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Antimicrobial resistance profile and associated factors of hospital-acquired gram-negative bacterial pathogens among hospitalized patients in northeast Ethiopia

BMC Microbiology volume 24, Article number: 339 (2024) Cite this article

Abstract

Background

Antimicrobial resistance is a major global public health issue. Infections caused by resistant species are associated with higher mortality rates, longer hospital stays, medication failure, and rising medical costs. The World Health Organisation has declared multidrug resistance-associated infections as an epidemic of public health concern.

Objective

This study aimed to evaluate the antimicrobial resistance profile and associated factors of hospital-acquired Gram-negative bacterial pathogens among hospitalized patients in Northeast Ethiopia.

Materials and methods

A health facility-based cross-sectional study was conducted among hospitalized patients from March 2021 to February 2022. About 810 clinical specimens were collected, transported, and processed from admitted patients following the standard bacteriological procedures. The clinical samples were inoculated onto blood agar, MacConkey agar, and chocolate agar. Furthermore, the species identification was done using gram reactions, colony morphology, and color and biochemical tests. Antimicrobial susceptibility tests, extended-spectrum beta-lactamase, and carbapenemase production were performed as per the clinical laboratory standard institute guidelines. For analysis, the information was entered into Epi-data and exported to SPSS. A P value of < 0.05 with a 95% confidence interval was considered as a statistically significant association.

Results

Out of 810 clinical specimens, 285/810 (35.2%) developed bacterial infections. From the isolated bacteria, E. coli was the predominant bacteria accounting for 78/285 (27.4%) followed by K. pneumoniae, 69/285(24.42%), whereas P. vulgaris accounted for the least, 7/285 (2.5%). Overall, 132/285 (46.3%) and 99/285 (34.7%) of culture-positive patients were infected by extended-spectrum beta-lactamase and carbapenemase-producing bacteria. The overall multidrug resistance rate of the isolated bacteria was 89.4%. The highest antibiotic resistance rates were detected for doxycycline (92.9%), amoxicillin-clavulanic acid (83.9%), and ampicillin (93%). The least antibiotic resistance rate was observed for meropenem at 41.1% and amikacin at 1.7%, respectively.

Conclusions and recommendations

In the study area, significant health concerns include a range of hospital-acquired bacterial infections associated with elevated rates of multidrug resistance, Extended-spectrum beta-lactamase (ESBL), and carbapenemase-producing bacterial pathogens. Consequently, it is recommended to conduct drug-susceptibility testing of isolates and molecular detection at a national level to optimize antibiotic usage for treating prevalent bacterial infections in this area.

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Introduction

The most commonly identified Hospital-acquired infections are caused by Gram-negative organisms including the Enterobacteriaceae family, Pseudomonas aeruginosa, and Acinetobacter baumannii [1]. Most gram-negative bacteria, facultative anaerobes, and bacilli do not form spores. Escherichia spp., Klebsiella spp., Proteus spp., Enterobacter spp., Citrobacter spp., Providencia spp., Serratia spp., Salmonella spp., and Shigella spp. are some of the important genera in the Enterobacteriaceae family that are medically important [2,3,4].

Antimicrobial resistance (AMR) is a significant global public health issue. Infections brought on by resistant species are associated with increased mortality rates, prolonged hospital stays, medication failure, and rising medical expenses. The World Health Organization has declared MDR-associated infections to be an epidemic of public health concern [5]. In Ethiopia, antibacterial agents of the beta-lactam group including penicillin G, ampicillin, amoxicillin, ceftriaxone, ceftazidime and cefotaxime are the most commonly prescribed antibiotics for treating infections caused by multi-drug resistant (MDR) Enterobacteriaceae. However, these bacteria can hydrolyze many beta-lactam antibiotics through the production of beta-lactamases such as extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and carbapenemase [6].

Antimicrobial resistance extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacilli have spread globally and become endemic in numerous countries [7]. Cefoxitin, cephalothin, cefazolin, most penicillins, and beta-lactamase inhibitors are therapeutically important for Enterobacteriaceae that encode cephalosporin and mediate resistance to cefoxitin, cephalothin, cefazolin, and most penicillins [8].

These antibacterial medicines are critical in the treatment of potentially fatal nosocomial or hospital-acquired infections. The rise of carbapenem resistance may threaten or halt the advancement of modern medical treatments. Relatively few novel antibiotics will be discovered in the foreseeable future, making carbapenem-resistant Enterobacteriaceae a global priority [2].

Extended-spectrum beta Lactamase and CP-producing Enterobacteriaceae are a major issue in hospitals around the world. The problem is serious because ESBL enzymes can hydrolyze almost all beta-lactams except carbapenems and cephamycin [9]. Carbapenems are the last line of defense against MDR Enterobacteriaceae infections. However, carbapenem intermediate or resistant Enterobacteriaceae is a global public health issue [10, 11]. The carriage of ESBL and CP Enterobacteriaceae in hospitalized patients is a threat to the future of antibiotic treatment. The high prevalence of ESBL and CP Enterobacteriaceae in healthy asymptomatic people has a significant public health impact on the management of both hospital and community-acquired illnesses [12].

In sub-Saharan Africa, there is a high rate of antibiotic resistance to commonly used antibiotics, despite the difficulty of estimating the size of the problem of antibacterial resistance and the limited capacity for its detection and surveillance. Civil conflicts, poor sanitation, a lack of effective infection control measures, and an increase in the population with immune system disorders all contribute to the aggravation of this condition [13]. Although infection caused by AMR, ESBL, and CP-producing Gram-negative is a global threat, the burden is disproportionately high in low-income countries in Africa, where self-treatment, hospital overcrowding, lack of antibiotic prescription guidelines, poor infection control practices, poor hygiene, and antibiotic misuse are common [14].

