Heat mapping was conducted during this study using SPSS and Microsoft Excel 2010.

Results

Patients’ demographic data and comorbidities

A total of 99 patients infected with A. baumannii were included in this study. Analysis of patient profiles revealed no difference between males and females in susceptibility to infection (P = 0.366) where infections in males accounted for 54.5% compared to 45.5% in females. The range of patient ages was between 19 and 91 years, the mean age ± standard deviation was 53.9 ± 19.08, and the highest incidence of infection was significantly found in patients over 60 years old, representing 47.5% with a P value equal to 0.009, followed by 29.3% of patients between 19 and 40 years and then 23.2% for those from 41 to 60 years.

Out of the 99 patients, 71.7% had underlying comorbidities. The most common underlying comorbidities were heart diseases, which were present in 54.5% (54/99) of the patients. Other common comorbidities were hypertension (HTN) and kidney diseases which were significantly higher in diabetic patients compared to non-diabetics (Table 2).

Table 2 Comorbidity factors associated with A. baumannii infections
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Specimen types

A. baumannii isolates were collected from different patients’ specimens including blood, BAL, chest tube, pus, pleural effusion, sputum, urine, and wound. Interestingly, A. baumannii was isolated from different specimens from the same patient (3%), indicating mixed A. baumannii infections. Sputum was the main source of the isolates in 2018 and 2019 accounting for 68% and 65.5% of isolates respectively. In 2021, wound samples were the most predominant, accounting for 40.9%, while blood specimens in 2022 reached 60.9% (Table 3).

Table 3 Source of A. baumannii isolates
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Antibiotic susceptibility test for diabetic and non-diabetic patients’ isolates

According to the Centers for Disease Control and Prevention (CDC), MDR is identified as the resistance of isolates to three or more different antibiotic classes. In this study, nine antibiotics were tested for resistance in the prospective study using Kirby Bauer method, while CT was determined by broth microdilution method. the documented MDR rates of A. baumannii isolates were 56% and 86.2%, in 2018 and 2019, respectively (Fig. 1). These rates increased to 100% and 95.6% in 2021 and 2022, respectively (Fig. 2), with an average MDR rate of 83.8% during the entire study period. The obtained results of the susceptibility test were classified into two parts: non-carbapenem antibiotics and carbapenem antibiotics.

Fig. 1
figure 1

Antibiotic susceptibility heat mapping of A. baumannii in 2018 and 2019. S: sensitive, I: intermediate, R: resistance, CFS: cefoperazone/Sulbactam, TPZ: piperacillin/tazobactam, CRO: ceftriaxone, FEP: cefepime, CTX: cefotaxime, GEN: gentamicin, AK: amikacin, TE: tetracycline, TGC: tigecycline, LEV: levofloxacin, CIP: ciprofloxacin, IPM imipenem, and MEM meropenem

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Fig. 2
figure 2

Heat mapping of antibiotic resistance against A. baumannii clinical isolates in 2021 and 2022. S sensitive, I intermediate, R: resistance, TPZ: piperacillin/tazobactam, CRO: ceftriaxone, FEP: cefepime, AK: amikacin, TE: tetracycline, LEV: levofloxacin, IPM: imipenem, MEM: meropenem, DOR: doripenem, and CT: colistin

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Non-carbapenem antibiotics

Antibiotic susceptibility data was collected from patient’s files during 2018 and 2019 as antibiotic susceptibility was conducted and recorded as a routine part of patient care. Samples collected during 2021 and 2022 were examined by the authors. During the study, bacterial resistance increased and reached 80% to 100% for TPZ, FEP, AK, and LEV in the years 2021 and 2022 regardless of diabetes condition. TE showed the highest activity reaching 65.9% susceptibility, while CRO showed 100% resistance in 2019, 2021, and 2022. TPZ and TE showed fluctuating high levels of resistance as shown in Fig. 3. Table 4 represents the percentage of antibiotic resistance among diabetic and non-diabetic isolates with a high resistance rate observed in both groups. Higher resistance percentages (> 70%) were observed for AK, FEP, CTX, CRO, LEV, and TPZ in both groups, while CIP, GEN, IMP, and MEM showed more than 70% resistance in the non-diabetic group only. Conversely, TGC and CT showed lower resistance in diabetics (23.1%, and 26.3%, respectively) and non-diabetics (42.9%, and 42.3%, respectively). In the diabetic group, CFS, GEN, and DOR showed moderate resistance ranging from 45.5% to 50% in contrast to the non-diabetic group where the resistance ranged from 50% to 77.8%. No significant differences in antibiotic susceptibility among diabetic and non-diabetic patients were reported except for FEP (P = 0.043).

