Descriptive analysis of frequency and antimicrobial susceptibility of pathogens isolated from acute leukemia patients with febrile neutropenia over a five-year period at a tertiary hospital

Descriptive analysis of frequency and antimicrobial susceptibility of pathogens isolated from acute leukemia patients with febrile neutropenia over a five-year period at a tertiary hospital | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Descriptive analysis of frequency and antimicrobial susceptibility of pathogens isolated from acute leukemia patients with febrile neutropenia over a five-year period at a tertiary hospital Adan Iftekhar, Afia Zafar, Mohammad Zeeshan, Usman Sheikh, Zehra Fadoo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8193956/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Mar, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 13 You are reading this latest preprint version Abstract Background Febrile neutropenia (FN) is a medical emergency in patients with acute leukemia due to profound neutropenia and immunosuppression, leading to life-threatening infections. Emerging antimicrobial resistance (AMR) further complicates management. Methods A retrospective descriptive study was conducted at a tertiary care hospital from January 2020 to December 2024. All pediatric and adult AL patients presenting with FN were included. Clinical records using ICD codes and laboratory data were analyzed to identify pathogen frequency, specimen source, and antimicrobial susceptibility patterns. Results A total of 478 FN episodes were identified through medical records, of which 217 (45%) were microbiologically documented. Among 381 isolated pathogens, Gram-negative rods (GNR) (n = 154, 40.4%) marginally exceeded Gram-positive cocci (GPC) (n = 148, 39%), followed by fungi (n = 41, 11%), viral (n = 24, 6%), parasitic (n = 8, 2%), and mycobacterial pathogens (n = 6, 1.6%). Blood was the most common culture source (n = 246, 71%). Predominant organisms included: Coagulase-negative staphylococci (CoNS) (n = 82, 24%), Enterococcus species (n = 23, 6.7%), and Staphylococcus aureus (n = 19, 5.5%) among GPCs; E. coli (n = 57, 16.6%), Pseudomonas aeruginosa (n = 22, 6.4%), and Klebsiella species (n = 20, 6%) among GNRs. Among GPCs, 77 CoNS isolates (95%) were methicillin-resistant, and 16 Enterococcus isolates (76%) were vancomycin-resistant. Among GNRs, Enterobacteriaceae showed resistance to ceftriaxone (n = 68, 77%), piperacillin-tazobactam (n = 51, 63%), and carbapenems (n = 34, 47%). Among fungi, Candida auris showed universal resistance to fluconazole, while echinocandins remained active against all Candida species. Conclusion Among culturable pathogens, CoNS were predominant. A high burden of multidrug-resistant organisms was identified, particularly vancomycin-resistant Enterococcus and carbapenem-resistant Enterobacteriaceae. Current empiric therapy (meropenem ± vancomycin) may no longer provide optimal coverage. Regular AMR surveillance and adjustment of empiric regimens are essential for improving outcomes. Febrile neutropenia acute leukemia antimicrobial susceptibility multidrug resistance antimicrobial resistance Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Febrile neutropenia (FN) represents a major oncologic emergency and remains one of the most serious complications in patients undergoing treatment for hematologic malignancies. Among hematologic malignancies, patients with acute leukemia (AL) experience the most profound and prolonged neutropenia, making them particularly vulnerable to severe infections. The underlying immune dysfunction, driven by impaired granulocyte function( 1 – 3 ) and altered humoral immunity, with reduced IgG and IgM levels, creates an environment conducive to a wide range of pathogens ( 4 ). Moreover, repeated hospitalizations and prolonged treatments further increase the likelihood of hospital-acquired infections with multidrug-resistant (MDR) pathogens. Severe complications due to delayed diagnosis and limited access to intensive care facilities increase mortality tenfold in low-resource settings ( 5 ). Appropriate empirical antibiotic treatment at the right time helps reduce neutropenia-associated mortality. A pathogen profile and resistance pattern can guide antibiotic selection. In higher-income countries, around the 1970-80s, Gram-negative rods (GNRs) predominated, but following the prophylactic use of fluoroquinolones and central line insertions, Gram-positive cocci (GPCs) became more common ( 6 ), particularly Coagulase-negative staphylococci (CoNS), viridans streptococci, and enterococci ( 7 ). Methicillin-resistant CoNS are reported at very high rates among cancer patients ( 8 ). Resistant Enterococcus species, particularly those resistant to ampicillin and vancomycin, are particularly relevant in transplant populations, where they rank among the leading causes of bloodstream infections ( 9 ). GNRs are now being reported more frequently than GPCs in many centers ( 10 , 11 ). GNRs such as Escherichia coli (E.coli) , Acinetobacter species, and Pseudomonas aeruginosa ( P.aeruginosa) remain clinically significant ( 12 , 13 ), complicated by the increasing prevalence of extended-spectrum β-lactamase and carbapenemase-producing MDR strains, underscoring the evolving resistance landscape in high-resource healthcare settings ( 14 – 17 ). Studies from Pakistan have shown similar trends. A 1991 study conducted at our tertiary care hospital found P. aeruginosa (31%) as the most frequent isolate, while a later study conducted at the same center (1999–2002) showed an almost equal distribution of GPCs and GNRs ( 18 ). By 2016–2017, Staphylococcus. Aureus ( S. aureus) and CoNS had become predominant pathogens ( 19 ). At our institution, the current empiric regimen for FN consists of meropenem, while vancomycin is added for patients with identified risk factors for Methicillin-resistant S. aureus (MRSA) or MR CoNS infection. Early empiric antibiotic administration within the first hour of suspicion remains the cornerstone of management ( 20 ). In light of the increasing antimicrobial resistance (AMR) and the observed shift in the frequency and distribution of isolated organisms over time, we aimed to analyze the frequency and antimicrobial susceptibility of pathogens isolated from AL patients with FN over a five-year period, aiming to ensure optimal infection management and improved outcomes in such patients. Objectives To determine the frequency of isolated pathogens and their antimicrobial susceptibility patterns in FN patients with AL, and to evaluate the appropriateness of the current empiric regimen of meropenem and vancomycin used at our institution. Methods After obtaining an ERC exemption (Case No. 2023-8609-24894), this descriptive, retrospective, single-center study was conducted at the Clinical Microbiology Laboratory, Aga Khan University, from January 1, 2020, to December 31, 2024. Patient identities were masked and replaced with coded numbers. Febrile neutropenia (FN) was defined as a single oral temperature ≥ 38.3°C or sustained ≥ 38.0°C for over 1 hour in a patient with ANC < 500 cells/µL or expected to fall below 500 cells/µL within 48 hours ( 21 ). All pediatric and adult patients admitted with an FN episode, who were undergoing treatment for AL were included in this study. Each FN event of a patient was taken as a single episode. The FN episodes were identified in the medical records of AL patients using ICD Codes. Blood, tracheal aspirate, bronchoalveolar lavage, ear, nose, wound, and throat swabs, urine, stool, cerebrospinal fluid, and central line tip samples submitted for culture were included in the study. Culturable microorganisms were identified using standard microbiological protocols, including microscopy (Gram stain, lactophenol cotton blue stain, and Kinyoun stain), colony morphology, and biochemical characteristics, with additional confirmation for select pathogens using commercially available API bioMérieux strips. Additionally, some yeast isolates obtained after 2021 were identified using the Vitek®. Antibiotic susceptibility testing of isolates was performed using the Kirby-Bauer disc diffusion method ( Oxoid discs), and automated minimum inhibitory concentrations were determined using the Vitek system (bioMérieux) or the broth microdilution technique. Antimicrobial susceptibility testing was interpreted according to Clinical and Laboratory Standards Institute or European Committee on Antimicrobial Susceptibility Testing breakpoints applicable during the study period. Non-cultural diagnostic methods were also included to detect viral, parasitic, and selected bacterial and fungal infections. These diagnoses were established through serological assays, antigen detection tests, polymerase chain reaction, and microscopy, as reported in the laboratory records. Electronic medical records of patients were retrospectively reviewed. Relevant data were extracted from the Hospital Information Management System using patients’ medical record numbers, with admission and discharge dates cross-verified to ensure accurate identification of each hospitalization episode. Two independent reviewers collected and cross-referenced the data, which was subsequently recorded on a secure Excel spreadsheet. Any duplicate entries were excluded, defining duplicate as the same organism with an identical antimicrobial susceptibility pattern recovered from the same patient during the same hospitalization; only the first isolate was included in the analysis. The collected variables comprised demographic characteristics; clinical risk factors such as chemotherapy status, disease relapse, history of bone marrow transplantation, severity and duration of neutropenia, presence of central venous lines, and a history of more than four previous hospital admissions; as well as clinical progression, culture types, isolated pathogens, and their antimicrobial susceptibilities. In this study, descriptive statistical analysis was performed using frequency and percentage calculations in Microsoft Excel 2016 and Stata 18. Results Over a five-year period, January 1, 2020, to December 31, 2024, a total of 478 FN episodes were recorded. Among these, no microbiologically documented