Etiology of bacterial pneumonia and multi-drug resistance pattern among pneumonia suspected patients in Ethiopia: a systematic review and meta-analysis

Background Bacterial pneumonia can affect all age groups, but people with weakened immune systems, young children, and the elderly are at a higher risk. Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa are the most common causative agents of pneumonia, and they have developed high MDR in recent decades in Ethiopia. This systematic review and meta-analysis aimed to determine the pooled prevalence of bacterial pneumonia and multidrug resistance in Ethiopia. Methods The articles were searched extensively in the electronic databases and grey literature using entry terms or phrases. Studies meeting the eligibility criteria were extracted in MS Excel and exported for statistical analysis into STATA version 14 software. The pooled prevalence of bacterial pneumonia and multidrug resistance were calculated using a random-effects model. Heterogeneity was assessed by using the I2 value. Publication bias was assessed using a funnel plot and Egger’s test. A sensitivity analysis was done to assess the impact of a single study on the pooled effect size. Result Of the 651 studies identified, 87 were eligible for qualitative analysis, of which 11 were included in the meta-analysis consisting of 1154 isolates. The individual studies reported prevalence of bacterial pneumonia ranging from 6.19 to 46.3%. In this systematic review and metanalysis, the pooled prevalence of bacterial pneumonia in Ethiopia was 37.17% (95% CI 25.72–46.62), with substantial heterogeneity (I2 = 98.4%, p < 0.001) across the studies. The pooled prevalence of multidrug resistance in bacteria isolated from patients with pneumonia in Ethiopia was 67.73% (95% CI: 57.05–78.40). The most commonly isolated bacteria was Klebsiella pneumoniae, with pooled prevalence of 21.97% (95% CI 16.11–27.83), followed by Streptococcus pneumoniae, with pooled prevalence of 17.02% (95% CI 9.19–24.86), respectively. Conclusion The pooled prevalence of bacterial isolates from bacterial pneumonia and their multidrug resistance were high among Ethiopian population. The initial empirical treatment of these patients remains challenging because of the strikingly high prevalence of antimicrobial resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-024-03000-1.


Introduction
Pneumonia is an infection-induced inflammation of the lung tissue due to infectious caused by bacteria and other agents [1].There is a very wide variety of pneumoniaresponsible pathogens with the largest agents are bacteria [2] and resulting in approximately 7 million deaths annually [3].The most common causative agents are Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H.influenzae), Klebsiella pneumoniae (K.pneumoniae), Pseudomonas aeruginosa (P.aeruginosa), Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus) [4].In Spain, S. pneumoniae was the leading species in causing bacterial pneumonia which accounts for 31.7%[5].Varying prevalence of bacterial pneumonia were reported in different parts of Ethiopia; 42.9% in southern Ethiopia and 32.1% in central Ethiopia, with S. pneumoniae and K. pneumoniae were predominant isolates, respectively [6,7].
Bacterial pneumonia causes complications for everyone, but individuals with weakened immune systems, children, and the elderly are at higher risk [8].Community and hospital-acquired pneumonia are the two main types of pneumonia.In the community, with a high prevalence, and it causes significant morbidity and mortality [9].Patients living with HIV/AIDS especially those who had co-infection with one or more microorganisms, and older age individuals are more susceptible for infections with bacterial pneumonia [10].The positive culture rate was slightly higher in women than in men and higher prevalence rates of lower respiratory tract infections were observed in age groups greater than or equal to 45 years [11].
The main problem concerning about treatment of bacteria causing pneumonia is multidrug resistance (MDR) (antibiotic resistance to at least three or more than three classes), extensively drug resistant (XDR) (resistance to all antibiotics classes except one), and pan-drug resistant (PDR) (resistance to all groups of antibiotics) [12,13].There are different mechanisms in which bacteria can escape from the effect of antibiotics.Resistance to one or more groups of antimicrobial agents may be innate or acquired by bacteria.The antibiotic resistance crisis is due to emerging and dissemination antibiotic resistance pathogen in the hospital and environments, inappropriate drug use, over use and consumption of drug resistant pathogens from animal sources and crops [14].
In China most frequently prescribed antibiotics including penicillin, erythromycin, tetracycline and clindamycin resistance were pertained by S. aureus, and S. pneumoniae was highly resistant to erythromycin, azithromycin and clindamycin.E. coli, was resistant to ampicillin, gentamicin, and ciprofloxacin.K. pneumoniae, has the highest resistance to gentamicin and ampicillin [15].Similarly, cotrimoxazole was 100% resistant to S. aureus and S. pneumoniae.K. pneumoniae was resistant to most of the antibiotics showing more than 50% resistance to ceftriaxone and cefotaxime drugs respectively [16].
Nigeria's Analysis of pneumonia-associated bacteria among HIV/AIDS patients in Nigeria showed that P. aeruginosa were highly resistant to all antibiotics including ciprofloxacin and ceftazidime whereas E. coli, S. aureus and K. pneumoniae were resistance to commonly prescribing drugs [17].Gram-negative bacilli were highly resistant to ampicillin tetracycline, ciprofloxacin, and trimethoprim-sulfamethoxazole [7].On the other hand, most of the isolates were less resistant to amikacin.Methicillin resistance was observed in isolates of S. aureus [18].This study is the first systematic review and meta-analysis to report the national burden of bacterial pneumonia and MDR in Ethiopia; and it aimed to summarize the findings of local studies and estimate the pooled prevalence of bacterial pneumonia and MDR in Ethiopia.