Fig. 3
figure 3

Percentage of A. baumannii antibiotic resistance over the study years. TPZ piperacillin/tazobactam, CRO ceftriaxone, FEP cefepime, AK amikacin, TE tetracycline, LEV levofloxacin

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Table 4 Percentage of A. baumannii antibiotic resistance among diabetic and non-diabetic patients throughout the whole study period
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Carbapenem antibiotics

Carbapenems susceptibility test

The retrospective and prospective data from the years 2018, 2019, 2021 and 2022 revealed that 86.1% and 73.7% of A. baumannii isolates were resistant to IPM and MEM, respectively. For the years 2021 and 2022, 48.9% of A. baumannii isolates were resistant to DOR. It should be noted that IPM and MEM susceptibility were included in both the retrospective and prospective data, while the assessment of DOR was included only in the prospective study.

It was observed that MEM was still effective against A. baumannii during 2018 and 2019. Although the sensitivity of MEM decreased by almost thirty percent during 2019, there was still antibiotic activity noted (37.5%). In contrast to IPM, it had little to no effect over the four-year period (Fig. 4).

Fig. 4
figure 4

Carbapenems susceptibility test against A. baumannii isolates in each studied year. a IMP susceptibility results, b MEM susceptibility results, and c DOR susceptibility results

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A susceptibility test for DOR was performed on the collected 45 isolates during 2021 and 2022. Although DOR is not commercially available in the Egyptian market, high resistance rates were observed among A. baumannii isolates (Fig. 4c).

In diabetic patients, resistance rates for IPM, MRM, and DOR were found to be 68.8%, 61.8%, and 47.4% respectively. In non-diabetics, the resistance rates were 97.9% for IPM, 83.3% for MEM, and 50% for DOR. A significant difference was noted between diabetics and non-diabetics in terms of resistance to IPM and MEM (P = 0.001 and 0.031, respectively) (Table 4).

Trends of CRAB

Following regular reports of the antimicrobial susceptibility results for A. baumannii reveals a growing trend of antimicrobial resistance was identified. The resistance ranged from 69.6% to 100% in IPM, 40% to 91.3% in MEM, while DOR showed resistance ranging from 40.9% to 56.5% during the study period (Fig. 4).

Carbapenem resistance genes detection

In the prospective study, 45 isolates were collected during the years 2021 and 2022. For those isolates, five carbapenem resistance genes were detected by PCR (Fig. 5). OXA-51 has been detected in all isolates of A. baumannii. Notably, VIM was the most prevalent resistance gene as it was detected in 97.7% of the isolates. At least two resistance genes were detected in all CRAB isolates. However, there was no significant difference between diabetics and non-diabetics regarding the presence of these resistance genes in isolated CRAB (Table 5).

Fig. 5
figure 5

Detection of carbapenemase genes in A. baumannii isolates M: 1 kb DNA ladder, a: represents OXA-51 with amplicon size 353 bp, b: OXA-23 with amplicon size 501 bp, c: GES with amplicon size 834 bp, d: VIM with amplicon size 390 bp, and e: NDM with amplicon size 621 bp

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Table 5 Detection of CR genes in CRAB isolates among diabetic and non-diabetic
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Assessment of antibiotic combinations

Double-disk synergy test

For determination of the effect of different antibiotic combinations, four antibiotic combinations including Dor- IMP, AK-FEP, AK-CRO, AK-FEP and AK-CRO and TPZ-AK were examined using the double-disk synergy test. None of the isolates showed increase in zones of inhibition compared to individual antibiotic discs used (Supplementary file).

Checkerboard assay against A. baumannii clinical isolates

A preliminary six isolates of MDR A. baumannii were selected equally from diabetic and non-diabetic groups for assessment of MEM/ TGC combination effect. The selection criteria were based on their high resistance profiles to antibiotics. The combination demonstrated a synergistic effect against four isolates and an additive effect against two isolates. Following this, an additional six isolates; equally from diabetic and non-diabetic groups; were tested. MEM /TGC synergism was observed in three isolates while an additive effect was seen in the remaining three isolates.