etiology was identified in 261 episodes (54.6%), while 217 (45%) FN events were associated with microbiologically proven infections, corresponding to 162 distinct patients, some of whom were admitted multiple times and experienced more than one infection during different episodes. The patient population was evenly divided between adults and children, with acute leukemia subtypes nearly equally represented (Acute Lymphoid Leukemia: 47.5%; Acute Myeloid Leukemia: 52.4%). Most patients were on active or recent chemotherapy (n = 202, 93%), and had central venous lines (n = 151, 69.5%). A subset had undergone bone marrow transplantation (7.8%) or had multiple prior hospital admissions (39.2%). Overall, 36 patients (22%) died during hospitalization. Detailed patient characteristics are summarized in Table 1 . Table 1 Demographics, risk factors, and clinical course of 162 patients enrolled during the study period (2020–2024). Variable n (%) Total patients 162 Adults 81 (50) Male 100 (61.7) ALL 77 (47.5) AML 85 (52.4) Post-chemotherapy 202 (93) Relapse 59 (27.1) Bone marrow transplant recipient 17 (7.8) Duration of neutropenia > 7 days 210 (96.7) Central line 151 (69.5) Previous admissions > 4 85 (39.17) Hospitalized > 10 days 145 (66.8) Expired 36 ( 22 ) Legend The values in the columns are presented as the number (n) of patients or episodes, followed by the corresponding percentage (%) within the relevant group. The hematological diseases referenced are ALL (Acute Lymphoblastic Leukemia) and AML (Acute Myeloid Leukemia). The risk factors and hospital course sections refer to FN (Febrile Neutropenia) episodes. The risk factor Central line refers to the presence of a central venous catheter. A total of 381 pathogens (culturable: 342 and non-culturable: 39) were identified, with GNR (n = 154; 40.4%) slightly exceeding GPCs organisms (n = 148; 39%), while fungi were the third most common pathogen identified (n = 41; 11%), followed by viral (n = 24; 6%) parasitic (n = 8; 2%) and mycobacterial infections (n = 6, 1.6%), as shown in Fig. 1. Figure 1. Distribution of culturable and non-culturable pathogens. Insert Fig. 1 here. Legend : Fig. 1 is a bar chart showing the distribution of pathogens identified in this study. The X-axis: types of pathogens, the Y-axis: percentages of isolations. Among culture-positive cases, blood culture was the most common source (n = 246; 71.3%), followed by respiratory specimens (n = 41; 12%) and urine (n = 24; 7%), as shown in Fig. 2. Figure 2. The distribution of culture-positive specimen sources Insert Fig. 2 here. Legend The pie chart shows the different specimen types used to culture the pathogens and their frequencies. Among culturable pathogens, CoNS (24%), Enterococcus species (6.7%), and S. aureus (5.5%) were the predominant GPCs. The most frequent GNRs were E. coli (16.6%), P. aeruginosa (6.4%) and Klebsiella species (6%). Aspergillus flavus complex (3.5%) and Candida parapsilosis (1.75%) were the major fungal pathogens, as seen in Fig. 3. Figure 3. Predominant culturable bacterial and fungal organisms isolated during febrile neutropenic events. Insert Fig. 3 here. Legend Pathogens (X axis) are shown as bar charts, with their frequencies expressed as percentages (Y axis). Of 39 non-culturable pathogens, 24 (61.5%) were viral, 8 (20.5%) were parasitic, 4 (10.2%) were bacterial, and 3 (7.6%) were fungal. This is shown in Table 2 . Table 2 Distribution of 39 non-culturable pathogens, their sources, and frequency (%) Category Pathogen Source Frequency (n) Viral (n = 24, 61.5%) Rhinovirus Respiratory 4 COVID-19 Respiratory 4 Coronavirus OC43 Respiratory 3 Parainfluenza virus Respiratory 2 Dengue virus Blood 2 Enterovirus Respiratory 1 Adenovirus Respiratory 1 Human metapneumovirus Respiratory 1 Influenza A Respiratory 1 HIV Blood 1 HCV Blood 1 Varicella-zoster virus (VZV) Clinical 1 CMV Blood 1 Measles virus Blood 1 Parasitic (n = 8, 20.5%) Giardia lamblia Stool 3 Entamoeba histolytica Stool 2 Blastocystis hominis Stool 2 Plasmodium vivax Blood 1 Bacterial (n = 4, 10.2%) Helicobacter pylori Stool 2 Clostridium difficile Stool 1 IGRA positive (latent TB) Blood 1 Fungal (n = 3, 7.6%) Pneumocystis jirovecii Respiratory 3 Table 2 . Table 2 . Distribution of 39 non-culturable pathogens, their sources, and frequency (%). Insert Table 2 here. Legend The table shows the distribution of 39 non-culturable pathogens across the Viral, Parasitic, Bacterial, and Fungal groups. The column Source indicates the clinical sample or site from which the pathogen was isolated. The Frequency (%) column shows the percentage occurrence of each pathogen among the total non-culturable pathogens detected. The total number of pathogens detected is denoted by “n”. Among Enterobacteriaceae, only a small percentage of isolates remained susceptible to piperacillin-tazobactam (pip-taz) (n = 30, 37%) and ceftriaxone (n = 20, 23%), while nearly half exhibited resistance to carbapenems (n = 34, 47%). P. aeruginosa isolates showed resistance in 6 (29%) to meropenem, 5 (24%) to imipenem, 4 (20%) to pip-taz, 4 (19%) to ciprofloxacin, and 3 (16%) to ceftazidime. Acinetobacter species demonstrated multidrug resistance, with 50% resistant to most agents except minocycline. Pseudomonas species showed resistance in 2 isolates (100%) to pip-taz, one isolate (14%) to ceftazidime, and four isolates (50%) to carbapenems, as depicted in Fig. 4. Figure 4. Heat map showing antimicrobial susceptibility patterns of predominant GNRs. Insert Fig. 4 here. Legend This heatmap displays the percentage susceptibility of various bacterial isolates to commonly used antibiotics. Each cell lists the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color coding reflects susceptibility ranges as shown in the figure. Among GPCs, 5 (24%) Enterococcus isolates were susceptible to vancomycin. All other GPCs remained fully susceptible to vancomycin. Oxacillin susceptibility was observed in 4 (5%) CoNS isolates and 5 (28%) S. aureus isolates. This is highlighted in Fig. 5. Figure 5. Antimicrobial susceptibility patterns of predominant GPCs. Insert Fig. 5 here. Legend This heatmap summarizes the antimicrobial susceptibility profiles of CoNS, Staphylococcus aureus, Enterococcus species, and Streptococcus species. Each cell presents the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to susceptibility categories as defined in the figure. Among Candida isolates, azole resistance was confined to Candida auris , which was uniformly resistant to fluconazole. Candida parapsilosis showed fluconazole susceptibility in 5 isolates (84%), while Candida albicans and C. tropicalis were fully susceptible to azoles. All Candida species were susceptible to caspofungin and amphotericin B, as shown in Fig. 6. Figure 6. Antimicrobial susceptibility patterns of predominant Candida isolates. Insert Fig. 6 here. Legend This heatmap presents the antifungal susceptibility patterns of Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida auris against commonly tested antifungal agents. Each cell shows the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to the susceptibility categories as shown in the figure. Discussion The antimicrobial susceptibility pattern observed in this study provides critical insight into the therapeutic challenges in managing FN cases in our setting. Our findings demonstrate a high burden of MDR organisms, with concerning trends across multiple drug classes. Enterobacteriaceae, the most frequently isolated pathogens amongst GNRs, exhibited high resistance to beta-lactam antibiotics (i.e., 77% to 3rd-generation cephalosporins, 81% to amoxicillin-clavulanate, 63% to pip-taz, and 47% to carbapenems). A recent study conducted across 16 countries reported reduced susceptibility rates of 66.1% for meropenem and 53.6% for pip-taz, which are close to our findings ( 22 ). These resistance levels are considerably higher than those reported from HICs settings and underscore the growing threat of carbapenem resistance in Pakistan and other Lower Middle-Income Countries (LMICs). A study from Colombia reported that 40.5% of Enterobacteriaceae isolates were resistant to pip-taz, 33.3% to cefepime, and only 8.2% to meropenem ( 23 ). Similarly, fluoroquinolone activity was markedly reduced, with 87% of Enterobacteriaceae resistant to ciprofloxacin, reflecting widespread resistance likely driven by empirical or prophylactic antimicrobial use. Aminoglycosides retained moderate to good activity against Enterobacteriaceae, with 83% susceptibility to amikacin and 61% to gentamicin. P. aeruginosa isolates in our study demonstrated relatively low resistance to key beta-lactam antibiotics, with 20% resistant to pip-taz and 16% to ceftazidime. Although these rates are lower than those observed for Enterobacteriaceae in the same cohort, they still indicate the presence of emerging resistance. Historical data from the same institution reported a 6% rate of imipenem resistance among P. aeruginosa isolates, obtained from FN patients during 2001–2006 ( 24 ). A study from China involving a similar patient population reported carbapenem-resistant P. aeruginosa ranging from 0% to 21.2% in bloodstream infections (BSI) cases between 2013 and 2022 ( 25 ). In our current study (2020–2024), resistance to meropenem and imipenem increased to 29% and 24%, respectively. Resistance to ciprofloxacin was 19%, which, although lower than that observed for Enterobacteriaceae (87%), further highlights the emergence of fluoroquinolone resistance. Collectively, these findings indicate a progressive rise in AMR, limiting therapeutic options for critically ill neutropenic patients. Aminoglycosides demonstrated high activity (over 90% susceptibility) when tested, supporting their role as potential adjuncts in site-specific therapy. Acinetobacter species isolates in our study exhibited high resistance to beta-lactam antibiotics, with 46% resistant to pip-taz and 50% to ceftazidime and carbapenems. A similar study in FN children reported an even higher proportion of carbapenem-resistant Acinetobacter species , reaching 87.5% ( 26 ). Resistance to both fluoroquinolones and aminoglycosides was observed in 50% of Acinetobacter isolates. These findings highlight the substantial challenge posed by MDR