Additionally, limited therapeutic options available to treat infection, poor clinical outcomes, and untreatable hospital-acquired infections are now prominent topics in hospital settings. Hospitalized patients are easily infected with these microorganisms and eventually serve as reservoirs [15]. Patients infected with AMR, ESBL, and carbapenemase-generating bacteria are less likely to be treated with beta-lactam antibiotics, resulting in treatment failure, mortality, and increased infectiousness [16].

However, data are scarce in Ethiopia, especially in the study area. Therefore, a study on ESBL and CP Enterobacteriaceae among admitted patients is essential to generate baseline data, for guiding local empirical therapy, planning local infection control programs, developing antimicrobial prescription protocols for different infections, and enhancing awareness and support evidence-based strategies through engagement with local communities and policymakers. As a result, the purpose of this study was to determine the antimicrobial resistance profile and associated factors of hospital-acquired Gram-negative bacterial pathogens among hospitalized patients in Northeast Ethiopia.

Materials and methods

Study design, period, and area

A health facility-based cross-sectional study was conducted from March 2021 to February 2022, in Northeast Ethiopia involving five hospitals: Dessie Comprehensive Specialized Hospital, Boru-Meda General Hospital, Selam General Hospital, and Bati General Hospital. According to the South Wollo Health Department’s monthly report, these five hospitals collectively serve over 17 million people in Northeast Ethiopia. Each hospital had different wards and clinics such as medical, orthopedics, ART clinics, TB clinics, surgical, gynecology, pediatrics, Intensive care unit (ICU), and Neonatal ICU.

Population

The study populations were all patients who were admitted to the wards of five hospitals: Dessie Comprehensive Specialized Hospital, Boru-Meda General Hospital, Selam General Hospital, and Bati General Hospital. Specifically, the study included patients who had been admitted to these hospitals medical, orthopedics, ART, surgical, gynecology, pediatric ward, ICU, and NICU for more than 48 h with clinically presumptive nosocomial bacterial infections were included in the study.

Sample size determination and sampling technique

The sample size of this study was calculated using a single population proportion formula with a 95% confidence level and a 5% margin of error. A 35% prevalence of Enterobacteriaceae was reported from a previous study done in Arbaminch, Southwest Ethiopia [17]. and considered for sample size determination. The minimum sample size was calculated to be 350 however, a total of 810 hospitalized patients were included during the study period. A systematic random sampling technique was employed to enroll study participants. The sample was proportionally allocated by wards of admission and then the sample size from each ward was proportionally determined by using the proportionate allocation formula: nj = n/N*Nj, where: nj is the sample size of the jth stratum, Nj is the population size of the jth stratum, nt = n1 + n2 + .+ nk is the total sample size, and N = N1 + N2 + .+ Nk is the total population size.

Inclusion and exclusion criteria

Patients suspected of nosocomial Gram-negative bacterial infections in areas such as the urinary tract, bloodstream, lower respiratory tract, meningitis, eye, ear, and wound infections were eligible for the study if they had been admitted to medical, orthopedic, ART, surgical, gynecology, pediatrics, ICU, or NICU wards for over 48 h. Exclusions comprised patients receiving antibiotics at the time of sample collection, along with those providing incomplete data or inadequate specimens (such as saliva and contaminated sputum).

Data collection

A pre-tested structured questionnaire was used to gather socio-demographic data (age, residence, occupation) and clinical history (current and previous antibiotic use, prior extended hospital stays). Data were collected by physicians through face-to-face interviews with patients or their caregivers during sample collection. Recruitment began on the first-day patients reached 48 h of hospitalization. Specimens were aseptically collected from suspected cases and promptly transported. Gram-negative isolates and their antibiotic susceptibility, ESBL, and CP profiles were recorded on a separate data worksheet.

Specimen collection and processing

Clinical specimens were collected from each patient after a physical examination was done by physician. All specimens were collected from study participants after 48 h of admission and right before the patient was discharged by using preferred leak-proof containers according to microbiological techniques. Blood, urine, wound swabs, pus, CSF, body fluid, eye and ear discharge, and purulent sputum were collected from admitted patients presumptive of bloodstream infection, urinary tract, wound, meningitis and peritonitis, ear and eye) and lower respiratory tract infections, respectively.

Sputum sample collection and processing

Each patient was given instructions on how to collect sputum and cover the lid. Approximately 2 mL of sputum samples were collected using a clean, dry, sterile, wide-necked, leak-proof container and transported to Wollo University Medical Microbiology laboratory for analyses. When an unavoidable delay in processing was anticipated, sputum samples were stored at 4 °C. Sputum specimens with a lot of watery saliva were excluded from being processed using microbiological procedures. The sputum was immediately smeared and examined for appropriateness for culturing. Gram staining with more than 25 polymorphic nuclear leukocytes and less than 10 epithelial cells was considered good and the specimen was inoculated on blood agar (BA) (HiMediaTM), chocolate agar, and MacConkey (MAC) agar (HiMediaTM) incubated for 24 h at 37 °C [18,19,20].