Design and protocol registration
This systematic review and meta-analysis were designed to estimate the pooled prevalence of bacterial pneumonia and their multi-drug resistance pattern in Ethiopia based on the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) [19].The review protocol was registered in the international prospective register of systematic review (PROSPERO) under registration number CRD42023414098.omission during electronic database searches, a direct google search was carried out using listed references in included articles.The comprehensive and extensive searching strategy has been employed using condition, context, population, and outcome of interest (CoCoPop) formulating questions and searching terms were (''prevalence"), ("epidemiology") ("magnitude"), and ("bacterial pneumonia") and ("antimicrobial resistance"), ("antibiotic resistance") and ("antibiotic susceptibility"), ("hospitalacquired pneumonia"), ("community-acquired pneumonia") and ("Ethiopia").The search terms were combined using the Boolean operators "OR" and "AND" to fit the advanced searching of articles.

Eligibility criteria
The authors developed a selection criteria checklist for study eligibility before identifying appropriately published, relevant full-text articles either in local or international journals.We included published and preprint (study done at Bahirdar University) of original articles that reported bacterial pneumonia and their antimicrobial resistance pattern in all age populations of Ethiopia, studies written in English, and laboratory-based observational (e.g., cross-sectional) studies.We excluded studies with no confirmation of bacterial isolates using phenotypic and/or genotypic methods, qualitative studies, review papers, commentaries, case series, case reports, conference proceedings, and abstracts.

Data extraction
Data extraction was performed by four independent reviewers (HD, MT, OM, and HE) using a standard extraction format adapted from the Joanna Briggs Institute (JBI) data extraction format [20] and recorded them in a Microsoft Excel spreadsheet.
The extracted data includes, the first author's name and year of publication, the study period, the study design, the study region, the total sample size, the number of isolates, the criteria for diagnosing bacterial isolates causing pneumonia, the number and percentage of Gram-positive and Gram-negative bacteria, and the prevalence MDR of commonly identified bacteria.

Quality assessment
Four authors (MT, AG, HD, and MAB) carefully assessed the quality of the articles using JBI quality appraisal tool.The full texts of the articles were used to determine whether the study met the selection criteria or whether the eligibility of the article was called into question [30].By using the critical appraisal checklists, studies with an average score of 50-75% were considered of good quality, while scores greater than 75% were considered of high quality.As a result, articles of both good and high quality were included for the analysis [31] (Supplementary Table 1).

