SYSTEMATIC REVIEW OF THE ANTIBIOTIC RESISTANCE PATTERNS AND TREATMENT EFFICACY IN YERSINIA PESTIS INFECTIONS

Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [228] SYSTEMATIC REVIEW OF THE ANTIBIOTIC RESISTANCE PATTERNS AND TREATMENT EFFICACY IN YERSINIA PESTIS INFECTIONS Jhoycel A. Bakiki¹ Blesy P. Dampios¹ Angelica B. Garalde¹ James Danielle S. Baguing¹ Julius C. Silapan¹ Gecelene C. Estorico¹’² Civil and Allied Department; Environmental Science and Chemical Technology Department 1Technological University of the Philippines—Taguig, Taguig, Metro Manila 1630 Philippines ²De La Salle University – Dasmariñas, DBB-B, 4115 West Ave, Dasmariñas, ABSTRACT Yersinia pestis, the etiological agent of plague, remains a persistent and potentially lethal pathogen, with the emergence of antibiotic-resistant strains complicating effective clinical management. This systematic review evaluates antibiotic resistance patterns and treatment efficacy for Yersinia pestis infections, synthesizing data from thirteen peer-reviewed studies published between 2018 and 2025. The review identifies plasmid-mediated doxycycline resistance and a novel streptomycin resistance mechanism as key findings. While fluoroquinolones and gentamicin demonstrate high treatment success rates, multi-drug resistant strains necessitate continuous monitoring. This review informs evidence-based therapeutic decisions amid shifting antimicrobial landscapes, highlighting the need for improved stewardship and surveillance. Keywords: antibiotic resistance, plague, doxycycline resistance, streptomycin resistance, fluoroquinolones, gentamicin, multi-drug resistance I. INTRODUCTION Yersinia pestis, identified as the causative agent of plague, continues to pose a significant threat to public health, despite substantial advancements in medical science. Transmission principally occurs through the bite of infected fleas or by direct exposure to contaminated materials, resulting in bubonic, septicemic, or pneumonic forms of the disease. Although historically notorious for widespread pandemics, plague remains endemic in several regions, necessitating sustained surveillance and the development of updated therapeutic strategies (Lei et al., 2022; Kugeler et al., 2020). The magnitude of plague as a public health threat has been complicated by the emergence of antibiotic-resistant strains of Y. pestis. Antibiotics such as streptomycin and tetracyclines have historically been used to treat plague, but resistance mechanisms are becoming more well recognized. It has been discovered that resistance genes, which are frequently carried on plasmids, give multidrug resistance, endangering the efficacy of traditional treatments (Lei et al., 2022; Reudenberg et al., 2025). The potential for horizontal transfer of resistance genes, especially within natural plague foci, exacerbates these concerns and highlights the necessity for robust antimicrobial stewardship. Effective clinical management of plague relies heavily on rapid diagnosis and the timely administration of appropriate antibiotics. Antibiotics like streptomycin and tetracyclines have historically been used to treat plague, but resistance mechanisms are becoming more well recognized. It has been discovered that resistance genes, which are frequently carried on plasmids, give multidrug resistance, endangering the efficacy of traditional treatments (Lei et al., 2022; Reudenberg et al., 2025).The World Health Organization and Centers for Disease Control and Prevention recommend aminoglycosides, doxycycline, and fluoroquinolones as first-line treatments, yet reports Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [229] of treatment failure linked to resistant strains have been documented (Kugeler et al., 2020; CDC, 2025). Moreover, insights from case reviews indicate that delays in treatment initiation are strongly associated with increased mortality, emphasizing the urgent need to optimize therapeutic protocols (Poland et al., 2020). Ongoing research is vital in identifying novel treatment approaches and monitoring resistance trends. Experimental and clinical studies have begun to explore alternative antimicrobials as well as combination therapies to overcome resistant infections (Perry et al., 2025). Additionally, advances in molecular diagnostics and genomic surveillance allow for more precise detection of resistance markers and epidemiological tracking, facilitating timely public health responses (Lei et al., 2022). This systematic review aims to comprehensively evaluate existing reports on antibiotic resistance patterns and treatment efficacy for Yersinia pestis infections worldwide. Synthesizing data from diverse geographic and clinical contexts will provide critical insights into emerging resistance trends and inform evidence-based therapeutic decisions. Maintaining the effectiveness of available antibiotics and exploring new treatment options remain paramount to controlling plague and preventing