Acinetobacter species in FN patients, as beta-lactams, often first-line empiric options, including carbapenems, show limited efficacy. Pseudomonas species isolates in our study exhibited high resistance to beta-lactam antibiotics, with 100% resistant to pip-taz and 14% to ceftazidime. Resistance was also observed to carbapenems, exceeding 50% and ciprofloxacin at 19%. These findings reinforce the declining utility of fluoroquinolones as empiric therapy in high-resistance settings ( 27 ). However, they showed a relatively better response to aminoglycosides (> 75% susceptible) than to β-lactams. Guidelines on the treatment of the FN patient suggest avoiding aminoglycosides; however, combination therapy provided greater initial appropriate therapy than β-lactam monotherapy, broader coverage than fluoroquinolones, and improved outcomes, even in neutropenic patients ( 28 ), as seen in a 2002 meta-analysis. Colistin showed the highest intermediate susceptibility among MDR Enterobacteriaceae, P. aeruginosa , and Acinetobacter species (86.6% of GNRs), making it a potential choice for empiric therapy in FN patients. Tigecycline susceptibility was also over 90% among Enterobacteriaceae and 100% in Acinetobacter species. However, the use of these agents should be judicious due to potential toxicity, limited tissue penetration, and the risk of emerging resistance. Among GPCs, a substantial prevalence of methicillin resistance was documented in both CoNs (95%) and S. aureus (72%). Notably, Staphylococci, which represent the largest proportion of GPCs, and Streptococcus species exhibited 100% susceptibility to vancomycin. In contrast, only 24% of Enterococci were vancomycin susceptible. Given that Enterococcus species constitute 6.7% of the GPCs in this study, the considerable incidence of vancomycin-resistant Enterococcus (VRE) (76%) signifies a growing concern. This emerging threat has been previously highlighted in a study that identified VRE in three tertiary care hospitals within the country ( 29 ). Fungal susceptibility patterns were acceptable, with universal susceptibility of Candida species to echinocandins and amphotericin B. However, the emergence of azole-resistant isolates is concerning. Candida auris (n = 3) and one isolate each of Candida parapsilosis and Candida rugosa were resistant to fluconazole, representing 25% of all Candida isolates. The emergence of Candida auris resistance (15%) is alarming and consistent with global alerts regarding this pathogen’s rapid spread in healthcare settings ( 30 ). Although Candida parapsilosis was historically considered fully susceptible to fluconazole, resistance in this species is of particular concern, as it has been increasingly reported to develop reduced susceptibility to azoles due to biofilm formation and genetic mutations ( 31 ). One of the 20 Candida isolates in our study (5%) was Candida rugosa , a species that studies indicate is emerging as a cause of invasive fungal infections and is also showing a trend toward increased resistance to azole antifungal agents ( 32 ). In our study, GNRs and GPCs were almost equally distributed (40.4% vs. 39%), with no statistically significant difference (p-value = 0.66). A previous study on FN isolates conducted at the same institution in 2008 reported a clear predominance of GPCs ( 24 ). Historically, GPCs have dominated in FN patients, particularly in HICs, due to the widespread use of central lines and prophylactic fluoroquinolones ( 7 ). In contrast, recent studies from LMICs continue to report a predominance of GNRs ( 33 )( 34 ). BSIs were the most frequent source of culture-positive episodes (71.3%), with CoNS predominating among GPCs, consistent with other studies ( 35 ). CoNS are normal skin flora that can enter the bloodstream through central venous catheters and other invasive devices commonly used in cancer patients. Among GNRs, Escherichia coli , Pseudomonas aeruginosa , and Klebsiella spp. were the most common organisms frequently implicated in serious infections among neutropenic hosts ( 36 , 37 ). Fungal pathogens accounted for 11% of isolates. This aligns with previous studies reporting that invasive fungal infections occur in about 15–25% of high-risk patients, particularly those with prolonged neutropenia, organ dysfunction, or prior fungal infection or colonization, most commonly observed in hematologic malignancies and transplant recipients ( 38 ). Among the fungal infections, 27 (69%) cases were classified as invasive fungal disease, including 19 (48.7%) cases of candidemia and 8 (20.5%) proven invasive fungal infections from other sites. The remaining cases included 4 (10.2%) classified as probable and 5 (13%) as possible invasive fungal infections, as per the Consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC-MSG) ( 39 ). In previous studies, fungal isolates in blood cultures of FN patients were reported at approximately 4% ( 24 ), whereas in our study, 7.7% were fungal. This indicates a slight increase in fungal bloodstream infections and suggests early consideration of antifungal therapy in cases of persistent FN. In our study, Aspergillus flavus complex and Candida parapsilosis were the most frequent fungal isolates. Aspergillus flavus has been reported as the predominant Aspergillus species in both clinical and environmental isolates in Pakistan, consistent with our findings ( 40 ). While Candida albicans was traditionally the most frequent species, recent years have seen a significant rise in non-albicans Candida infections, with Candida parapsilosis now emerging as a leading cause of invasive candidiasis ( 41 , 42 ). This study provides a comprehensive overview of the clinical and microbiological characteristics of FN episodes in patients with hematologic malignancies over a five-year period at a tertiary care center. Of 478 recorded FN episodes, microbiologically documented infections were identified in 45.3% of cases, aligning closely with global data showing that 30–50% of FN episodes are associated with a defined infectious etiology ( 43 ). Our patient population was evenly distributed between pediatric and adult patients, with acute leukemia subtypes nearly equally represented (ALL 47.5%, AML 52.4%). Most patients were post-chemotherapy and exhibited severe neutropenia lasting more than seven days, both of which are well-established risk factors for invasive infections. Additionally, nearly 70% of patients had central venous catheters, which are known to increase the risk of BSI. The mortality rate of 22% observed in this cohort is comparable to rates reported in other LMIC settings ( 44 ), but remains higher than those observed in high-income countries ( 45 ). It is unclear whether this mortality was due to sepsis or the primary disease, as this was not specifically analyzed in our study. Our study provides a large dataset from a tertiary care center in Pakistan, assessing microbiologically documented FN in AL. Inclusion of both culturable and non-culturable pathogens (bacterial, fungal, viral, and parasitic) offers a comprehensive infection profile, supporting clinical decision-making and antimicrobial stewardship. A limitation of the current study is its single-center, retrospective design, which may limit the generalizability of the findings to other settings. Additionally, molecular characterization of resistant organisms, including the detection of resistance enzymes and genes, was not performed. This limits our ability to fully understand the underlying mechanisms of resistance and their potential for nosocomial transmission. Future multicenter prospective studies incorporating genomic surveillance may help clarify transmission dynamics and resistance mechanisms. Conclusion In conclusion, our study highlights a shifting epidemiology of infections in FN acute leukemia patients, with near-equal distribution of GPCs and GNRs, and a significant burden of MDR organisms. Meropenem with vancomycin may no longer provide optimal empirical coverage in this setting. High carbapenem resistance among Enterobacteriaceae, rising VRE, MR Staphylococci, and azole-resistant Candida species highlight the urgent need to reconsider empiric antibiotic choices. Routine antimicrobial resistance surveillance, antimicrobial stewardship, early escalation to antifungal therapy for persistent fever, and the adoption of rapid diagnostic tools are essential to improving patient outcomes in this high-risk population. Abbreviations Febrile neutropenia FN acute leukemia AL multidrug-resistant MDR Gram-negative rods GNRs Gram-positive cocci GPC Coagulase-negative staphylococci CoNS Methicillin-resistant MR Escherichia coli E. coli Pseudomonas aeruginosa P. aeruginosa Staphylococcus. Aureus S. aureus Methicillin-resistant Staphylococcus aureus MRSA antimicrobial resistance AMR Piperacillin-tazobactam Pip-taz Bloodstream infections BSI Lower Middle-Income Countries LMICs vancomycin-resistant Enterococcus VRE Declarations Ethics approval and consent to participate: Our study was reviewed and approved as an exemption by the Ethics Review Committee, Aga Khan University. The case number is: 2023-8609-24894. The study is conducted as per protocol, in accordance with all Aga Khan University standards. Consent for publication: The data were entirely unidentifiable, hence no consent for publication was needed. Competing interests: The authors declare that they have no competing interests. Funding: No funding was required for this study. Author Contribution AI conceived the study, contributed to study design, and participated in data interpretation. AZ collaborated on the study design and supervised all microbiological analysis. MZ contributed to data acquisition, statistical analysis, and drafting of the manuscript. US assisted with data collection and contributed to data interpretation. ZF provided clinical oversight for hematology-oncology aspects and critically reviewed the manuscript for important intellectual content. SW contributed to data analysis, manuscript drafting, and figure and table preparation. AB assisted with data acquisition and literature review. AS contributed to data management and manuscript drafting. MSA assisted with data processing and verification. SI supervised the overall project, reviewed all analyses, and provided major revisions to the manuscript. All authors read and approved the final manuscript. 