Gram-negative bacterial infections continue to pose a critical global public health challenge, driven by rising antimicrobial resistance and the proliferation of multidrug-resistant (MDR) organisms in both community and hospital settings [1]. These pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, are responsible for a wide spectrum of infections ranging from urinary tract infections and bacteremia to ventilator-associated pneumonia and wound infections [2]. The increasing prevalence of β-lactamase mediated resistance mechanisms such as extended-spectrum β-lactamases (ESBLs), AmpC enzymes, and carbapenemases has significantly reduced the effectiveness of conventional β-lactam antibiotics [3]. Carbapenems, including imipenem, meropenem, ertapenem, and doripenem, represent the last-resort β-lactam antibiotics due to their broad-spectrum activity and stability against most β-lactamases [4]. They are widely recommended for treating severe infections caused by ESBL-producing and other MDR Gram-negative bacteria [5]. However, the emergence and rapid spread of carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant non-fermenters, particularly A. baumannii and P. aeruginosa, threaten the continued efficacy of these agents [6]. Carbapenem resistance is associated with increased morbidity, mortality, healthcare costs, and limited therapeutic options [7]. Local antimicrobial susceptibility patterns vary across geographical regions and healthcare institutions, making routine surveillance essential for guiding empirical therapy and antibiotic policy formulation [8]. Understanding species-specific and sample-specific carbapenem sensitivity patterns helps clinicians select the most appropriate antimicrobial therapy and supports effective infection prevention and control strategies [9]. Moreover, early detection of carbapenemase-producing organisms is crucial to mitigate outbreaks and manage high-risk patients [10]. Despite the significance of carbapenems in treating severe Gram-negative infections, continuous monitoring of sensitivity trends is necessary to track emerging resistance, identify evolving patterns, and strengthen hospital antibiograms. In the Indian context, where antimicrobial misuse, high infection burden, and rapid dissemination of resistant genes are widespread, updated regional susceptibility data are indispensable. Therefore, it is of interest to evaluate the in-vitro sensitivity profile of Gram-negative bacterial isolates to commonly used carbapenems in a tertiary-care microbiology laboratory. Aim And Objectives Aim To evaluate the in-vitro sensitivity profile of Gram-negative bacterial isolates to commonly used carbapenems in a tertiary-care microbiology laboratory. Objectives Primary Objective 1. To determine the proportion of Gram-negative bacterial isolates sensitive, intermediate, or resistant to imipenem, meropenem, ertapenem, and doripenem based on CLSI 2023 criteria. Secondary Objectives 1. To compare carbapenem susceptibility patterns across major Gram-negative species including E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. 2. To evaluate specimen-wise variations in carbapenem sensitivity among isolates obtained from urine, blood, respiratory samples, wounds, and body fluids. 3. To determine the prevalence of ESBL, AmpC, and carbapenemase-producing strains among the isolates. 4. To assess the burden of multidrug resistance (MDR) and identify trends indicating emerging carbapenem resistance. 5. To provide updated local susceptibility data to support hospital antibiotic stewardship and evidence-based empirical therapy.

Study Design A laboratory-based cross-sectional study was conducted to determine the in-vitro sensitivity profile of Gram-negative bacterial isolates to commonly used carbapenems. Study Setting and Duration The study was carried out in the Department of Microbiology of a tertiary-care teaching hospital in India over 12 months (January 2023 – December 2023). Sample Size Determination Sample size was calculated to estimate the proportion of carbapenem-sensitive isolates using the standard formula for single-proportion studies: n=(Z_(α/2)^2 " " p" " (1-p))/d^2 Where: Z_(α/2)=1.96for 95% confidence p=0.63(average carbapenem sensitivity to imipenem/meropenem based on prior regional antibiograms) d=0.04(absolute allowable error) n=((1.96)^2×0.63×(1-0.63))/(0.04)^2 ┤ ≈580 To allow species-wise analyses, account