Blood specimen collection and processing

Ten ml of venous whole blood from adults, five ml from children, and two ml from neonates were collected aseptically. Immediately after collection, the blood was inoculated directly onto Tryptone Soya Broth (TSB) (Oxoid, UK). The blood culture bottles were inoculated, incubated at 37 °C for 7 days, and then inspected. Blood culture bottles that showed visible signs of growth were subculture onto Blood Agar and MacConkey Agar (HiMediaTM), then incubated for 48 h at 37 °C [21].

Urine specimen collection and processing

Clean-catch urine (10 ml) was collected and 0.001 ml was inoculated into Cysteine Lactose Electrolyte Deficient Medium using a calibrated wire loop. After 24-hour incubation at 37 °C, colony counts were performed bacterial growth of 105 for non-catheterized patients and 103–105 CFU/mL of urine for catheterized patients were sub-cultured onto MacConkey agar (MAC) and Blood agar (BA) plates and incubated at 37 °C for 24 h under an aerobic atmosphere [22].

Wound swab sample collection and processing

Pus samples were aseptically collected and placed in a Brain Heart Infusion transport medium. After 24-hour incubation, cultures were sub-cultured onto Blood Agar and MacConkey Agar for 24 h at 37 °C [23] .

Cerebrospinal and body fluid

Aseptic collection of CSF and other fluids involved inoculation onto MacConkey agar and Blood agar plates, then incubation at 37 °C for 24 h [23].

Eye and ear discharge

Swabs from ears and conjunctiva were collected aseptically and transported in Amies transport medium. Samples were cultured on MacConkey agar and Blood agar plates for 24 h at 37 °C [23].

Identification of bacterial isolates

Following appropriate plated agar incubation, bacterial isolates were characterized using standard microbiological procedures, including colony morphology, pigmentation, hemolysis patterns, and Gram stain staining. A quantitative analysis of sputum cultures revealed bacterial counts exceeding 105 CFU/mL [18]. Bacterial isolates were identified using biochemical tests such as oxidase, carbohydrate fermentation, hydrogen sulphide production, motility, indole formation, triple sugar iron agar (TSI), citrate utilization, lysine decarboxylase or methyl red Voges-Proskauer tests, urea hydrolysis, and satellite tests [20, 23]. All the suspected isolates were further confirmed by an automated Vitek2 Compact (Biomerieux, France).

Antimicrobial susceptibility test

Antimicrobial susceptibility testing was performed on isolated bacteria using the Kirby Bauer disc diffusion method on Muller Hilton agar (HiMedia). For fastidious organisms, 5% sheep blood and Muller Hinton agar were used. Pure colonies from nutrient agar were transferred to tryptone-soya broth and incubated at 37 °C until the turbidity met a 0.5 McFarland standard. The suspension was evenly distributed onto Muller Hinton agar plates with a sterile swab. Antimicrobial discs were applied to the inoculated plates and incubated at 37 °C for 16–18 h. Antimicrobial agents were selected based on CLSI recommendations and local (Ethiopian) prescription habits for Gram-negative bacteria. The standard antimicrobial discs (Oxoid Ltd) and the corresponding concentrations were as follows: cefoxitin (FOX:30 µg), gentamicin (GM: 10 µg), amikacin (AM:30 µg), ciprofloxacin (CIP: 5 µg), trimethoprim-sulfamethoxazole (SXT: 1.25/23.75 µg), imipenem (IMP: 10 µg), meropenem (MEM: 10 µg), amoxicillin-clavulanic acid (AMC: 20/10 µg), cefotaxime (CTX: 30 µg), ceftazidime (CAZ: 30 µg ), ceftriaxone (CRO: 30 µg ), tetracycline (TE:30 µg) and chloramphenicol (CL:30 µg) [24]. Diameters of zones of inhibition were measured using a digital caliper. The antimicrobial susceptibility test results were interpreted as sensitive, intermediate, or resistant based on the standardized CLSI guidelines [25, 26]. The isolates were considered MDR, resistant to at least one antimicrobial in three or more antimicrobial categories [27].

Screening and confirmation of ESBL production

ESBL-producing Gram-negative isolates were screened using the Kirby Bauer disk diffusion method [25]. After streaking bacterial suspension on Muller Hinton agar, ceftazidime and cefotaxime disks were incubated overnight at 37 °C. Isolates with inhibition zone diameters ≤ 22 mm for ceftazidime and/or ≤ 27 mm for cefotaxime were considered suspected ESBL producers. Confirmation involved placing ceftazidime and cefotaxime disks alone and in combination with clavulanic acid (30 µg/10 µg) at a distance of 25 mm on the plates, followed by overnight incubation at 37 °C. An increase in inhibition zone diameter of ≥ 5 mm for the combination disk compared to the individual disks confirmed ESBL production [19].

Screening and detection of carbapenemase production

Isolates resistant to imipenem or meropenem (zone of inhibition ≤ 19 mm) were suspected carbapenemase producers [19] and tested using a modified carbapenem inactivation method (mCIM) following CLSI guidelines [24, 26]. Gram-negative isolates were emulsified in TSB with a meropenem disk (10 µg) and incubated for 4 h. After swabbing the indicator organism (E. coli ATCC®25,922) on MHA, meropenem-containing TSB was dispensed and plates were incubated at 37 °C for 24 h. A zone of inhibition diameter of 6–15 mm or the presence of pinpoint colonies within a 16–18 mm zone confirmed carbapenemase production [25].