Among all the twelve isolates, the synergism of MEM and TGC combination was detected in seven isolates, while it shows additive effect in five isolates. Out of the six diabetic isolates, a synergistic effect of MEM and TGC combination was detected in 50% and additive effect in 50%. On the other hand, 66.7% of non-diabetic isolates showed combination synergism, and 33.3% showed additive activity. However, no significance difference between diabetic and non-diabetic selected isolates in both synergism (P = 0.705) and additive (P = 0.655) effects was determined.

Further, study of the presence of carbapenem resistance genes among the twelve isolates revealed that 11 isolates had the VIM gene, eight had the OXA-23 gene, only four had the NDM gene, and no isolates had the GES gene. Among the eleven isolates positive for the VIM gene, synergism was detected in six isolates, and additive effects were observed in five isolates. For the eight isolates positive for the OXA-23 gene, four showed synergism and four showed an additive effect of the antibiotic combination. In regard to isolates carrying the NDM gene, two showed synergism and two showed an additive effect.

Discussion

Antibiotic resistance is rapidly spreading throughout the world causing significant treatment issues [41]. A. baumannii has emerged as a significant nosocomial pathogen. It has a remarkable capacity to develop resistance that limits treatment options [23]. A few decades ago, infections brought on by A. baumannii could be successfully treated with carbapenems such as IPM and MEM. Globally, the widespread trend of carbapenem resistance which has been estimated to range from 50% to 100% has resulted in the absence of effective antibiotic options, with the exception of CT and TGC [42,43,44].

Besides, CRAB has become an urgent public health threat [45]. Therefore, antibiotic combination therapy is strongly advised [46]. Our study aimed to determine the antibiotic resistance patterns of A. baumannii isolates and factors affecting them among diabetic and non-diabetic Egyptian patients and correlate the detection of resistance genes with the susceptibility to different antibiotic combinations against CRAB isolates.

In our study, there was no significant difference in A. baumannii’s infection rate between males (54.5%) and females (45.5%). This agreed with the findings reported by Sannathimmappa et al., in which they reported that males and females infected with A. baumannii were 48% and 52% respectively [47]. In contrast, Mamoria et al., reported that males were more susceptible to A. baumannii infection with a frequency of isolation reaching 75.36% in males [48]. In our study, 46.5% of the infected patients were 60 years or older. The elder patients are more susceptible to infection with resistant microorganisms due to the multiple uses of antibiotics over the course of their lives [49]

The most serious infections caused by A. baumannii are HAP and septicemia. In the current study, most of the A. baumannii isolates were obtained from sputum (45.45%) and blood samples (23.23%). Similar results were reported by several studies where respiratory secretions, including sputum, bronchial lavage, endotracheal and chest tube secretions, were the most common specimen for Acinetobacter isolates, while the isolation rate from blood specimens ranged from 7 to 25% [50,51,52].

Diabetic patients have a higher risk of both opportunistic and nosocomial infections which can result in severe morbidity [53, 54]. Diabetics are more susceptible to other diseases than non-diabetics such as chronic kidney diseases, heart diseases, and septic shock [55]. The results of this study support the increased risk of diabetes, as the incidence rate of A. baumannii infections for HTN, heart problems, and kidney diseases was higher in diabetics compared to non-diabetic patients.

In Egypt, tracing antibiotic resistance of A. baumannii revealed increased rates of resistance over the past decade. In a multi-centered study conducted from 2011 to 2012, the MDR A. baumannii reached 80% [56]. After that, several studies carried out between 2013 and 2018 reported resistance rates ranged from 82% to 100% [57,58,59,60,61]. In studies carried between 2019 and 2020, the MDR rate was documented to be 100% [62,63,64]. Our results are consistent with these previous studies, where the MDR rates of A. baumannii increased over time with isolation of pan-drug-resistant A. baumannii strains.