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Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":125339,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDistribution of culturable and non-culturable pathogens.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eFigure 1 is a bar chart showing the distribution of pathogens identified in this study. The X-axis: types of pathogens, the Y-axis: percentages of isolations.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong culture-positive cases, blood culture was the most common source (n = 246; 71.3%), followed by respiratory specimens (n = 41; 12%) and urine (n = 24; 7%), as shown in Figure 2.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/85f095a4a67553fec0ab1cdd.png"},{"id":98106545,"identity":"2a0a634f-e066-49ea-9eba-a38a85f9455e","added_by":"auto","created_at":"2025-12-13 00:12:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":167465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eThe distribution of culture-positive specimen sources\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eThe pie chart shows the different specimen types used to culture the pathogens and their frequencies.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong culturable pathogens, CoNS (24%), \u003cem\u003eEnterococcus\u003c/em\u003especies (6.7%), and \u003cem\u003eS. aureus\u003c/em\u003e (5.5%) were the predominant GPCs. The most frequent GNRs were \u003cem\u003eE. coli\u003c/em\u003e (16.6%), \u003cem\u003eP. aeruginosa\u003c/em\u003e (6.4%) and \u003cem\u003eKlebsiella \u003c/em\u003especies (6%). \u003cem\u003eAspergillus flavus\u003c/em\u003e complex (3.5%) and \u003cem\u003eCandida parapsilosis\u003c/em\u003e (1.75%) were the major fungal pathogens, as seen in Figure 3.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/7128575b688434c4266ddf0c.png"},{"id":98429740,"identity":"a477915d-3c29-468a-ba1d-d5d52320cf23","added_by":"auto","created_at":"2025-12-17 16:44:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160584,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePredominant culturable bacterial and fungal organisms isolated during febrile neutropenic events.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003ePathogens (X axis) are shown as bar charts, with their frequencies expressed as percentages (Y axis).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOf 39 non-culturable pathogens, 24 (61.5%) were viral, 8 (20.5%) were parasitic, 4 (10.2%) were bacterial, and 3 (7.6%) were fungal. This is shown in \u003cdel\u003e\u003cstrong\u003eThis is detailed in \u003c/strong\u003e\u003c/del\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/e7198980bfa3b4928f80307f.png"},{"id":98106547,"identity":"41041e90-c771-41a4-8a5d-36b11350f2ab","added_by":"auto","created_at":"2025-12-13 00:12:32","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":383852,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eHeat map showing antimicrobial susceptibility patterns of predominant GNRs.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003eThis heatmap displays the percentage susceptibility of various bacterial isolates to commonly used antibiotics. Each cell lists the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color coding reflects susceptibility ranges as shown in the figure.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/1d595fe3384357e48beae4f8.jpg"},{"id":98429763,"identity":"44c6473f-1dd4-4dbe-9313-5cd16d6614b8","added_by":"auto","created_at":"2025-12-17 16:44:07","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":331941,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAntimicrobial susceptibility patterns of predominant GPCs.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eThis heatmap summarizes the antimicrobial susceptibility profiles of CoNS, Staphylococcus aureus, Enterococcus species, and Streptococcus species. Each cell presents the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to susceptibility categories as defined in the figure.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/ac1ac858d3d5b7690c21073d.jpg"},{"id":98429744,"identity":"da78ef4b-c6c5-4603-b1e6-a024136dba27","added_by":"auto","created_at":"2025-12-17 16:44:05","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":135439,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAntimicrobial susceptibility patterns of predominant Candida isolates.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLegend: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eThis heatmap presents the antifungal susceptibility patterns of Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida auris against commonly tested antifungal agents. Each cell shows the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to the susceptibility categories as shown in the figure.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/634c881418ac7ec275814aec.jpg"},{"id":104252005,"identity":"bf39f09d-f3cd-4073-b1e0-dccd83c208ef","added_by":"auto","created_at":"2026-03-09 16:16:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2510320,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/2b1194c6-3400-4f24-9452-4946f50d5e12.pdf"},{"id":98430063,"identity":"c579057d-b840-4cb4-9cd7-065b1aac1011","added_by":"auto","created_at":"2025-12-17 16:44:44","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":249523,"visible":true,"origin":"","legend":"","description":"","filename":"FNProjectsorteddata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8193956/v1/d612382f13269c2ee41b3ef6.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Descriptive analysis of frequency and antimicrobial susceptibility of pathogens isolated from acute leukemia patients with febrile neutropenia over a five-year period at a tertiary hospital","fulltext":[{"header":"Background","content":"\u003cp\u003eFebrile neutropenia (FN) represents a major oncologic emergency and remains one of the most serious complications in patients undergoing treatment for hematologic malignancies. Among hematologic malignancies, patients with acute leukemia (AL) experience the most profound and prolonged neutropenia, making them particularly vulnerable to severe infections. The underlying immune dysfunction, driven by impaired granulocyte function(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and altered humoral immunity, with reduced IgG and IgM levels, creates an environment conducive to a wide range of pathogens (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Moreover, repeated hospitalizations and prolonged treatments further increase the likelihood of hospital-acquired infections with multidrug-resistant (MDR) pathogens. Severe complications due to delayed diagnosis and limited access to intensive care facilities increase mortality tenfold in low-resource settings (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Appropriate empirical antibiotic treatment at the right time helps reduce neutropenia-associated mortality. A pathogen profile and resistance pattern can guide antibiotic selection.\u003c/p\u003e\u003cp\u003eIn higher-income countries, around the 1970-80s, Gram-negative rods (GNRs) predominated, but following the prophylactic use of fluoroquinolones and central line insertions, Gram-positive cocci (GPCs) became more common (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), particularly \u003cem\u003eCoagulase-negative staphylococci\u003c/em\u003e (CoNS), viridans streptococci, and enterococci (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Methicillin-resistant CoNS are reported at very high rates among cancer patients (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Resistant \u003cem\u003eEnterococcus\u003c/em\u003e species, particularly those resistant to ampicillin and vancomycin, are particularly relevant in transplant populations, where they rank among the leading causes of bloodstream infections (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGNRs are now being reported more frequently than GPCs in many centers (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). GNRs such as \u003cem\u003eEscherichia coli (E.coli)\u003c/em\u003e, \u003cem\u003eAcinetobacter\u003c/em\u003e species, and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (\u003cem\u003eP.aeruginosa)\u003c/em\u003e remain clinically significant (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), complicated by the increasing prevalence of extended-spectrum β-lactamase and carbapenemase-producing MDR strains, underscoring the evolving resistance landscape in high-resource healthcare settings (\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eStudies from Pakistan have shown similar trends. A 1991 study conducted at our tertiary care hospital found \u003cem\u003eP. aeruginosa\u003c/em\u003e (31%) as the most frequent isolate, while a later study conducted at the same center (1999\u0026ndash;2002) showed an almost equal distribution of GPCs and GNRs (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). By 2016\u0026ndash;2017, \u003cem\u003eStaphylococcus. Aureus\u003c/em\u003e (\u003cem\u003eS. aureus)\u003c/em\u003e and CoNS had become predominant pathogens (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). At our institution, the current empiric regimen for FN consists of meropenem, while vancomycin is added for patients with identified risk factors for Methicillin-resistant \u003cem\u003eS. aureus\u003c/em\u003e (MRSA) or MR CoNS infection.\u003c/p\u003e\u003cp\u003eEarly empiric antibiotic administration within the first hour of suspicion remains the cornerstone of management (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In light of the increasing antimicrobial resistance (AMR) and the observed shift in the frequency and distribution of isolated organisms over time, we aimed to analyze the frequency and antimicrobial susceptibility of pathogens isolated from AL patients with FN over a five-year period, aiming to ensure optimal infection management and improved outcomes in such patients.