Quality assurance

Data completeness and accuracy were ensured throughout and after collection, following Standard Operating Procedures (SOP) for microbiological procedures. Clinical specimens were handled correctly from collection to processing. Media, reagents, and Muller Hinton agar antimicrobial discs were checked for expiry before use, and culture medium integrity was verified for sterility and physical defects. Quality control included testing new batches against control strains: ESBL confirmation used K. pneumoniae (ATCC 700603) and E. coli (ATCC 25922); AmpC beta-lactamase testing used E. cloacae (ATCC BAA 1143) and E. coli (ATCC 25922); and carbapenem resistance was assessed using E. coli (ATCC 25922). Antibiotic disc performance was validated using Enterococcus faecalis (ATCC 29122) and a cotrimoxazole disc [25].

Hospital-Acquired Infection (HAI): An infection that arises in a patient during their stay in a healthcare facility, which was not present or developing at the time of admission, and infections that appear 48 h or more after admission, and infections acquired through healthcare procedures [28].

Statistical analysis

The data were entered into epi-data version 4.6.0.4 and exported to SPSS version 25 for analysis. Descriptive statistics were performed and results were displayed using graphs and tables. Binary logistic regression was done and those variables with P ≤ 0.25 in the bivariate analysis were subjected for multivariate analysis to identify the independent factors associated with the nosocomial infection rate. P ≤ 0.05 with the odds ratio with a 95% confidence interval was considered statistically significant.

Result

Socio- demographic and clinical characteristics of study participants

A total of 810 study participants with symptoms of bacterial infection were involved in the study. The mean (± SD) age of participants was 40.09 (± 12.24) years old, ranging from 4 days to 85 years. The majority of study participants were males (57.4%), urban dwellers (59.3%), and married (72.72%). In addition, 25.2% of participants were unable to read and write, and 24.6% were daily workers. By considering behavioral characteristics, 64.3%, 62.1%, and 52%. study participants were non-smokers, never drinking alcohol and chat chewing respectively, from all study participants 18.6% and 35.6% had a history of hospitalization in the last 6 months and a habit of eating uncooked fruit and vegetable products, respectively. Moreover, 41.4% of the study participants had underlying chronic disease and of these, HIV accounted for 51.7% (Table 1).

Table 1 Socio-demographic, behavioral, and clinical characteristics of study participants (n = 810) at health facilities in north-eastern region Ethiopia, 2022
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Hospital-acquired infection rate

As Fig. 1 shows, 810 clinical samples were collected from admitted patients with a culture positivity rate of 35.2% (285/810) (95% CI, 30.2-40.2%). The proportion of culture-confirmed bloodstream, urinary tract, wound infection, meningitis and peritonitis, eye and ear infection, and lower respiratory tract infection were 18.6%, 30%, 88.8%, 19.7%, 10%, and 29.9%, respectively. The proportion of Gram-negative infection was 141/465 (31.2%) for males. The proportion of Gram-negative bacterial infection was significantly higher among rural than urban dwellers: 185/327 (56.6%) vs. 200/483(41.4%). Patients with chronic diseases had a higher infection rate of 155/355(46.3%) than the control group 130/475 (27.4%). HIV patients had the highest proportion of healthcare-associated infection among chronic infectious diseases, accounting for 80/158 (50.6%). Similarly, patients who had previously been admitted to the hospital had a higher proportion of nosocomial infections (healthcare-associated infections) (43.3%) than the control group 220(33.3%). Similarly, patients who were admitted to the ART clinic had a higher proportion of 80 (50.6%) of healthcare-associated infections with Gram negative bacteria (Table 1).

Fig. 1
figure 1

Proportion of culture confirmed nosocomial infection among hospitalized patients at north-eastern region Ethiopia, from February-August 2022

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Gram-negative bacterial isolates

From the recovered, Gram-negative bacteria, E. coli was the most predominant isolate, accounting for 27.4% (78/285), followed by K. pneumoniae, 69/285 (24.42%), whereas P. vulgaris accounted for the least, 7/285 (2.5%). In blood, urine, wounds, CSF and body fluids, eye and ear samples, and sputum samples, the overall culture positivity rate of Gram-negative isolates was 30/285 (10.5%), 70/285 (24.6%), 114/285 (40%), 15/285 (5.3%), 10/285 (3.5%), and 46/285 (16.6%), respectively. The proportion of E. coli was higher (34.3%) among urinary tract-infected patients. However, in wounds with a higher proportion of K. pneumoniae and E. coli, 30.7% each was isolated, and in bloodstream infection, the proportions of E. coli and K. pneumoniae were higher, at 30% and 16.7% respectively (Table 2) and Fig. 1.

Distribution of ESBL and CP-producing gram-negative infections clinical specimens

Among 285 patients, 46.3% and 34.7% had infections with ESBL and carbapenemase-producing (CP) Gram-negative bacteria, respectively. ESBL-producing bacteria were isolated from the bloodstream (43.3%), urinary tract (45.7%), wound (48.2%), meningitis (40%), peritonitis (40%), eye and ear infections (45.6%), and lower tract infections (45.6%). CP-producing bacteria were found in the bloodstream (30%), urinary tract (35.7%), wound infection (35.1%), meningitis and peritonitis (26.7%), eye and ear infections (30%), and lower tract infections (33.3%) (Table 2).