Resistance to carbapenems is a specific concern, as they were the most effective antibiotics against resistant microbes. The widespread usage of antimicrobial drugs in ICUs during the last decade has resulted in the rise of CRAB globally. Outbreaks of CRAB have been documented all over the world, including the Middle East [65]. Generally, resistance to MEM and IMP gradually increased in hospitals. Our findings regarding MEM and IMP resistance demonstrated that the resistance to MEM was 40%, while it reached 90.9% for IMP in 2018. These findings are in agreement with a study conducted in Minya, Egypt, during 2016 and 2017. The study revealed that the incidence of MEM resistance was approximately 40% [66]. Another study done in Mansoura University hospitals from 2016 and 2017 demonstrated 100% resistance rates for both IMP and MEM [59].

Our findings, derived from the collected samples during 2022, showed a resistance rate to DOR of 56.5%. Comparable results were reported by the Asia–Pacific areas of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, performed from 2012 to 2019, where 61.5% of the isolates were resistant to DOR [67]. Since DOR is not commercially available in Egypt, the observed high resistance may be attributed to acquisition of new virulence factors and resistance genes.

Clinical data showed that diabetes is a risk factor for the acquisition of A. baumannii infection. Moreover, high antibiotic resistance patterns were found in diabetic patients [26, 68, 69]. We noted a significant difference in IMP and MEM resistance between diabetics and non-diabetics. Contrarily, a study conducted in Saudi Arabia from 2008 to 2011 demonstrated a non-significant difference between diabetic and non-diabetic patients in IPM and MEM resistance [70].

OXA-51 gene was found in all of the isolates tested in our investigation. This is in agreement with many studies that revealed that the OXA-51 gene is found in all A. baumannii isolates, and it is widely employed for confirming A. baumannii’s identification [71, 72].

In this study, the presence of multiple carbapenem resistance genes were investigated in the isolates collected during the years 2021 and 2022. These genes are VIM, OXA-23, NDM, and GES where they were detected in 97.7%, 67.4%, 27.9%, and 20.9%, respectively, across CRAB. Regarding VIM gene, similar findings were reported in a study carried out at Alexandria University Hospital in Egypt between 2010 and 2015, where the VIM gene was detected in 100% of the CRAB isolates [73]. Another study carried out in Kasr Al-Aini Hospital during 2018 and 2019 revealed that OXA-23 was detected across CRAB in 81.2%, while VIM and NDM were detected only in 0.6% and 10.4%, respectively [74]. The difference in acquiring VIM and NDM genes between the two studies may be strongly related to the excessive use of carbapenems in treatment.

Several studies have reported the prevalence of carbapenemases in isolated CRAB [75,76,77,78,79]. A study conducted in Egypt between 2010 and 2015 by Abouelfetouh et al., revealed that Class D carbapenemase genes, including blaOXA-51 and blaOXA-23, were found in 100% of the isolates, while class B carbapenemase genes, including blaVIM and blaNDM, were found in 100% and 21.1% of the isolates, respectively [73]. In a study carried out by Al-Agamy et al. in 2012, Class A carbapenemase gene blaGES was detected in 27.5% of A. baumannii isolates [78].

As a result of increased rates of CRAB infections, carbapenem monotherapy is not a current option for treating infections caused by A. baumannii. Various national and international programs recommend the combined use of two or more antimicrobial agents in order to increase their antibacterial activity and to minimize drug-resistant mutants [80].

In this study, different combinations were evaluated. Due to previous reports of the effectiveness of dual carbapenem combination in treating carbapenem-resistant gram negative bacterial infections, we investigated the effect of the DOR/ IMP combination [81, 82]. We also evaluated the effect of β-lactam antibiotics in combination with aminoglycosides, in the presence or absence of β-lactamase inhibitors, to further explain the significance of β-lactams and the development of β-lactamase inhibitors in combating resistance by inactivating class A and some class C serine β-lactamases [83]. Unfortunately, all of these combinations showed no additive or synergistic effect.

On the other hand, TGC with MEM showed an in vitro synergistic effect by 50% and 66.7% toward CRAB isolates in both diabetics and non-diabetics, respectively, and an additive activity by 50% in diabetics and 33.3% in non-diabetics, respectively.