\u003c/p\u003e"},{"header":"Objectives","content":"\u003cp\u003eTo determine the frequency of isolated pathogens and their antimicrobial susceptibility patterns in FN patients with AL, and to evaluate the appropriateness of the current empiric regimen of meropenem and vancomycin used at our institution.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eAfter obtaining an ERC exemption (Case No. 2023-8609-24894), this descriptive, retrospective, single-center study was conducted at the Clinical Microbiology Laboratory, Aga Khan University, from January 1, 2020, to December 31, 2024. Patient identities were masked and replaced with coded numbers.\u003c/p\u003e\u003cp\u003eFebrile neutropenia (FN) was defined as a single oral temperature\u0026thinsp;\u0026ge;\u0026thinsp;38.3\u0026deg;C or sustained\u0026thinsp;\u0026ge;\u0026thinsp;38.0\u0026deg;C for over 1 hour in a patient with ANC\u0026thinsp;\u0026lt;\u0026thinsp;500 cells/\u0026micro;L or expected to fall below 500 cells/\u0026micro;L within 48 hours (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAll pediatric and adult patients admitted with an FN episode, who were undergoing treatment for AL were included in this study. Each FN event of a patient was taken as a single episode. The FN episodes were identified in the medical records of AL patients using ICD Codes.\u003c/p\u003e\u003cp\u003eBlood, tracheal aspirate, bronchoalveolar lavage, ear, nose, wound, and throat swabs, urine, stool, cerebrospinal fluid, and central line tip samples submitted for culture were included in the study. Culturable microorganisms were identified using standard microbiological protocols, including microscopy (Gram stain, lactophenol cotton blue stain, and Kinyoun stain), colony morphology, and biochemical characteristics, with additional confirmation for select pathogens using commercially available API \u003cb\u003ebioM\u0026eacute;rieux\u003c/b\u003e strips. Additionally, some yeast isolates obtained after 2021 were identified using the Vitek\u0026reg;.\u003c/p\u003e\u003cp\u003eAntibiotic susceptibility testing of isolates was performed using the Kirby-Bauer disc diffusion method (\u003cb\u003eOxoid\u003c/b\u003e discs), and automated minimum inhibitory concentrations were determined using the Vitek system \u003cb\u003e(bioM\u0026eacute;rieux)\u003c/b\u003e or the broth microdilution technique. Antimicrobial susceptibility testing was interpreted according to Clinical and Laboratory Standards Institute or European Committee on Antimicrobial Susceptibility Testing breakpoints applicable during the study period.\u003c/p\u003e\u003cp\u003eNon-cultural diagnostic methods were also included to detect viral, parasitic, and selected bacterial and fungal infections. These diagnoses were established through serological assays, antigen detection tests, polymerase chain reaction, and microscopy, as reported in the laboratory records.\u003c/p\u003e\u003cp\u003eElectronic medical records of patients were retrospectively reviewed. Relevant data were extracted from the Hospital Information Management System using patients\u0026rsquo; medical record numbers, with admission and discharge dates cross-verified to ensure accurate identification of each hospitalization episode. Two independent reviewers collected and cross-referenced the data, which was subsequently recorded on a secure Excel spreadsheet. Any duplicate entries were excluded, defining duplicate as the same organism with an identical antimicrobial susceptibility pattern recovered from the same patient during the same hospitalization; only the first isolate was included in the analysis.\u003c/p\u003e\u003cp\u003eThe collected variables comprised demographic characteristics; clinical risk factors such as chemotherapy status, disease relapse, history of bone marrow transplantation, severity and duration of neutropenia, presence of central venous lines, and a history of more than four previous hospital admissions; as well as clinical progression, culture types, isolated pathogens, and their antimicrobial susceptibilities. In this study, descriptive statistical analysis was performed using frequency and percentage calculations in Microsoft Excel 2016 and Stata 18.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOver a five-year period, January 1, 2020, to December 31, 2024, a total of 478 FN episodes were recorded. Among these, no microbiologically documented etiology was identified in 261 episodes (54.6%), while 217 (45%) FN events were associated with microbiologically proven infections, corresponding to 162 distinct patients, some of whom were admitted multiple times and experienced more than one infection during different episodes.\u003c/p\u003e\u003cp\u003eThe patient population was evenly divided between adults and children, with acute leukemia subtypes nearly equally represented (Acute Lymphoid Leukemia: 47.5%; Acute Myeloid Leukemia: 52.4%). Most patients were on active or recent chemotherapy (n\u0026thinsp;=\u0026thinsp;202, 93%), and had central venous lines (n\u0026thinsp;=\u0026thinsp;151, 69.5%). A subset had undergone bone marrow transplantation (7.8%) or had multiple prior hospital admissions (39.2%). Overall, 36 patients (22%) died during hospitalization. Detailed patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographics, risk factors, and clinical course of 162 patients enrolled during the study period (2020\u0026ndash;2024).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e162\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdults\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (50)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100 (61.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (47.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAML\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (52.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePost-chemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e202 (93)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRelapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59 (27.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone marrow transplant recipient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (7.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of neutropenia\u0026thinsp;\u0026gt;\u0026thinsp;7 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e210 (96.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCentral line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e151 (69.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious admissions\u0026thinsp;\u0026gt;\u0026thinsp;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (39.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalized\u0026thinsp;\u0026gt;\u0026thinsp;10 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e145 (66.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExpired\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003e\u003cem\u003eThe values in the columns are presented as the number (n) of patients or episodes, followed by the corresponding percentage (%) within the relevant group. The hematological diseases referenced are ALL (Acute Lymphoblastic Leukemia) and AML (Acute Myeloid Leukemia). The risk factors and hospital course sections refer to FN (Febrile Neutropenia) episodes. The risk factor Central line refers to the presence of a central venous catheter.\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eA total of 381 pathogens (culturable: 342 and non-culturable: 39) were identified, with GNR (n\u0026thinsp;=\u0026thinsp;154; 40.4%) slightly exceeding GPCs organisms (n\u0026thinsp;=\u0026thinsp;148; 39%), while fungi were the third most common pathogen identified (n\u0026thinsp;=\u0026thinsp;41; 11%), followed by viral (n\u0026thinsp;=\u0026thinsp;24; 6%) parasitic (n\u0026thinsp;=\u0026thinsp;8; 2%) and mycobacterial infections (n\u0026thinsp;=\u0026thinsp;6, 1.6%), as shown in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 1. Distribution of culturable and non-culturable pathogens.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;1 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eLegend\u003c/b\u003e: \u003cem\u003eFig.\u0026nbsp;1 is a bar chart showing the distribution of pathogens identified in this study. The X-axis: types of pathogens, the Y-axis: percentages of isolations.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAmong culture-positive cases, blood culture was the most common source (n\u0026thinsp;=\u0026thinsp;246; 71.3%), followed by respiratory specimens (n\u0026thinsp;=\u0026thinsp;41; 12%) and urine (n\u0026thinsp;=\u0026thinsp;24; 7%), as shown in Fig.\u0026nbsp;2.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 2. The distribution of culture-positive specimen sources\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;2 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003e\u003cem\u003eThe pie chart shows the different specimen types used to culture the pathogens and their frequencies.\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eAmong culturable pathogens, CoNS (24%), \u003cem\u003eEnterococcus\u003c/em\u003e species (6.7%), and \u003cem\u003eS. aureus\u003c/em\u003e (5.5%) were the predominant GPCs. The most frequent GNRs were \u003cem\u003eE. coli\u003c/em\u003e (16.6%), \u003cem\u003eP. aeruginosa\u003c/em\u003e (6.4%) and \u003cem\u003eKlebsiella\u003c/em\u003e species (6%). \u003cem\u003eAspergillus flavus\u003c/em\u003e complex (3.5%) and \u003cem\u003eCandida parapsilosis\u003c/em\u003e (1.75%) were the major fungal pathogens, as seen in Fig.\u0026nbsp;3.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 3. Predominant culturable bacterial and fungal organisms isolated during febrile neutropenic events.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;3 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003e\u003cem\u003ePathogens (X axis) are shown as bar charts, with their frequencies expressed as percentages (Y axis).\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eOf 39 non-culturable pathogens, 24 (61.5%) were viral, 8 (20.5%) were parasitic, 4 (10.2%) were bacterial, and 3 (7.6%) were fungal. This is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDistribution of 39 non-culturable pathogens, their sources, and frequency (%)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCategory\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePathogen\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSource\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFrequency (n)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eViral (n\u0026thinsp;=\u0026thinsp;24, 61.