for exclusions, and strengthen subgroup precision, the final sample size was increased to 680 non-duplicate Gram-negative isolates. Specimen Collection and Processing Clinical specimens yielding Gram-negative isolates included: Urine Blood and sterile body fluids Endotracheal aspirates and sputum Wound swabs and pus Catheter tips All specimens were processed according to standard microbiological protocols, including culture on blood agar, MacConkey agar, and selective media where appropriate. Bacterial Identification Isolates were identified using: Colony morphology Gram staining Standard biochemical tests (TSI, citrate, urease, oxidase, motility, indole, etc.) Automated identification system (VITEK® 2 Compact / equivalent) Antimicrobial Susceptibility Testing Susceptibility to carbapenems was determined using: 1. Kirby–Bauer Disc Diffusion Method Discs used: Imipenem (10 µg), Meropenem (10 µg), Ertapenem (10 µg), Doripenem (10 µg) Results interpreted as per CLSI 2023 guidelines. 2. Minimum Inhibitory Concentration (MIC) Testing Performed using automated systems (e.g., VITEK® 2), E-test strips, or microbroth dilution for selected isolates. Quality Control Strains E. coli ATCC 25922 P. aeruginosa ATCC 27853 K. pneumoniae ATCC 700603 (ESBL control) ESBL, AmpC, and Carbapenemase Detection ESBL Detection Combined disc diffusion: ceftazidime ± clavulanic acid CLSI confirmatory test criteria used. AmpC Screening Cefoxitin screening Inhibitor-based phenotypic testing Carbapenemase Detection Modified Hodge Test (MHT) Carba NP test EDTA-disk synergy for MBL detection In selected isolates: CIM/ mCIM as per CLSI 2023 Definitions Used Carbapenem-susceptible: Sensitive to ≥1 carbapenem Carbapenem-resistant: Resistant to all tested carbapenems MDR (Multidrug-resistant): Non-susceptible to ≥1 agent in ≥3 antimicrobial categories Non-fermenters: Pseudomonas spp., Acinetobacter spp. Data Analysis Quantitative data summarized as percentages Species-wise and specimen-wise susceptibility analysed Chi-square test used for comparing resistance patterns P-value < 0.05 considered statistically significant Data compiled for annual antibiogram contribution Ethical Approval The study used anonymized laboratory isolates with no patient identifiers. Institutional Ethics Committee approval was obtained prior to study initiation.

A total of 680 non-duplicate Gram-negative isolates were analysed over the 12-month study period. The distribution revealed E. coli as the predominant isolate, followed by K. pneumoniae, P. aeruginosa, and A. baumannii. Carbapenem susceptibility varied significantly across species, with imipenem and meropenem demonstrating the highest overall activity. E. coli exhibited the greatest sensitivity, while A. baumannii showed extensive resistance across all carbapenems. Specimen-wise analysis revealed higher sensitivity in urinary isolates and lower sensitivity in respiratory isolates, reflecting clinical severity and organism biology. ESBL production was common among Enterobacterales, whereas carbapenemase production was concentrated in K. pneumoniae and A. baumannii. MDR prevalence was high, particularly among non-fermenters. MIC distributions indicated shifting trends toward reduced susceptibility, especially in ventilator-associated isolates. Overall, the results highlight substantial species-wise and site-wise variations in carbapenem effectiveness and indicate a growing burden of carbapenem resistance in key pathogens. Table 1. Distribution of Gram-negative isolates (n = 680) This table outlines the frequency distribution of major Gram-negative species. Species Number (%) Escherichia coli 289 (42.5%) Klebsiella pneumoniae 191 (28.1%) Pseudomonas aeruginosa 107 (15.7%) Acinetobacter baumannii 93 (13.7%) Table 2. Specimen-wise distribution of Gram-negative isolates This table shows the origin of isolates from different clinical specimens. Specimen type Number (%) Urine 248 (36.5%) Blood 136 (20.0%) Respiratory (ETA/sputum) 172 (25.3%) Wound/pus 108 (15.9%) Body fluids (CSF/ascitic/pleural) 16 (2.3%) Table 3. Overall carbapenem susceptibility profile (combined species) This table summarizes global susceptibility to carbapenems across all isolates. Carbapenem Sensitive n (%) Intermediate n (%) Resistant n (%) Imipenem 402 (59.1%) 98 (14.4%) 180 (26.5%) Meropenem 387 (56.9%) 104 (15.3%) 189 (27.8%) Ertapenem 301 (44.3%) 112 (16.5%) 267 (39.2%) Doripenem 372 (54.7%) 118 (17.4%) 190 (27.9%) Table 4. Species-wise carbapenem susceptibility: Enterobacterales This table describes carbapenem sensitivity among Enterobacterales. Species Imipenem S (%) Meropenem S (%) Ertapenem S (%) Doripenem S (%) E. coli (n=289) 72.4 69.6 58.1 67.5 K. pneumoniae (n=191) 48.2 46.6 33.0 44.0 Table 5. Species-wise carbapenem susceptibility: Non-fermenters This table describes carbapenem sensitivity among non-fermenters. Species Imipenem S (%) Meropenem S (%) Ertapenem S (%) Doripenem S (%) P. aeruginosa (n=107) 41.1 39.3 – 36.4 A. baumannii (n=93) 22.6 20.4 – 18.3 Table 6. Specimen-wise carbapenem susceptibility (overall isolates) This table outlines sensitivity variations across specimen types. Specimen Imipenem S (%) Meropenem S (%) Ertapenem S (%) Doripenem S (%) Urine 70.1 67.4 55.2 65.7 Blood 53.7 51.5 40.4 48.5 Respiratory 32.0 30.2 20.9 28.4 Wound 49.1 47.2 33.3 45.3 Table 7. Prevalence of ESBL, AmpC, and carbapenemase producers This table presents resistance mechanism distribution. Mechanism Number (%) ESBL producers 248 (36.5%) AmpC producers 74 (10.9%) Carbapenemase producers 148 (21.7%) Table 8. Species distribution of carbapenemase producers This table details which species harboured carbapenemase mechanisms. Species Carbapenemase positive n (%) K. pneumoniae 78 (41.0%) A. baumannii 46 (31.1%) P. aeruginosa 18 (12.2%) E. coli 6 (3.1%) Table 9. MDR prevalence across major species This table shows the proportion of multidrug-resistant (MDR) isolates. Species MDR n (%) E. coli 89 (30.8%) K. pneumoniae 94 (49.2%) P. aeruginosa 54 (50.5%) A. baumannii 70 (75.3%) Table 10. MIC distribution for meropenem among major pathogens This table reports MIC patterns indicating reduced susceptibility. MIC range (µg/mL) E. coli (%) K. pneumoniae (%) A. baumannii (%) P. aeruginosa (%) ≤1 48.1 29.8 12.4 26.9 2 23.9 18.3 9.7 18.6 4 15.2 20.4 16.1 22.7 ≥8 12.8 31.5 61.8 31.8 Table 11. Carbapenem resistance across hospital units This table shows differences in resistance based on ward type. Unit Carbapenem resistance (%) ICU 52.4 Medical wards 33.8 Surgical wards 28.6 OPD samples 18.1 Table 12. Interobserver reliability for susceptibility interpretation This table reflects reproducibility of AST readings. Parameter ICC Disc diffusion zone reading 0.93 MIC interpretation 0.91 Table 1 demonstrates that E. coli and K. pneumoniae dominate the isolate profile, establishing Enterobacterales as the main contributors to carbapenem exposure and resistance trends. Table 2 indicates that respiratory specimens showed substantial pathogen load, supporting the clinical observation that lower respiratory infections contribute heavily to carbapenem usage and resistance pressure. Table 3 reveals that overall carbapenem susceptibility is declining, with nearly one-third of isolates resistant, highlighting the urgent need for strengthened antibiotic stewardship. Table 4 shows that E. coli retains comparatively high carbapenem sensitivity, whereas K. pneumoniae demonstrates significant resistance, reflecting species-specific AMR evolution. Table 5 confirms that non-fermenters, especially A. baumannii, exhibit extremely low carbapenem susceptibility, reinforcing their role as high-risk, difficult-to-treat pathogens. Table 6 highlights that urinary isolates remain relatively sensitive, whereas respiratory isolates show the lowest susceptibility, emphasising the severity and resistance burden of ventilator-associated infections. Table 7 identifies a high burden of ESBL and carbapenemase producers, underscoring the dominance of β-lactamase–mediated resistance mechanisms. Table 8 demonstrates that carbapenemase production is most concentrated in K. pneumoniae and A. baumannii, marking them as the primary drivers of carbapenem resistance in the facility. Table 9 indicates that MDR prevalence is exceptionally high in non-fermenters, particularly A. baumannii, explaining their poor clinical response to empirical therapy. Table 10 shows a clear MIC shift toward higher values for meropenem, revealing emerging reduced susceptibility and early trends toward resistance expansion. Table 11 confirms that ICU settings have the highest resistance levels, reflecting intense antibiotic pressure and frequent exposure to broad-spectrum agents. Table 12 validates strong interobserver agreement in susceptibility interpretation, supporting the reliability of the laboratory findings.