Table 2 Isolation rate of nosocomial clinical isolates in clinical samples collected from different sites of infection among patients at north-eastern region Ethiopia, 2022
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Fig. 2
figure 2

Multi-drug resistance pattern of nosocomial clinical isolates among hospitalized patients at north-eastern region Ethiopia, from February -August 2022. Abbreviations MDR multi-drug resistant; NMDR non-multi-drug resistant; R0 no antibiotic-resistant; R1 to R5 resistant to 1 antimicrobial class category to 5 antimicrobial categories

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Prevalence of ESBL and CP-producing gram-negative bacteria

Overall, 132 (46.3%) of Gram-negative bacterial isolates were ESBL producers, with the highest rates observed in P. aeruginosa (54.8%), E. coli (43.6%), K. pneumoniae (47.8%), and Acinetobacter species (53.8%). Resistance to meropenem (MEM) was observed in 134 (47.3%) isolates, while 99 (34.7%) were carbapenemase producers, including P. aeruginosa (41.9%), C. freundii (36.8%), K. pneumoniae (36.2%), and P. mirabilis (50%). (Table 3).

Table 3 ESBL and carbapenemase production of clinical isolates from study participants at north-eastern region Ethiopia, 2022
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Antibiotic resistance profiles of clinical gram-negative bacterial isolates

The majority of bacterial isolates showed high resistance rates to doxycycline (92.9%), amoxicillin-clavulanic acid (83.9%), and ampicillin (93%). Conversely, the lowest resistance rates were observed for meropenem (41.1%) and amikacin (41.7%). E. coli demonstrated higher resistance to ampicillin (87.2%), doxycycline (91%), and amoxicillin-clavulanic acid (85.9%), with lower resistance rates observed for amikacin (38.4%) and meropenem (39.8%). Similarly, K. pneumoniae exhibited higher resistance to doxycycline (94.2%), amoxicillin-clavulanic acid (88.4%), and ampicillin (95.6%), with lower resistance rates seen for amikacin (37.7%) and gentamicin (39.1%). P. aeruginosa showed higher resistance to ciprofloxacin (66.1%), cefotaxime (64.5%), and ceftazidime (61.3%), while meropenem showed the lowest resistance rate (40.3%). C. freundii exhibited resistance to doxycycline (89.6%), ampicillin (89.6%), chloramphenicol (73.6%), and ceftazidime (63.2%), with lower resistance rates observed for amikacin and meropenem (42.1% each) (Table 4).

Table 4 Antimicrobial susceptibility pattern of clinical isolates from study participants at north-eastern region Ethiopia, 2022
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Multiple drug resistance patterns of the isolates

In total, 277 of 285 bacterial isolates (97.2%) were resistant to at least one antimicrobial class, with 266 (93.3%) resistant to two or more. The overall multidrug-resistant (MDR) rate was 89.4% (255/285 isolates). K. pneumoniae (92.7%), E. coli (91.0%), P. aeruginosa (93.5%), C. freundii (89.5%), Acinetobacter species (92.3%), and H. influenzae (83.3%) all had high MDR rates. A subset of isolates (22.2%) was resistant to five or more antimicrobial agents. Notably, some strains of C. freundii, Acinetobacter species, and Proteus species demonstrated complete MDR (Fig. 2and Table 5).

Table 5 Multi-drug resistance profile of bacterial isolates from study participants at north-eastern region Ethiopia, 2022
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Abbreviations MDR multi-drug resistant; R0 No antibiotic resistance, R1 resistance to one class, R2 resistance to two class, R3 resistance to three class, R4 resistance to four, R4 resistance to four antibiotics class, R5 resistance to five and more than five antibiotics class.

Factors associated with hospital acquired infection

The study identified several independent risk factors for nosocomial Gram-negative bacterial infections, including illiteracy, rural residence, occupational factors (merchant and daily labor), urinary catheter use, and chronic diseases. Specifically, illiteracy (AOR: 5.6; 95%CI: 1.74–25.99), rural residence (AOR: 7.3; 95%CI: 1.23–25.33), smoking (AOR: 7.7; 95%CI: 1.55–44.33), and being in surgical, paediatric, or orthopaedics wards were significant predictors. Patients with underlying chronic diseases such as HIV, liver, and kidney failure were also at increased risk. Interestingly, patients receiving three or more antibiotics upon admission showed a 65% lower risk of nosocomial infection compared to those receiving none (Table 6).

Table 6 Association of independent variables with nosocomial infection of Gram-negative bacilli among study participants from study participants at north-eastern region Ethiopia, 2022
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Discussion

Hospital-acquired infection, particularly due to increasing AMR, ESBL, and CP Enterobacteriaceae pathogens, is a global problem in the healthcare setting [29]. Carbapenem-resistant Gram-negative bacteria have developed resistance to almost all antibiotics and are producing illnesses with high morbidity and fatality rates [26, 30].

In the present study, the overall prevalence of Hospital-acquired Gram-negative bacterial infection was 285/810 (35.2%). This is comparable with previous studies done in Hawassa, Ethiopia which accounted for 28% [31], Uganda with prevalence of (32%) [32] and India prevalence of (37%) [33]. However, the current study was lower than previous studies done in Ethiopia 49% [34], 46.7% and 48.7% [35, 36] Bahir Dar, Ethiopia 49.4% [37], Tanzania with prevalence 42.2% [38], Addis Ababa 54.4% [39] and Jimma, Ethiopia 64% [40]. In the current study, the predominant Gram-negative bacteria were Escherichia coli with a prevalence rate of 78/285 (27.4%) followed by K. puenimoniae accounting for 69/285 (24.2%), P. aeruginosa 39/285 (21.8%) and C. freundii with 19/285 (6.7%). The least isolated was P. vulgaris, which accounted for 7/285 (2.5%). This is concurrent with findings from other studies in Ethiopia [41,42,43], Burkina Faso [44], Uganda [45], India [46], Yemen [47, 48]. However, it is higher than other studies conducted in India [49], Addis Abeba, Ethiopia and Dessie, Ethiopia [46, 50]. Whereas the present study findings were lower than those reported by the University of Gondar, Northwest Ethiopia [51]. This could be due to the differences in sample size, infection site, patient age, various types of samples from various wards, medical system, duration of stay [51].