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRhinovirus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCOVID-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCoronavirus OC43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParainfluenza virus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDengue virus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEnterovirus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdenovirus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman metapneumovirus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfluenza A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVaricella-zoster virus (VZV)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCMV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeasles virus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParasitic (n\u0026thinsp;=\u0026thinsp;8, 20.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGiardia lamblia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStool\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEntamoeba histolytica\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStool\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBlastocystis hominis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStool\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlasmodium vivax\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBacterial (n\u0026thinsp;=\u0026thinsp;4, 10.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHelicobacter pylori\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStool\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClostridium difficile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStool\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIGRA positive (latent TB)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFungal (n\u0026thinsp;=\u0026thinsp;3, 7.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePneumocystis jirovecii\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. \u003cb\u003eDistribution of 39 non-culturable pathogens, their sources, and frequency (%).\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003ehere.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003eThe table shows the distribution of 39 non-culturable pathogens across the Viral, Parasitic, Bacterial, and Fungal groups. The column Source indicates the clinical sample or site from which the pathogen was isolated. The Frequency (%) column shows the percentage occurrence of each pathogen among the total non-culturable pathogens detected. The total number of pathogens detected is denoted by \u0026ldquo;n\u0026rdquo;.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eAmong Enterobacteriaceae, only a small percentage of isolates remained susceptible to piperacillin-tazobactam (pip-taz) (n\u0026thinsp;=\u0026thinsp;30, 37%) and ceftriaxone (n\u0026thinsp;=\u0026thinsp;20, 23%), while nearly half exhibited resistance to carbapenems (n\u0026thinsp;=\u0026thinsp;34, 47%). \u003cem\u003eP. aeruginosa\u003c/em\u003e isolates showed resistance in 6 (29%) to meropenem, 5 (24%) to imipenem, 4 (20%) to pip-taz, 4 (19%) to ciprofloxacin, and 3 (16%) to ceftazidime. \u003cem\u003eAcinetobacter species\u003c/em\u003e demonstrated multidrug resistance, with 50% resistant to most agents except minocycline. \u003cem\u003ePseudomonas species\u003c/em\u003e showed resistance in 2 isolates (100%) to pip-taz, one isolate (14%) to ceftazidime, and four isolates (50%) to carbapenems, as depicted in Fig.\u0026nbsp;4.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 4. Heat map showing antimicrobial susceptibility patterns of predominant GNRs.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;4 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003eThis heatmap displays the percentage susceptibility of various bacterial isolates to commonly used antibiotics. Each cell lists the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color coding reflects susceptibility ranges as shown in the figure.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eAmong GPCs, 5 (24%) Enterococcus isolates were susceptible to vancomycin. All other GPCs remained fully susceptible to vancomycin. Oxacillin susceptibility was observed in 4 (5%) CoNS isolates and 5 (28%) S. aureus isolates. This is highlighted in Fig.\u0026nbsp;5.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 5. Antimicrobial susceptibility patterns of predominant GPCs.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;5 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003e\u003cem\u003eThis heatmap summarizes the antimicrobial susceptibility profiles of CoNS, Staphylococcus aureus, Enterococcus species, and Streptococcus species. Each cell presents the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to susceptibility categories as defined in the figure.\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eAmong Candida isolates, azole resistance was confined to \u003cem\u003eCandida auris\u003c/em\u003e, which was uniformly resistant to fluconazole. \u003cem\u003eCandida parapsilosis\u003c/em\u003e showed fluconazole susceptibility in 5 isolates (84%), while \u003cem\u003eCandida albicans\u003c/em\u003e and \u003cem\u003eC. tropicalis\u003c/em\u003e were fully susceptible to azoles. All Candida species were susceptible to caspofungin and amphotericin B, as shown in Fig.\u0026nbsp;6.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure 6. Antimicrobial susceptibility patterns of predominant Candida isolates.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInsert Fig.\u0026nbsp;6 here.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e\u003cp\u003e\u003cem\u003eThis heatmap presents the antifungal susceptibility patterns of Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida auris against commonly tested antifungal agents. Each cell shows the number of susceptible isolates, followed by the percentage susceptible in parentheses. Color shading corresponds to the susceptibility categories as shown in the figure.\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe antimicrobial susceptibility pattern observed in this study provides critical insight into the therapeutic challenges in managing FN cases in our setting. Our findings demonstrate a high burden of MDR organisms, with concerning trends across multiple drug classes. Enterobacteriaceae, the most frequently isolated pathogens amongst GNRs, exhibited high resistance to beta-lactam antibiotics (i.e., 77% to 3rd-generation cephalosporins, 81% to amoxicillin-clavulanate, 63% to pip-taz, and 47% to carbapenems). A recent study conducted across 16 countries reported reduced susceptibility rates of 66.1% for meropenem and 53.6% for pip-taz, which are close to our findings (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). These resistance levels are considerably higher than those reported from HICs settings and underscore the growing threat of carbapenem resistance in Pakistan and other Lower Middle-Income Countries (LMICs). A study from Colombia reported that 40.5% of Enterobacteriaceae isolates were resistant to pip-taz, 33.3% to cefepime, and only 8.2% to meropenem (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Similarly, fluoroquinolone activity was markedly reduced, with 87% of Enterobacteriaceae resistant to ciprofloxacin, reflecting widespread resistance likely driven by empirical or prophylactic antimicrobial use. Aminoglycosides retained moderate to good activity against Enterobacteriaceae, with 83% susceptibility to amikacin and 61% to gentamicin. \u003cem\u003eP. aeruginosa\u003c/em\u003e isolates in our study demonstrated relatively low resistance to key beta-lactam antibiotics, with 20% resistant to pip-taz and 16% to ceftazidime. Although these rates are lower than those observed for Enterobacteriaceae in the same cohort, they still indicate the presence of emerging resistance. Historical data from the same institution reported a 6% rate of imipenem resistance among \u003cem\u003eP. aeruginosa\u003c/em\u003e isolates, obtained from FN patients during 2001\u0026ndash;2006 (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). A study from China involving a similar patient population reported carbapenem-resistant \u003cem\u003eP. aeruginosa\u003c/em\u003e ranging from 0% to 21.2% in bloodstream infections (BSI) cases between 2013 and 2022 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In our current study (2020\u0026ndash;2024), resistance to meropenem and imipenem increased to 29% and 24%, respectively. Resistance to ciprofloxacin was 19%, which, although lower than that observed for Enterobacteriaceae (87%), further highlights the emergence of fluoroquinolone resistance. Collectively, these findings indicate a progressive rise in AMR, limiting therapeutic options for critically ill neutropenic patients. Aminoglycosides demonstrated high activity (over 90% susceptibility) when tested, supporting their role as potential adjuncts in site-specific therapy. \u003cem\u003eAcinetobacter species\u003c/em\u003e isolates in our study exhibited high resistance to beta-lactam antibiotics, with 46% resistant to pip-taz and 50% to ceftazidime and carbapenems. A similar study in FN children reported an even higher proportion of carbapenem-resistant \u003cem\u003eAcinetobacter species\u003c/em\u003e, reaching 87.5% (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Resistance to both fluoroquinolones and aminoglycosides was observed in 50% of \u003cem\u003eAcinetobacter\u003c/em\u003e isolates. These findings highlight the substantial challenge posed by MDR \u003cem\u003eAcinetobacter species\u003c/em\u003e in FN patients, as beta-lactams, often first-line empiric options, including carbapenems, show limited efficacy. \u003cem\u003ePseudomonas species\u003c/em\u003e isolates in our study exhibited high resistance to beta-lactam antibiotics, with 100% resistant to pip-taz and 14% to ceftazidime. Resistance was also observed to carbapenems, exceeding 50% and ciprofloxacin at 19%. These findings reinforce the declining utility of fluoroquinolones as empiric therapy in high-resistance settings (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). However, they showed a relatively better response to aminoglycosides (\u0026gt;\u0026thinsp;75% susceptible) than to β-lactams. Guidelines on the treatment of the FN patient suggest avoiding aminoglycosides; however, combination therapy provided greater initial appropriate therapy than β-lactam monotherapy, broader coverage than fluoroquinolones, and improved outcomes, even in neutropenic patients (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), as seen in a 2002 meta-analysis. Colistin showed the highest intermediate susceptibility among MDR Enterobacteriaceae, \u003cem\u003eP. aeruginosa\u003c/em\u003e, and \u003cem\u003eAcinetobacter species\u003c/em\u003e (86.6% of GNRs), making it a potential choice for empiric therapy in FN patients. Tigecycline susceptibility was also over 90% among Enterobacteriaceae and 100% \u003cem\u003ein Acinetobacter species.