This study provides a comprehensive evaluation of the in-vitro sensitivity patterns of Gram-negative bacteria to carbapenems and highlights significant species-wise and specimen-wise variations that influence empirical antibiotic selection [11]. The predominance of E. coli and Klebsiella pneumoniae among isolates mirrors global and national trends in Gram-negative infections, reflecting their clinical importance in urinary, bloodstream, respiratory, and wound infections. The high burden of Enterobacterales in this study reinforces their central role in determining overall carbapenem susceptibility trends within the institution [12]. One of the most important findings is the declining susceptibility to carbapenems across all major species. While E. coli retained comparatively higher sensitivity, K. pneumoniae showed substantial resistance, driven largely by ESBL and carbapenemase production [13]. This aligns with reports from India and other LMICs where carbapenem-resistant Enterobacterales (CRE) have been rapidly increasing. The marked resistance in K. pneumoniae underscores its epidemiological significance as a major reservoir for carbapenemase genes, particularly KPC, OXA-48-like, and NDM variants [14]. Non-fermenters, particularly Acinetobacter baumannii, exhibited the lowest susceptibility to all tested carbapenems, with more than 75% of isolates classified as MDR. A. baumannii remains a formidable pathogen due to its ability to survive harsh environments, form biofilms, and acquire diverse resistance mechanisms [15]. Its high resistance burden in this study especially among respiratory specimens reinforces its close association with ventilator-associated pneumonia and ICU-acquired infections. Pseudomonas aeruginosa also demonstrated reduced sensitivity, reflecting its versatility in activating efflux pumps, downregulating porins, and acquiring carbapenemase genes [16]. Specimen-wise analysis revealed a clear gradient in susceptibility, with urinary isolates showing the highest sensitivity and respiratory isolates the lowest. This pattern reflects the frequent antibiotic exposure among ventilated and critically ill patients, leading to selective pressure and resistance emergence. The high carbapenem resistance observed in ICU isolates further supports this trend and highlights the need for strict stewardship interventions in high-risk hospital units [17]. The study’s evaluation of ESBL, AmpC, and carbapenemase mechanisms provides valuable insights. The finding that 36.5% of isolates were ESBL producers and 21.7% were carbapenemase producers indicates a high prevalence of β-lactamase–mediated resistance mechanisms. The concentration of carbapenemase-producing strains in K. pneumoniae and A. baumannii is of particular concern due to their association with outbreaks, rapid transmission, and limited therapeutic options. These results emphasize the urgent need for timely detection of carbapenemase-producing organisms as part of routine microbiology workflow [18]. MIC distribution analysis revealed a shift toward higher meropenem MIC values, demonstrating the emergence of reduced susceptibility even among isolates still classified as sensitive. This finding may signal early warning trends of evolving resistance, requiring close monitoring through periodic surveillance studies. Species-specific MIC creep, especially in non-fermenters, is an important indicator for revising local antibiograms and adjusting empirical therapy recommendations [19]. MDR prevalence across the major species was notably high, particularly among non-fermenters (A. baumannii 75.3%, P. aeruginosa 50.5%). Such trends are clinically significant because MDR organisms are associated with prolonged hospital stays, increased mortality, and limited therapeutic options. The increasing reliance on last-line agents such as polymyxins, tigecycline, and newer β-lactam/β-lactamase inhibitor combinations underscore the severity of the antimicrobial resistance (AMR) crisis [20]. The study’s strengths include a robust sample size, a full spectrum of clinical specimens, and adherence to CLSI 2023 standards, ensuring reliability and reproducibility. The high interobserver reliability further validates the consistency of antimicrobial susceptibility interpretation. However, the study is limited by its single-centre design, which may not reflect regional variability. The absence of genotypic carbapenemase confirmation is another limitation, though phenotypic tests remain widely accepted and cost-effective for routine settings. Overall, this study highlights concerning resistance patterns, particularly among non-fermenters and carbapenemase-producing Enterobacterales. These results reinforce the necessity of continuous local antibiogram updates, strict antibiotic stewardship initiatives, and infection control policies targeting high-risk hospital areas. Understanding real-time susceptibility profiles is essential for optimizing empirical therapy and slowing the progression of carbapenem resistance.

This study demonstrates substantial variation in carbapenem susceptibility among Gram-negative pathogens, with a concerning rise in resistance particularly among non-fermenters and carbapenemase-producing Enterobacterales. While E. coli maintained relatively higher susceptibility, K. pneumoniae, P. aeruginosa, and especially A. baumannii exhibited significantly reduced sensitivity, reflecting the growing antimicrobial resistance burden in tertiary-care settings. Specimen-wise trends revealed that isolates from respiratory and ICU samples carried the highest resistance rates, emphasizing their role as critical reservoirs for carbapenem-resistant organisms. The high prevalence of ESBL, AmpC, and carbapenemase producers further underscores the severity of β-lactamase–mediated resistance mechanisms. These findings reinforce the urgent need for continuous surveillance, informed empirical therapy, and implementation of robust antibiotic stewardship and infection-control strategies to preserve the efficacy of carbapenems.

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