Outcome variables
Two findings were drawn from this systematic review and meta-analysis.The first goal was to determine the pooled estimates of bacterial pneumonia among pneumonia suspected Ethiopian patients.The second goal was to calculate the pooled prevalence of MDR of common pathogens.

Data processing and analysis
The data were analyzed by using STATA version 14.0 statistical software.A random effect model was applied to estimate the pooled estimate and MDR of the isolates.A potential source of heterogeneity was investigated by subgroup and meta-regression analysis.The Cochran's Q test and I 2 statistics were used to quantify and assess the presence of heterogeneity between studies.The p-value of < 0.05 for I 2 statistics was used to determine the presence of heterogeneity [21] and Der Simonian-Laired random effects model was employed [22].Subgroup analysis was done based on the patient's region, city, study design, and HIV sero-status.The results were presented using table and forest plot.Publication bias was evaluated using inspection of funnel plot symmetry and Egger's test statistics.The Trim-and-Fill was used in asymmetrical funnel plots to integrate missing studies and estimate adjusted effect size.Meta-regression was also used to further assess the cause of heterogeneity.

The pooled prevalence of bacterial pneumonia
A total of 11 studies reported that bacterial pneumonia infections were detected in 1151 samples out of a total of 3423 samples taken from bacterial pneumonia suspected patients who visit the health care system.In this systematic review and meta-analysis, the overall pooled prevalence of bacterial pneumonia in Ethiopia was 37.17% (95% CI 25.72-48.62%)with substantial heterogeneity (I 2 = 98.4%, p < 0.001) across the studies.(Fig. 2).

Sensitivity analysis
According to our sensitivity analysis finding, each study did not affect the pooled estimate of the proportion indicating the precise aggregate result.When individual studies were omitted, the pooled effect size lay within the 95% confidence interval of the overall pooled effect size.This demonstrated that no single study had an impact on the overall pooled prevalence of bacterial pneumonia infection in Ethiopia (Table 4).

Publication bias
The funnel plot was used to assess the impact of the small-studies effect or publication bias on estimated pooled prevalence.In this study, the asymmetry of the funnel plot illustrated the presence of publication bias with over 63.6% of the studies skewed to the right side of the triangular zone (Fig. 5).Furthermore, Egger's test  statistics also confirmed the presence of significant publication bias at a P-value < 0.001 (Table 5) (Fig. 6).

Trim and fill analysis of the pooled prevalence of bacterial pneumonia in Ethiopia
Due to the presence of slightly significant publication bias, we performed a trim and fill analysis.After incorporating 6 studies, the trim and fill analysis revealed a pooled prevalence of bacterial pneumonia in Ethiopia was 21.33% (95% CI:10.86-31.798)(Table 6).

Meta-regression
Meta-regression was carried out to further explore the potential sources of heterogeneity or variability among studies included in the meta-analysis.We included continuous study characteristics as covariates including published year, sample size, and number of isolates.In this study, total isolates and sample size were the responsible variables for the existence of heterogeneity between studies (P < 0.001) (Table 7).