One of the advised antibiotics against CRAB is TGC, which was recommended for HAP/VAP by the recent guidelines [29]. However, TGC monotherapy was linked to a great death rate in patients with HAP [84]. In contrast, a prospective observational research found that TGC/IPM combination therapy had a considerably lower death rate in patients with CRAB associated-VAP than sulbactam/imipenem combination therapy [85]. In this study, the high percentage of the synergistic effect of TGC with MEM makes it one of the CRAB treatment alternatives.

Conclusion

A. baumannii is a MDR pathogen causing serious nosocomial infections with limited treatment options. The rate of MDR among diabetics and non-diabetics has increased; however, diabetic status is more critical due to chronic conditions and decreased immunity. Nowadays, A. baumannii has shown increased resistance to antibiotics used in the treatment, including carbapenems which have become ineffective. Only the combination of TGC and MEM has shown an in vitro synergistic effect that requires further in vivo investigations. Searching for new antibiotics or antibiotic combinations based on the type of resistant genes is a crucial factor for treating MDR A. baumannii. The presence of the VIM gene in almost all isolates from both diabetic and non-diabetic patients may be the cause of the failure of most combination therapies so targeting this gene is essential for effective treatment. Furthermore, in vitro and in vivo studies evaluating other combination therapies based on the type of resistant genes are needed.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Abbreviations

A. baumannii :

Acinetobacter baumannii

ATLAS:

Antimicrobial testing leadership and surveillance

BAL:

Bronchoalveolar lavage

CDC:

Centers of Disease Control and Prevention

CLSI:

Clinical and Laboratory Standards Institute

CRAB:

Carbapenem-resistant Acinetobacter baumannii

DCT:

Double-Carbapenem Therapy

ESBL-E:

Extended-spectrum β-lactamase-Producing Enterobacterales

EUCAST:

European Committee on Antimicrobial Susceptibility Testing

FIC:

Fractional inhibitory concentration

GES :

Guiana extended-spectrum β-lactamase

HAI:

Healthcare-associated infections

HAP:

Hospital acquired pneumonia

HTN:

Hypertension

ICUs:

Intensive care units

IDSA:

The infectious Diseases Society of America

IMP :

Imipenemase

MBLs :

Metallo-β-lactamases

MDR:

Multidrug-resistant

MICs:

Minimum inhibitory concentrations

NDM :

New Delhi MBL

OXA :

Oxacillinase

PCR:

Polymerase chain reaction

SIM :

Seoul Imipenemase

VAP:

Ventilator associated pneumonia

VIM :

Verona integron-encoded metallo-β-lactamases

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Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Microbiology and Immunology Department, Faculty of Pharmacy, Future University in Egypt, Cairo, 11835, Egypt

    Aya M. Ghareeb & Marwa M. Raafat

  2. Critical Care Medicine Department, Kasr Al Ainy Hospitals, Cairo University, Cairo, Egypt

    Naglaa S. Bazan

  3. Clinical Pharmacy Department, King Khalid University, Abha, Saudi Arabia

    Naglaa S. Bazan

  4. Microbiology and Immunology Department, Faculty of Pharmacy, Cairo University, Giza, Egypt

    Reham Samir

Authors
  1. Aya M. Ghareeb
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  2. Marwa M. Raafat
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  3. Naglaa S. Bazan
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  4. Reham Samir
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Contributions

Reham Samir and Marwa M. Raafat who conceived and designed the experiments; Aya M. Ghareeb performed the experiments; Naglaa S. Bazan supervised and provided access to patient’s samples and data; Marwa M. Raafat and Aya M. Ghareeb analyzed the data and wrote the paper. Reham Samir and Naglaa S. Bazan critically revised the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Aya M. Ghareeb.

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Ethics approval

The study was carried out after receiving ethical approval from Cairo University’s Research Ethics Committee (approval number: MI 2798). The study used bacterial isolates obtained from clinical samples that had already been cultivated as part of normal work in the Microbiology laboratory of Cairo University Hospitals’ Critical Care Medicine Department, Kasr Alini Hospitals, Cairo University, Cairo, Egypt.

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Informed consent was obtained from all individual participants included in the study.

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Ghareeb, A.M., Raafat, M.M., Bazan, N.S. et al. Carbapenem-resistant Acinetobacter baumannii infections among diabetic and non-diabetic patients and possible effective combination treatments. Futur J Pharm Sci 10, 90 (2024). https://doi.org/10.1186/s43094-024-00661-x

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