In the current study, the most common isolates from the urinary tract, wound infection, and bloodstream infection were E. coli and K. pneumoniae. This is also consistent with other Ethiopian reports [42, 52, 53]. This may be attributed to the fact that E. coli and K. pneumoniae are commonly found in the natural flora of the gastrointestinal tract. Particularly in females, they often enter the urinary tract from contaminated feces and can subsequently spread to other organs, leading to illness. Additionally, their fimbriae structure facilitates colonization and invasion of various body sites [54, 55].

As indicated by periodic outbreaks, Gram-negative bacilli have long been recognized as major causes of hospital-acquired infections around the world, with a wide range of antibiotic resistance that makes them dangerous in the healthcare setting and have posed significant issues for global healthcare management [56]. In the present study, Gram-negative bacilli isolate revealed high levels of resistance to doxycycline (92.9%), amoxicillin-clavulanic acid (83.9%), and ampicillin (93.3%), respectively. This could be due to the widespread availability and indiscriminate use of these antibiotics in the areas. However, meropenem and amikacin showed relative sensitivity due to less frequent prescribed and amikacin is unavailable in the local area. This finding is supported by studies done in Bahir Dar, Ethiopia [57], Vietnam [58], and Kenya [59]. However other studies showing high rate resistance were reported in studies from Jimma, Ethiopia for amoxicillin-clavulanic acid (90.3%) [60], Benin for amoxicillin-clavulanic acid (85.7%) and cefotaxime (56.5%) [61] and India for cefotaxime (76.3%) and ceftazidime (64.5% [62]. This is because Gram-negative bacilli are known to acquire resistant plasmids from intra and inter-species sources, which is important for obtaining resistance genes for a variety of antimicrobial drugs. In this study, meropenem and amikacin resistance were found in lower proportions in Gram-negative bacilli, which could be due to a lack of meropenem and amikacin prescription practice in Ethiopia, as these antibiotics are used as a last resort in the treatment of serious infections and are comparatively more expensive.

According to the international standard for definition of drug resistance [27], multi-drug resistance was observed in 89.4% of the total isolated bacteria in the current study. This was relatively similar to a study done in Gondar, reported as (93.5% and 87.4%) [42, 63], Bahirdar (93.1%) [64], Iran ( 88.5%) [65], India 93% and 95% [66, 67], Addis Abeba 92.9% [34] and Kenya 85% [59]. However, higher than the study from Bahirdar Ethiopia 76% [68], Debre Markos, Ethiopia 76.1% [69] and Cameron 79 0.4% [70]. Bahir Dar, Ethiopia (61.8%) [71], Addis Ababa (43.3%) [72], Dessie Ethiopia (74.6%) Nigeria (67.2%) [73] and Indonesia (47.7%) [74]. In another way, it was lower in Nepal (96.84%) [75]. However, our result was higher than a study reported from Ethiopia that ranged from; 17.9% -to 56.7% [76,77,78]; and a systematic review report of 59.7% overall MDR prevalence in Ethiopia [76], USA 46% [79], Bosnia and Herzegovina 78.4% [80], India 54.7% [81], Saudi Arabia 69% [82] and India 37 out of 73 were developed MDR [83]. The possible reason for this rise in MDR might be antibiotics are taken longer than necessary or when they are not needed, broad-spectrum antibiotics and Poor infection control increase infection rates, the likelihood of multidrug-resistant bacteria, and the risk of outbreaks in specific bacteria that could spread to the entire hospital and community [84].

About 92.7% of K. pneumoniae, 91.01% of E. coli, 93.5% of P. aeruginosa, 89.5% of C. freundii, 92.3% of Acinetobacter species, and 83.3% of H. influenzae isolates developed MDR. The main contributing factors might be the ability of K. pneumoniae and other bacteria to develop MDR by expressing resistance genes, including external and mobile genetic elements, producing extended-spectrum beta-lactamases and carbapenems, aminoglycoside-modifying enzymes, and porin-efflux mechanisms [85, 86]. The variation might be due to that isolated strain among populations, geographic differences, variation in local antimicrobial prescribing, and the incidence of resistant bacterial strains E. coli and C. freundii [87].

The present study showed that the highest ESBL production was observed in P. aeruginosa 54.8%) followed by Acinetobacter species (53.8%) and K. pneumoniae (47.8%%). Which was higher than the study-reported ESBL production in Arba Minch, E. coli (44%) [17], Gondar, E. coli (16.2%) [64], India, E. coli (44%) [88], in Burkina Faso, K. pneumonia (26%) [89], in Adamma, K. pneumonia (11.5%) [90], Morocco, reported as E. coli (19.4%) [91]. Whereas, the current study result of ESBL production was lower as compared to findings from Addis Ababa, reported as E. coli (70%) [72], Tanzania, reported as E. coli (68%) [92], Burkina Faso, reported as E. coli (78%) [44]. Although infection caused by ESBL and carbapenemase-producing Enterobacteriaceae is a global threat; the burden is high in low-income countries like Sub-Saharan Africa where widespread self-treatment, overcrowding of hospitals, absence of antibiotic prescription guidelines, poor infection control practices, and poor hygiene and antibiotic misuse are common [93] and unavailability of routine diagnosis of antimicrobial susceptibility testing.