\u003c/em\u003e However, the use of these agents should be judicious due to potential toxicity, limited tissue penetration, and the risk of emerging resistance.\u003c/p\u003e\u003cp\u003eAmong GPCs, a substantial prevalence of methicillin resistance was documented in both CoNs (95%) and \u003cem\u003eS. aureus\u003c/em\u003e (72%). Notably, Staphylococci, which represent the largest proportion of GPCs, and \u003cem\u003eStreptococcus\u003c/em\u003e species exhibited 100% susceptibility to vancomycin. In contrast, only 24% of Enterococci were vancomycin susceptible. Given that \u003cem\u003eEnterococcus\u003c/em\u003e species constitute 6.7% of the GPCs in this study, the considerable incidence of vancomycin-resistant Enterococcus (VRE) (76%) signifies a growing concern. This emerging threat has been previously highlighted in a study that identified VRE in three tertiary care hospitals within the country (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFungal susceptibility patterns were acceptable, with universal susceptibility of \u003cem\u003eCandida\u003c/em\u003e species to echinocandins and amphotericin B. However, the emergence of azole-resistant isolates is concerning. \u003cem\u003eCandida auris\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;3) and one isolate each of \u003cem\u003eCandida parapsilosis\u003c/em\u003e and \u003cem\u003eCandida rugosa\u003c/em\u003e were resistant to fluconazole, representing 25% of all Candida isolates. The emergence of \u003cem\u003eCandida auris\u003c/em\u003e resistance (15%) is alarming and consistent with global alerts regarding this pathogen\u0026rsquo;s rapid spread in healthcare settings (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Although \u003cem\u003eCandida parapsilosis\u003c/em\u003e was historically considered fully susceptible to fluconazole, resistance in this \u003cem\u003especies\u003c/em\u003e is of particular concern, as it has been increasingly reported to develop reduced susceptibility to azoles due to biofilm formation and genetic mutations (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). One of the 20 Candida isolates in our study (5%) was \u003cem\u003eCandida rugosa\u003c/em\u003e, a species that studies indicate is emerging as a cause of invasive fungal infections and is also showing a trend toward increased resistance to azole antifungal agents (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn our study, GNRs and GPCs were almost equally distributed (40.4% vs. 39%), with no statistically significant difference (p-value\u0026thinsp;=\u0026thinsp;0.66). A previous study on FN isolates conducted at the same institution in 2008 reported a clear predominance of GPCs (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Historically, GPCs have dominated in FN patients, particularly in HICs, due to the widespread use of central lines and prophylactic fluoroquinolones (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In contrast, recent studies from LMICs continue to report a predominance of GNRs (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). BSIs were the most frequent source of culture-positive episodes (71.3%), with CoNS predominating among GPCs, consistent with other studies (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). CoNS are normal skin flora that can enter the bloodstream through central venous catheters and other invasive devices commonly used in cancer patients. Among GNRs, \u003cem\u003eEscherichia coli\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eKlebsiella spp.\u003c/em\u003e were the most common organisms frequently implicated in serious infections among neutropenic hosts (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Fungal pathogens accounted for 11% of isolates. This aligns with previous studies reporting that invasive fungal infections occur in about 15\u0026ndash;25% of high-risk patients, particularly those with prolonged neutropenia, organ dysfunction, or prior fungal infection or colonization, most commonly observed in hematologic malignancies and transplant recipients (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAmong the fungal infections, 27 (69%) cases were classified as invasive fungal disease, including 19 (48.7%) cases of candidemia and 8 (20.5%) proven invasive fungal infections from other sites. The remaining cases included 4 (10.2%) classified as probable and 5 (13%) as possible invasive fungal infections, as per the Consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC-MSG) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). In previous studies, fungal isolates in blood cultures of FN patients were reported at approximately 4% (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), whereas in our study, 7.7% were fungal. This indicates a slight increase in fungal bloodstream infections and suggests early consideration of antifungal therapy in cases of persistent FN. In our study, \u003cem\u003eAspergillus flavus complex\u003c/em\u003e and \u003cem\u003eCandida parapsilosis\u003c/em\u003e were the most frequent fungal isolates. \u003cem\u003eAspergillus flavus\u003c/em\u003e has been reported as the predominant \u003cem\u003eAspergillus species\u003c/em\u003e in both clinical and environmental isolates in Pakistan, consistent with our findings (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). While \u003cem\u003eCandida albicans\u003c/em\u003e was traditionally the most frequent species, recent years have seen a significant rise in non-albicans Candida infections, with \u003cem\u003eCandida parapsilosis\u003c/em\u003e now emerging as a leading cause of invasive candidiasis (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study provides a comprehensive overview of the clinical and microbiological characteristics of FN episodes in patients with hematologic malignancies over a five-year period at a tertiary care center. Of 478 recorded FN episodes, microbiologically documented infections were identified in 45.3% of cases, aligning closely with global data showing that 30\u0026ndash;50% of FN episodes are associated with a defined infectious etiology (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Our patient population was evenly distributed between pediatric and adult patients, with acute leukemia subtypes nearly equally represented (ALL 47.5%, AML 52.4%). Most patients were post-chemotherapy and exhibited severe neutropenia lasting more than seven days, both of which are well-established risk factors for invasive infections. Additionally, nearly 70% of patients had central venous catheters, which are known to increase the risk of BSI. The mortality rate of 22% observed in this cohort is comparable to rates reported in other LMIC settings (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e), but remains higher than those observed in high-income countries (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). It is unclear whether this mortality was due to sepsis or the primary disease, as this was not specifically analyzed in our study.\u003c/p\u003e\u003cp\u003eOur study provides a large dataset from a tertiary care center in Pakistan, assessing microbiologically documented FN in AL. Inclusion of both culturable and non-culturable pathogens (bacterial, fungal, viral, and parasitic) offers a comprehensive infection profile, supporting clinical decision-making and antimicrobial stewardship.\u003c/p\u003e\u003cp\u003eA limitation of the current study is its single-center, retrospective design, which may limit the generalizability of the findings to other settings. Additionally, molecular characterization of resistant organisms, including the detection of resistance enzymes and genes, was not performed. This limits our ability to fully understand the underlying mechanisms of resistance and their potential for nosocomial transmission. Future multicenter prospective studies incorporating genomic surveillance may help clarify transmission dynamics and resistance mechanisms.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study highlights a shifting epidemiology of infections in FN acute leukemia patients, with near-equal distribution of GPCs and GNRs, and a significant burden of MDR organisms. Meropenem with vancomycin may no longer provide optimal empirical coverage in this setting. High carbapenem resistance among Enterobacteriaceae, rising VRE, MR Staphylococci, and azole-resistant \u003cem\u003eCandida species\u003c/em\u003e highlight the urgent need to reconsider empiric antibiotic choices.