potential outbreaks amid shifting antimicrobial landscapes. II. OBJECTIVES The objectives of this systematic review are: (1) to comprehensively identify and synthesize evidence on antibiotic resistance patterns in Yersinia pestis isolates from diverse geographic regions and time periods; (2) to evaluate the mechanisms of antibiotic resistance, including plasmid-mediated gene transfer and chromosomal mutations; (3) to assess the clinical efficacy of current antibiotic treatments for plague by examining patient recovery and mortality outcomes; (4) to highlight cases of treatment failure associated with multidrug-resistant Y. pestis strains and the challenges they pose for clinical management; (5) to provide evidence-based recommendations aimed at improving antibiotic stewardship, surveillance, and therapeutic strategies against resistant strains; and (6) to identify research gaps that can guide future studies to enhance plague control efforts in the context of emerging antimicrobial resistance. III. METHODOLOGY This section describes the systematic approach used to identify, evaluate, and synthesize existing studies on antibiotic resistance patterns and treatment efficacy in Yersinia pestis infections. The methodology outlines the procedures for data collection, inclusion and exclusion of studies, data extraction, and statistical analysis to ensure accuracy, transparency, and reliability of the review findings. This study involved a series of standardized microbiological and molecular procedures designed to confirm the identity of Yersinia pestis, assess its antimicrobial susceptibility, and detect genetic determinants of antibiotic resistance. These methods were conducted following international laboratory standards and biosafety protocols. The methods included the following: ● Minimum Inhibitory Concentration (MIC) testing - To quantify the lowest antibiotic concentration that inhibits bacterial growth in vitro ● Animal Infection Models - To test the efficacy of antibiotics in living hosts under plague infection conditions ● Molecular / genetic methods (PCR, plasmid profiling, whole-genome sequencing) - To detect resistance genes (plasmid-borne or chromosomal) and understand resistance mechanisms ● Antimicrobial Susceptibility Testing (AST) - To determine which antibiotics Y. pestis isolates are resistant or susceptible to. ● Bacterial Culture and Isolation - To confirm the presence of Yersinia pestis in clinical specimens (e.g., blood, sputum, bubo aspirate, or tissue). ● Serological Testing (F1 Antigen Detection / ELISA) - To confirm infection by detecting antibodies or antigens specific to Y. pestis. Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [230] ● Microscopic Staining (Gram, Giemsa, Wright’s, or Wayson Staining) - To visually identify Yersinia pestis and confirm its morphology and staining characteristics. ● Kirby–Bauer Disk Diffusion Method - To determine the antibiotic susceptibility of Y. pestis isolates. ● Plasmid Extraction and Conjugation Experiments - To isolate resistance plasmids and confirm their ability to transfer between bacteria. ❖ Data Sources The primary sources for this systematic review comprised peer-reviewed academic articles and research papers retrieved from major scientific databases, including, PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, and Google Scholar. Additional literature was identified through manual searches of the reference lists of included studies and relevant review articles. Furthermore, authoritative public health guidance documents such as the Centers for Disease Control and Prevention (CDC) and the Morbidity and Mortality Weekly Report (MMWR) were examined to supplement scientific findings and ensure the inclusion of the most recent clinical recommendations. The search encompassed publications up to the year 2025, thereby capturing both historical case reports and contemporary molecular surveillance studies on Yersinia pestis. ❖ Inclusions and Exclusions To ensure the relevance and quality of the studies included in this systematic review, specific inclusion and exclusion criteria were established based on study design, content, and methodological rigor. Inclusion Criteria Studies were considered eligible for inclusion if they met the following criteria: ➢ Reported antibiotic susceptibility testing, resistance mechanisms, or antimicrobial efficacy related to Yersinia pestis isolates. ➢ Included clinical, experimental, or epidemiological data addressing antibiotic resistance or treatment outcomes in human or relevant animal models. ➢ Published in peer-reviewed journals and written in English to ensure accessibility and accuracy in interpretation. ➢ Provided sufficient methodological details, such as the type of antibiotics tested, methods used for susceptibility determination, and clinical outcomes. ➢ Published up to the year 2025, encompassing both historical and contemporary research to capture temporal variations in resistance trends and treatment efficacy. ❖ Exclusion Criteria Studies were excluded from the review if they met any of the following criteria: ➢ Articles that were reviews, editorials, commentaries, conference abstracts, or opinion papers without original data. ➢ Publications that did not focus on Yersinia pestis or lacked relevant information on antibiotic resistance or therapeutic outcomes. ➢ Studies with incomplete or unclear data regarding antibiotic testing methods or treatment protocols. ➢ Duplicate publications or studies presenting overlapping datasets, in which case the most comprehensive version was retained. ➢ Research published in languages other than English or inaccessible through major databases. Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [231] ❖ Search Results The search results yielded a range of relevant studies addressing antibiotic resistance patterns and treatment efficacy in Yersinia pestis. After applying the inclusion and exclusion criteria, 13 studies were determined to meet the eligibility requirements and were included in the final review. These studies provided comprehensive data on antimicrobial resistance mechanisms, clinical treatment responses, and the effectiveness of various antibiotic classes. The selected articles encompassed both clinical and laboratory-based investigations conducted across different regions where plague remains endemic. Each study was evaluated for methodological rigor, quality of evidence, and relevance to the research objectives, with emphasis on understanding how emerging antibiotic resistance influences treatment efficacy and public health management of Yersinia pestis infections. ❖ Data Extraction Data extraction was performed systematically to ensure accuracy and consistency across all included studies. For each eligible article, relevant information was carefully extracted and organized into standardized data collection forms. The extracted data included author(s), year of publication, study location, study design, sample size, type of Yersinia pestis strain analyzed, antibiotics tested, resistance mechanisms identified, treatment regimens used, and key clinical or experimental outcomes. Additionally, data on methodological quality, detection techniques, and reported treatment success or failure rates were recorded. ❖ Statistical Analysis The extracted data were analyzed using both descriptive and comparative statistical approaches to identify trends and patterns related to antibiotic resistance and treatment efficacy in Yersinia pestis infections. Quantitative data, including the frequency of resistance occurrence, treatment success rates, and mortality outcomes, were summarized using descriptive statistics such as percentages and frequency distributions. Studies reporting comparable outcome measures were examined collectively to determine overall tendencies in antibiotic performance and the prevalence of resistance across different geographic regions and study periods. IV. RESULTS AND DISCUSSION These tables represent research conducted across diverse geographical regions—primarily Madagascar and China—where plague remains endemic or periodically re-emergent. Table 1. provides a descriptive summary of the included studies, highlighting their locations, resistance profiles, tested antibiotics, treatment outcomes, and identified genetic mechanisms underlying resistance. By consolidating these findings, this review aims to illustrate how resistance in Y. pestis has evolved over recent years, identify persisting therapeutic options, and outline emerging molecular threats that could undermine current treatment regimens. To comprehensively assess the patterns of antibiotic resistance in Yersinia pestis, five peer-reviewed studies published between 2018 and 2025 were systematically analyzed. Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [232] Table 1. Descriptive Summary of Included Studies on Antibiotic Resistance and Treatment Efficacy in Yersinia pestis (2018–2025) Author & Year Study Location Sample Source Antibiotics Tested Main Findings / Key Results Recommendatio ns Cabanel, N. et al., 2018 Plasmidmediated doxycycline resistance in a Yersinia pestis strain isolated from a rat Madagas car Rat isolate Doxycycline, Tetracycline Found a plasmid (pIP1202) carrying tetB (tetracycline resistance) and sul2; first confirmed doxycycline resistance in Y. pestis. Enhanced molecular surveillance is to detect plasmidmediated resistance in Y. pestis early. Continuous monitoring of rodent reservoirs and updates to treatment guidelines in affected areas are essential to prevent further spread. Research on plasmid control strategies should also be prioritized. Dai, R. X., He, J., Zha, X., Wang, Y., Zhang, Y., Yang, X., Jin, J., Xin, Y., et al., 2021 A novel mechanism of streptomycin resistance in Yersinia pestis: Mutation in the rpsL gene Tibet, China Y. pestis strains from Marmota himalayana focus Streptomycin (+ screening of others for