Furthermore, of the total isolated bacteria, 24.6%, 40%, and 16.6% caused bacterial infections in the urinary tract, wound infection, and lower respiratory tract, respectively. A similar finding was reported in Bahirdar Ethiopia [94, 95], a systematic review in Ethiopia indicated bacterial infections in the urinary tract, wound infections, and lower respiratory tract [96], Mexico [97]and China [98]. This could be because the bacteria are constantly exposed to a variety of beta-lactams, which cause plasmid and chromosomal genes to produce beta-lactamase, a major source of antibiotic resistance. The development of β-lactamase is the most common mechanism of Enterobacteriaceae resistance to penicillins, cephalosporins, and aztreonam. Beta-lactamases, which break the amide link in the antibiotic’s beta-lactam ring, render these antibiotics inactive [99]. To increase the accuracy of ESBL detection, it is recommended that at least two indicator cephalosporins be used in conjunction. The most often used antimicrobial medicines as markers in screening tests are ceftazidime, cefotaxime, ceftriaxone, and aztreonam.

In the current study, 34.7% of Gram-negative bacilli isolates were CP producers. Similar findings were reported in Nigeria [100] and India [101], which accounted for 34.5%. However, it is higher than reports from a previous study in western Ethiopia (2.7%) [42], Bahirdar Ethiopia (5.2%) [94], Addis Ababa Ethiopia (2%) [102], Addis Ababa (1.2%) [103], Arbaminch (1.43%) [17], Gondar (2.73%) [42] and Morocco (2.8%) [104], (16.5%) [37], Addis Ababa (12.2%) [52], India (12.4%) [105]. However, Our result was lower than compared findings in Uganda (22.4%) [103], Sudan (56%) [104], and India (23.0%) [106]. The difference in the study period could explain the increase in carbapenemase production. Furthermore, 75% of the CR isolates in the current study were CP. They are more easily spread, and resistance-determining genes can spread within and across enteric bacterial species at the same time [107]. The magnitude of ESBL-producing Gram-negative bacilli was 46.3% (132/285), which is comparable with the previous studies done in Burkina Faso (42%) [44], Bahir Dar Ethiopia (46%) [95]. However, it was lower than previous studies in Ethiopia Addis Ababa (58%), Bahir Dar (57.6%), Jimma (63.4%) [60], and elsewhere like India (62.7%) [89] and Uganda (89%) [103]. Different studies have found a higher prevalence of ESBL, which could be attributed to higher Enterobacteriaceae colonization in hospitals, which boosts the dissemination of ESBL genes in health-care-associated strains [107]. Furthermore, our findings were higher than compared to the same studies reported in Adama (25%) [90], Jimma (38%) [108], and Nepal (34%) [75]. This variation might indicate the increment of ESBL with time, which could be because of a rise in antibiotic use. Despite differences in the amount of ESBL, all data pointed to an increase in ESBL-producing isolates in developing countries, which might be attributed to widespread use of cephalosporins and poor compliance of patients with prescribed drugs, which might contribute to the occurrence of increased ESBL production in Enterobacteriaceae.

The proportion of carbapenemase-producing Gram-negative bacilli isolated from the bloodstream, urinary tract, wound infection, meningitis and peritonitis, eye and ear infections, and lower tract infections was 30%, 35.7%, 35.1%, 26.7%, 30%, and 33.3%, respectively. The present study showed that the highest carbapenemase-producing was observed in P. mirabilis (50%), followed by P. aeruginosa (41.9%), C. freundii (36.8%) and K. pneumoniae (36.2%). Similarly, a high rate of carbapenemase-producing bacteria were isolated were K. pneumoniae (30%) in Jimma, Ethiopia [41]. Regardless of the percentage, the rate of CP in the Bahirdar study was E. cloacae (20%), K. pneumoniae (9.7%), and E. coli (2.9%) [41], and in other parts of Ethiopia, E. cloacae, K. pneumoniae, and E. coli were the predominant CP producers [41, 42]. This might be due to the spread of carbapenem-producing Klebsiella spp. and E. coli. Several contributing factors, such as limiting a drug’s absorption, altering a drug’s target, inactivating a drug, and active efflux of a drug, were involved. These processes may be present in bacteria or have been acquired from other organisms. Significant factors include increased chromosomal cephalosporins activity, higher efflux system expression, lower porin expression, and carbapenemase driven by plasmids or integrons [109].