\u003c/p\u003e\u003cp\u003eRoutine antimicrobial resistance surveillance, antimicrobial stewardship, early escalation to antifungal therapy for persistent fever, and the adoption of rapid diagnostic tools are essential to improving patient outcomes in this high-risk population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFebrile neutropenia\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFN\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eacute leukemia\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAL\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003emultidrug-resistant\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMDR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGram-negative rods\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGNRs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGram-positive cocci\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGPC\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cem\u003eCoagulase-negative staphylococci\u003c/em\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cem\u003eCoNS\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMethicillin-resistant\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEscherichia coli\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eE. coli\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePseudomonas aeruginosa\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eP. aeruginosa\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eStaphylococcus. Aureus\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eS. aureus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMethicillin-resistant Staphylococcus aureus\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMRSA\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eantimicrobial resistance\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAMR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePiperacillin-tazobactam\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePip-taz\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBloodstream infections\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBSI\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLower Middle-Income Countries\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLMICs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003evancomycin-resistant Enterococcus\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eVRE\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cp\u003e Our study was reviewed and approved as an exemption by the Ethics Review Committee, Aga Khan University. The case number is: 2023-8609-24894. The study is conducted as per protocol, in accordance with all Aga Khan University standards.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003cp\u003eThe data were entirely unidentifiable, hence no consent for publication was needed.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests:\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNo funding was required for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAI conceived the study, contributed to study design, and participated in data interpretation. AZ collaborated on the study design and supervised all microbiological analysis. MZ contributed to data acquisition, statistical analysis, and drafting of the manuscript. US assisted with data collection and contributed to data interpretation. ZF provided clinical oversight for hematology-oncology aspects and critically reviewed the manuscript for important intellectual content. SW contributed to data analysis, manuscript drafting, and figure and table preparation. AB assisted with data acquisition and literature review. AS contributed to data management and manuscript drafting. MSA assisted with data processing and verification. SI supervised the overall project, reviewed all analyses, and provided major revisions to the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\u003cp\u003eNot Applicable\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eD\u0026ouml;hner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTerwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7(6):e577\u0026ndash;577.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhan M, Siddiqi R, Naqvi K. An update on classification, genetics, and clinical approach to mixed phenotype acute leukemia (MPAL). 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Arch Clin Infect Dis. 2013;8(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKrcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect. 2002;50(4):243\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChumbita M, Peyrony O, Teij\u0026oacute;n-Lumbreras C, Monz\u0026oacute;-Gallo P, Aiello TF, Gallardo-Pizarro A, et al. Current microbiological testing approaches and documented infections at febrile neutropenia onset in patients with hematologic malignancies. Int J Infect Dis. 2024;147:107183.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWondm SA, Tarekegn GY, Dagnew FN, Dagnew SB, Moges TA, Zeleke TK, et al. Clinical Outcome of Febrile Neutropenia and Associated Factors Among Adult Patients with Cancer Treated at Ethiopian Oncology Centers: A Retrospective Observational Study. Oncol Ther. 2025;13(3):711\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDE Castro Carpe\u0026ntilde;o J, Gasc\u0026oacute;n-Vilaplana P, Tejerina AMCFD, Ant\u0026oacute;n-Torres A, L\u0026oacute;pez-L\u0026oacute;pez R, Barnadas-Molins A, et al. Epidemiology and characteristics of febrile neutropenia in oncology patients from Spanish tertiary care hospitals: PINNACLE study. Mol Clin Oncol. 2015;3(3):725\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Febrile neutropenia, acute leukemia, antimicrobial susceptibility, multidrug resistance, antimicrobial resistance","lastPublishedDoi":"10.21203/rs.3.rs-8193956/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8193956/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eFebrile neutropenia (FN) is a medical emergency in patients with acute leukemia due to profound neutropenia and immunosuppression, leading to life-threatening infections. Emerging antimicrobial resistance (AMR) further complicates management.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective descriptive study was conducted at a tertiary care hospital from January 2020 to December 2024. All pediatric and adult AL patients presenting with FN were included. Clinical records using ICD codes and laboratory data were analyzed to identify pathogen frequency, specimen source, and antimicrobial susceptibility patterns.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 478 FN episodes were identified through medical records, of which 217 (45%) were microbiologically documented. Among 381 isolated pathogens, Gram-negative rods (GNR) (n\u0026thinsp;=\u0026thinsp;154, 40.4%) marginally exceeded Gram-positive cocci (GPC) (n\u0026thinsp;=\u0026thinsp;148, 39%), followed by fungi (n\u0026thinsp;=\u0026thinsp;41, 11%), viral (n\u0026thinsp;=\u0026thinsp;24, 6%), parasitic (n\u0026thinsp;=\u0026thinsp;8, 2%), and mycobacterial pathogens (n\u0026thinsp;=\u0026thinsp;6, 1.6%). Blood was the most common culture source (n\u0026thinsp;=\u0026thinsp;246, 71%). Predominant organisms included: Coagulase-negative staphylococci (CoNS) (n\u0026thinsp;=\u0026thinsp;82, 24%), \u003cem\u003eEnterococcus species\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;23, 6.7%), and \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;19, 5.5%) among GPCs; \u003cem\u003eE. coli\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;57, 16.6%), \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;22, 6.4%), and \u003cem\u003eKlebsiella species\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;20, 6%) among GNRs. Among GPCs, 77 CoNS isolates (95%) were methicillin-resistant, and 16 Enterococcus isolates (76%) were vancomycin-resistant. Among GNRs, Enterobacteriaceae showed resistance to ceftriaxone (n\u0026thinsp;=\u0026thinsp;68, 77%), piperacillin-tazobactam (n\u0026thinsp;=\u0026thinsp;51, 63%), and carbapenems (n\u0026thinsp;=\u0026thinsp;34, 47%). Among fungi, \u003cem\u003eCandida auris\u003c/em\u003e showed universal resistance to fluconazole, while echinocandins remained active against all Candida species.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAmong culturable pathogens, CoNS were predominant. A high burden of multidrug-resistant organisms was identified, particularly vancomycin-resistant \u003cem\u003eEnterococcus\u003c/em\u003e and carbapenem-resistant Enterobacteriaceae. Current empiric therapy (meropenem\u0026thinsp;\u0026plusmn;\u0026thinsp;vancomycin) may no longer provide optimal coverage. Regular AMR surveillance and adjustment of empiric regimens are essential for improving outcomes.\u003c/p\u003e","manuscriptTitle":"Descriptive analysis of frequency and antimicrobial susceptibility of pathogens isolated from acute leukemia patients with febrile neutropenia over a five-year period at a tertiary hospital","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-13 00:12:27","doi":"10.21203/rs.3.rs-8193956/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-15T17:41:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T06:35:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T04:04:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238030683869337514979139994034011934142","date":"2025-12-08T14:44:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-08T04:03:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190679845254301531644413499259055460575","date":"2025-12-08T03:50:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176412363793614644236963056405713744338","date":"2025-12-08T01:08:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60565761211772832335204639221073394942","date":"2025-12-07T14:47:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-06T16:22:19+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-28T13:20:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-26T12:15:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-26T12:13:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-11-24T13:17:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a0e94720-975f-4681-9501-bbd82c7b5ef1","owner":[],"postedDate":"December 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:14:20+00:00","versionOfRecord":{"articleIdentity":"rs-8193956","link":"https://doi.org/10.1186/s12879-026-12918-2","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-03-02 15:57:30","publishedOnDateReadable":"March 2nd, 2026"},"versionCreatedAt":"2025-12-13 00:12:27","video":"","vorDoi":"10.1186/s12879-026-12918-2","vorDoiUrl":"https://doi.org/10.1186/s12879-026-12918-2","workflowStages":[]},"version":"v1","identity":"rs-8193956","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8193956","identity":"rs-8193956","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}