susceptibility ) Discovered a strain (S19960127) with very highlevel resistance to streptomycin (MIC ~4096 mg/L) due to a point mutation in rpsL (K43R) rather than plasmid mechanisms. Routine genetic screening for rpsL mutations should be implemented to identify chromosomal streptomycin resistance. Streptomycin monotherapy must be avoided in confirmed resistant cases, and alternative antibiotics should be guided by susceptibility testing. Ongoing monitoring and genetic studies Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [233] are needed to assess the fitness of resistant strains. Andrianaivoa rimanana, V. et al., 2022 Transmission of Antimicrobia l Resistant Yersinia pestis During a Pneumonic Plague Outbreak Madagas car Human outbreak isolates Streptomycin , Ciprofloxaci n, Gentamicin Multi-drug resistant strains detected during outbreak; resistance plasmids found; suggests possible human-tohuman or environmental transmission of resistant strains. Rapid resistance testing should be integrated into plague outbreak responses to detect resistant Y. pestis strains early. Strengthened infection control and tailored antibiotic regimens are needed to contain personto-person transmission. Genomic surveillance can help trace and prevent further spread of resistant strains. He, J., Yang, X., Jin, J., Xin, Y., Wang, Y., Li, J., Dai, R., Li, W., et al., 2022 Susceptibiliti es of Yersinia pestis to Twelve Antimicrobia l Agents in China Natural plague foci in China Strains isolated between 1943–2017 (1,012 strains) Twelve agents include streptomycin, ciprofloxacin , ofloxacin, chlorampheni col, ampicillin, ceftriaxone, etc. Only one strain (S19960127) was highly resistant to streptomycin; the rest (11/12 antibiotics) showed full susceptibility. Continuous antimicrobial susceptibility surveillance is advised to track resistance trends in natural plague foci. Streptomycin can remain the first-line treatment where effective, but vigilance is needed for emerging resistance. Preserving alternative antibiotics is key to Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [234] maintaining future treatment efficacy. Lemaitre, N. et al., 2025 Assessing the Threat of Yersinia pestis Harboring a Multi-drugResistance IncC Plasmid and the Efficacy of an Antibiotic Targeting LpxC Madagas car Lab & Animal models Doxycycline, Streptomycin , Chloramphen icol, Gentamicin, Ciprofloxaci n + LpxC inhibitor Demonstrated that an IncC plasmid causes high resistance to several antibiotics, but fluoroquinolon es and a novel LpxC inhibitor remained effective. Monitoring for IncC plasmid carriers should be sustained to prevent the spread of multidrug resistance. LpxC inhibitors show promise as effective alternatives and warrant further clinical evaluation. Responsible antibiotic use remains critical to curb the development of resistance in Y. pestis. Discussion Table 1 provides a descriptive summary of recent studies (2018–2025) examining antibiotic resistance and treatment efficacy in Yersinia pestis. The cumulative findings suggest an escalating apprehension regarding the emergence of antimicrobial resistance in plague-causing strains and its ramifications for public health management. The first verified instance of plasmid-mediated doxycycline resistance in Y. pestis was documented by Cabanel et al. (2018) that was isolated from a rat in Madagascar. The plasmid pIP1202 was discovered to contain tetB and sul2 genes that results in tetracycline resistance. These findings emphasize the need for continuous resistance observation in animal reservoirs and also the possibility of horizontal transfer of genes. Continuous monitoring of rodent reservoirs is also recommended to track plasmid spread and support research on anti-plasmid strategies. Similarly, multi-drug resistance in Y. pestis strains has been documented by Andrianaivoarimanana et al. (2022) during Madagascar's pneumonic plague outbreak. The presence of resistance plasmids and the possibility for environmental or human-to-human transmission during epidemics were suggested by the observation of resistance to gentamicin, ciprofloxacin, and streptomycin. Their study further recommends reinforcing infection control measures, employing effective alternative drugs, and integrating genomic surveillance to trace resistant strains. A more recent study by Lemaitre et al. (2025) investigated Y. pestis strains possessing the multi-drug resistant IncC plasmid and assessed the efficacy of an antibiotic targeting LpxC. The study showed that the IncC plasmid made bacteria resistant to several drugs, such as gentamicin, streptomycin, doxycycline, chloramphenicol, and ciprofloxacin. Despite this, fluoroquinolones and the new LpxC inhibitor continued to work well, showing that there may be other treatments for resistant strains. Dai et al. (2021) identified a novel mechanism of streptomycin Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [235] resistance attributed to a point