The most important risk factors for Gram-negative bacilli infections were a history of antibiotic use, length of ICU stay, mechanical ventilation, and catheter use. Illiteracy (AOR: 5.6; 95% CI: 1.74–25.99), rural residence (AOR: 7.3; 95% CI: 1.23–25.33), cigarette smoking habit (AOR: 7.7; 95% CI: 1.55–44.33), surgical ward patients (AOR: 11.3; 95% CI: 6.5–146.3), pediatrics (AOR: 15.5; 95% CI: 2.4–155.8), When compared to hospitalized patients with no underlying chronic condition, additional chronic patients with HIV (AOR: 9.27; 95%CI: 1.3–53.8) and patients with liver and kidney failure (AOR: 8.55; 95%CI: 1.6-49.33) were statistically significantly at risk for hospital-associated infection rate of Gram-negative bacilli. Statistically significant risk for a hospital-associated infection rate of Gram-negative bacilli was also reported in previous studies in Taiwan [110], North India [111], and Bahir Dar, Ethiopia [57] in India: diabetes, HIV, neurological disease [81], Bosnia and Herzegovina: diabetes [80]. This could be due to patients being exposed to the two viruses through the hospital environment, health care professionals, linked gadgets, and cross-contamination. This could be because patients with underlying chronic diseases are more likely to visit hospitals, potentially exposing them to nosocomial infections. On the other hand, patients taking more than one drug type were less likely to develop Gram-negative bacilli infections as compared to patients who did not take antibiotics. According to the study, individuals who received three or more kinds of antibiotics upon admission were 65% more protected from nosocomial infection than those who did not receive any antimicrobials. Longitudinal studies to monitor changes in infection rates and resistance patterns over time will help assess the effectiveness of infection control measures and antibiotic stewardship programs. These studies can offer valuable insights into their impact on resistance trends.

Conclusion and recommendation

The study found a significant prevalence of healthcare-associated Gram-negative bacilli infections. E. coli was the most common isolate. The infections were distributed across various types, with wound infections being the most frequent. A substantial proportion of the infections were resistant to multiple drugs, with particularly high resistance rates observed for doxycycline, amoxicillin-clavulanic acid, and ampicillin. In contrast, resistance to meropenem and amikacin was comparatively lower. Carbapenem resistance is rapidly spreading among nosocomial infection isolates in the study area, which is linked to a high proportion of MDR, carbapenemase, and extended-spectrum beta-lactamase-producing isolates. Third-generation cephalosporin resistance is also a significant problem. To change the overuse of antimicrobials, it is necessary to improve infection prevention strategies and conduct more national surveillance on the profile of carbapenem resistance, carbapenemase, and ESBL and CP production, as well as conducting genomic studies, in nosocomial infection clinical isolates. Furthermore, more extensive molecular investigations, as well as research into the prevalence of ESBL and CP-producing Gram-negative bacilli infections in this region, are needed to get a better picture of the scope of the problem with ESBL and Gram-negative bacilli infections.

Limitation of the study

Due to a scarcity of confirmatory kits, ESBL, AmpC beta-lactamase, and carbapenemase were not genotypically confirmed. A molecular assay for the characterization of ESBL and carbapenemase genes in isolated Gram-negative bacilli was not performed. Healthy participants from the community were not included as a control group, even though it was beyond the scope of the study.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ATCC:

American Type Culture Collection

AMR:

Antimicrobial Resistance

ART:

Antiretroviral therapy

BA:

Blood Agar

BSI:

Blood Stream Infection

CR:

Carbapenem Resistance

CP:

Carbapenemase Producing

CLSI:

Clinical Laboratory and Standards Institute

ESBL:

Extended Spectrum Beta-Lactamases

ESBL:

Extended Spectrum Beta-Lactamases

FHCSH:

Felege Hiwot Comprehensive Specialized Hospital

FHCSH:

Felege Hiwot Comprehensive Specialized Hospital

LRTI:

Lower Respiratory Tract Infections

MAC:

MacConkey Agar

MHA:

Muller-Hilton Agar

MDR:

Multidrug resistance

SOPs:

Standard Operating Procedures

SPSS:

Statistical Package for Social Sciences

TSB:

Tryptic Soy Broth

UTI:

Urinary Tract Infection

BS:

Bekele Sharew

MT:

Mihret Tilahun

AS:

Agumas Shibabaw

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Acknowledgements

The authors would like to thank the Department of Medical Laboratory Science at Wollo University for providing the laboratory setup and facilities for the investigations. Health facilities, as well as all research participants and data collectors, are thanked for their cooperation throughout data collection.

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Authors and Affiliations

  1. Department of Medical Laboratory Science, College of Medicine and Health Sciences, Wollo University, Dessie, 1145, Ethiopia

    Mihret Tilahun & Agumas Shibabaw

  2. Department of Medical Laboratory Science, College of Health Sciences, Debre Tabor University, Debre-Tabor, Ethiopia

    Bekele Sharew

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  1. Mihret Tilahun
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All authors were involved in proposal writing and designing the study; and participated in the analysis and interpretation of data. All authors were involved in the data collection and drafting of the manuscript. All authors finalized the write-up of the manuscript. All authors critically revised the manuscript, read and approved the final manuscript for publication.

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Correspondence to Mihret Tilahun.

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Ethical approval and consent

This study was conducted by the Declaration of Helsinki. Ethical approval was received from the Ethical Review Committee of the College of Medicine and Health Sciences, Wollo University (Reference No: CMHS/HC/358/13). An official permission letter was obtained from each study health facility before data collection. All study participants participated voluntarily after getting written informed consent. Before beginning the study, written agreements and consent forms were obtained for all patients, and for those study participants whose age less than 18 years, parents/guardians participated to give assent for their children before data collection. Codes and secret lockers were used to maintain confidentially. All culture-positive cases were referred to the respective attending physicians for treatment and follow-up.

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Tilahun, M., Sharew, B. & Shibabaw, A. Antimicrobial resistance profile and associated factors of hospital-acquired gram-negative bacterial pathogens among hospitalized patients in northeast Ethiopia. BMC Microbiol 24, 339 (2024). https://doi.org/10.1186/s12866-024-03485-0

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BMC Microbiology

ISSN: 1471-2180

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