Discussions
Bacterial pneumonia is one of the most serious public health issues due to the high medical and economic costs that result in increased morbidity and mortality in people of all ages worldwide [33].Bacterial pneumonia is characterized by a productive cough, fever with shaking chills, shortness of breath, sharp chest pain during deep breaths, increasing rate of breathing and confusion may be the most noticeable symptom in the elderly [34].
The main aim of this study was to determine the pooled prevalence of bacterial pneumonia and MDR of bacterial isolates causing pneumonia in Ethiopia, involving about 3428 study participants.
In this meta-analysis, Gram-negative bacteria accounted for 61.5% of culture-positive samples.Similarly, another review article reported 76.13 to 95.3% of Gram-negative bacteria as the cause of bacterial pneumonia infections [53].The high prevalence of Gram-negative bacteria in various research is due to differences in sample size, geographic location, study period, study population, and respiratory flora specimen contamination.
In the current review, substantial heterogeneity with an (I 2 = 97.2%,p < 0.001) was found.This study's substantial heterogeneity is most likely not attributable to publication bias, but rather to variances in methodological concerns such as sample size, target population categories, and patient underpinning circumstances.The other difference could be attributed to the target group from which samples were collected and the antibiotic resistance crisis, primarily because antibiotics lose their efficacy over time due to the emergence and spread of resistance among bacterial pathogens, which is primarily caused by the overuse and inappropriate use of antibiotics, as well as the widespread use of antibiotics in agriculture and the food industry.Antibiotic resistance is a natural phenomenon in bacteria that cannot be stopped; however, various measures can be taken to reduce the  rate of its development and devise more effective strategies to control its spread.Sensitivity analysis, sub-group analysis, and metaregression have been carried-out to rule out the most possible causes of heterogeneity.The results of sensitivity analysis proved that there is no single study that impacted the pooled effect size.The pooled prevalence of bacterial pneumonia infections in Ethiopia was calculated by omitting each study sequentially and the computed pooled prevalence was within 95% CI of the overall pooled prevalence.Meta-regression has confirmed that a number of total pathogens isolates and sample size were a significant cause of heterogeneity in prevalence of bacterial pneumonia while publication year was not found to  be a significant cause.In addition to this, publication bias was assessed using funnel plot and Egger's test statistics, and trim and fill analysis was performed to fill the bias.
One of the notable strengths of this study is its comprehensive nature, being the first of its kind to conduct a thorough analysis of bacterial pneumonia and MDR within Ethiopia.It encompasses a wide range of studies conducted across multiple regions and cities of the country, providing a robust overview.
Furthermore, the study included various studies done in different target populations using clinical specimens to show a clear picture of bacterial pneumonia and MDR in the country.However, the results should be interpreted with caution, as the reviewed studies were highly heterogeneous in terms of prevalence, aetiology, study setups, study participants, disease conditions, clinical specimens, sample sizes, and AST methods.Therefore, to account for this heterogeneity, the random-effects model of Der Simonian and Laird was implemented in the meta-analyses.Moreover, subgroup analyses, sensitivity analysis, and meta-regression were conducted to further address and mitigate the impact of heterogeneity on the findings.

Conclusion
According to this systematic review and meta-analysis, the pooled prevalence of bacterial pneumonia infection and MDR have alarmingly increased and become a public health threat.The most common etiology identified was K. pneumoniae followed by S. pneumoniae.This indicates an urgent need of routine screening and appropriate treatment for better management of pneumonia suspected patients as well as effective controlling of the emergence of drug resistance.Furthermore, it serves as a wake-up call to international, continental, and national health bureaus, as well as other stakeholders, to develop targeted prevention and control strategies, and strengthen antibiotics stewardship programs for better management of hospital-acquired as well as community-acquired infections.Moreover, the data could be used for future complementary research and evidencebased decision-making both in clinical and public health approaches.

Fig. 2
Fig. 2 Forest plot showing the overall prevalence of bacterial pneumonia in Ethiopia

Fig. 4 Fig. 3
Fig. 4 Sub group analysis of MDR bacterial isolates by HIV sero-status bacterial pneumonia suspected patients in Ethiopia

Fig. 5
Fig. 5 Funnel plot on the prevalence of bacterial pneumonia in Ethiopia illustrating the presence of publication bias

Table 1
Overview of included studies

Table 2
Subgroup analysis of bacterial pneumonia by region, HIV sero-status, publication year and sample size

Table 3
Bacterial isolates from pneumonia-suspected patients in Ethiopia

Table 4
Sensitivity analysis of the included studies

Table 5
Egger's test statistics of the prevalence of bacterial pneumonia in Ethiopia

Table 6
Trim and fill analysis of the prevalence of bacterial pneumonia in Ethiopia

Table 7
Meta-regression analysis of prevalence and MDR pattern of bacterial pneumonia by different categories of studies included in the systematic review and meta-analysis *= significant causes of heterogeneity