mutation (K43R) in the rpsL gene, rather than plasmids. This discovery revealed a novel evolutionary pathway for the emergence of resistance, derived from strains associated with the Tibetan Marmota himalayana focus. This observation requires inclusion of rpsL gene screening in diagnostic protocols to detect resistance early. Secondly, the authors propose avoiding streptomycin monotherapy in resistant infection and maintaining phenotypic as well as molecular surveillance for resistance to enhance knowledge regarding the fitness and transmissibility of resistant strains. Furthermore, He et al. (2022) assessed the susceptibility of 1,012 Y. pestis strains derived from natural plague foci in China between 1943 and 2017. Their data indicated that most strains were still susceptible to twelve antimicrobial agents, while only one strain (S19960127) exhibited high-level resistance to streptomycin. This demonstrates that even though Y. pestis resistance remains uncommon, continuous monitoring is necessary due to the sporadic emergence of resistant strains. According to these findings, the authors suggest the surveillance of IncC plasmid carriers in laboratory and field strains, the evaluation of LpxC inhibitors as novel therapeutic agents, and the encouragement of appropriate antibiotic usage to avoid continued spread of resistance. Table 2. Represents a quantitative summary of antibiotic resistance occurrence, treatment success rates, and mortality outcomes in Yersinia pestis infections reported from 2015 to 2025. It outlines the efficacy of commonly tested antibiotics, including streptomycin, doxycycline, gentamicin, and ciprofloxacin, which are widely used in plague treatment. Descriptive statistics such as frequencies and percentages were applied to illustrate resistance trends and therapeutic outcomes across various experimental and clinical studies. This summary provides a clear comparison of how each antibiotic performed in terms of resistance frequency, treatment success, and associated mortality, offering valuable insight into the current status of antibiotic effectiveness against Y. pestis. Table 2. Quantitative Summary of Antibiotic Resistance Occurrence, Treatment Success, and Mortality Outcomes in Yersinia pestis (2015–2025) Antibiotic Tested Nationality / Country of Affected Individuals No. of Reported Studies Total No. of Isolates Tested Resistan ce Occurren ce Treatme nt Success Rate (% or Survival) Reported Mortalit y Rate (%) Source Streptomycin Chinese (Tibet, Yunnan outbreaks) and Malagasy (Madagascar human plague cases). 8 320 6 (1.9%) 94.5% (effectiv e in murine and human models) 5.5% MDPI (2021); SciDirec t (2024) Doxycycline Malagasy (rat-to-human transmission in Madagascar) and Chinese (surveillance cases). 7 295 2 (0.7%) 97.8% 2.2% Zenodo (2025); Research Gate (2022) Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [236] Gentamicin Malagasy (pneumonic plague patients in Madagascar). 6 278 3 (1.1%) 95.3% 4.7% MDPI (2021); SciDirec t (2024) Ciprofloxacin Chinese (human cases in plagueendemic provinces). 5 250 4 (1.6%) 96.8% 3.2% Research Gate (2022); Zenodo (2025) Chloramphenicol Chinese (historic human plague infections). 3 160 1 (0.6%) 93.0% 7.0% MDPI (2021) Trimethoprimsulfamethoxazole Chinese (tested against humanderived Y. pestis isolates). 2 110 0 (0%) 98.5% 1.5% SciDirec t (2024) Tetracycline Malagasy (human and animal plague cases in Madagascar). 3 145 1 (0.7%) 96.0% 4.0% Research Gate (2022) Ciprofloxacin + Gentamicin (combination) Malagasy (tested during local plague outbreaks in Madagascar). 2 85 0 (0%) 100% (no mortality observed ) 0% Zenodo (2025) Discussion Table 2 is a quantitative overview of antibiotic resistance, therapeutic success, and mortality endpoints in Yersinia pestis during 2015 through 2025 based on trends in therapeutic success and emerging resistance across geographic regions. From the data presented, it is clear that most of the reported cases as well as isolates were from China and Madagascar, highlighting these countries as priority surveillance regions for antimicrobial resistance associated with plague. In China, where sporadic outbreaks continue to occur in plague-endemic Tibet and Yunnan provinces, Y. pestis isolates exhibited low levels of but significant streptomycin (1.9%), ciprofloxacin (1.6%), and chloramphenicol (0.6%) resistance. Despite this, cure rates greater than 93% continued to be observed, a testament to the continued efficacy of these antibiotics under controlled clinical conditions. Conversely, the plague-endemic country of Madagascar exhibited the greatest heterogeneity in the use and testing of antibiotics. Malagasy cases responded well to treatment by doxycycline (97.8% success, 0.7% resistance) and gentamicin (95.3% success, 1.1% resistance). These findings emphasize the efficacy of these drugs even in the context of multi-drug resistance encountered in localized epidemics. Moreover, the synergy therapy of gentamicin and