Predominant infection among cancer patients are caused by bacteria followed by fungi infections.1Factors that predispose to infection may be host associated or treatment associated. The host-associated factors include underlying immune deficiencies, co-morbidities, past infections, poor nutritional status, and psychological stress.2 Treatment-associated factors are surgery, radiation, immunosuppressant therapies, antimicrobial use, and invasive procedures.3 In a study carried out at the National Cancer Institute in the United States, out of 887 episodes of fever in cancer patients, 320 (36%) were caused by a microbiologically documented infection which included 252 bacteremia, 53 focal bacterial infections and 15 were viral or fungal infections.4 In the recent years, a shift from gram positive to gram negative organisms has been documented in blood stream infection in cancer patients, however data varies depending upon the geographical area.5 Lung cancer attributes to annual mortality rate of about 1.2 million people in the world and is mostly complicated by pulmonary (50-70%) orpostoperative wound infections after pulmonary surgery (2.4-5%).6 They are usually caused by S. aureus including MRSA and coagulase negative Staphylococci. Postoperative pneumonia is seen in 2% to 25% of patients who undergo pulmonary resection.6 In most cases of pneumonia, pathogens like H. influenzae (41.7%), S. pneumoniae (25%), other Streptococci (12.5%), Enterobacter spp. (8.7%) and Pseudomonas spp. (25%) are observed.7 The incidence of invasive aspergillosis ranges from 1% to 8% among pulmonary cancer patients with Aspergillusfumigatus and Aspergillusflavus being the most common causative agents.8 Head and neck cancers are very common in India and account for about 23% of cancers in males and about 6.2% in females.9 About 90%–95% of the head and neck malignancies are oral squamous cell carcinomas.10In the year 2017, pharyngeal and laryngeal malignancies reported worldwide were 49,670 and 13,360 respectively.11Cytotoxic drugs and radiation leads to oral mucositis which is exacerbated by neutropenia and provide an opportunity for the emergence of the bacterial, viral, and fungal infections.12 Oral fungal infections with both Candidaalbicans and non-albicans species are very common among patients with cancer of the head and neck, particularly those who have received both chemotherapy and radiation as part of their treatment regimen.13 Cancer and sepsis have a physiologically plausible association, as infections are common complications among cancer patients undergoing surgeries or treatment within the hospital setting.14Bacteria are the primary causative agents of blood stream infections, with significant fluctuations in the spectrum of the isolates over time.15Knowledge of local epidemiology of causative organismsand their susceptibility pattern help physicians to initiate evidence based timely therapeutic management. As there is limited data as regard to the infections in patients with oral and respiratory cancer a prospective study was planned to study the spectrum of bacterial and fungal infections among cancers of oral cavity and respiratory tract.

Cross-sectional study was conducted in the department of Microbiology at Indira Gandhi Medical College Shimla after obtaining ethical clearance from Institutional Ethics Committee vide letter No. HFW(MC-II) B (12) ETHICS/2022/10396. The study was done from 1st June 2021 to 31st May 2022. The study included patients >18years of age diagnosed with oral cavity and respiratory tract cancer after obtaining informed consent. Patients not willing to participate in the study, having co morbid conditions (chronic kidney disease, patients with recent usage of corticosteroids or other immunosuppressive drugs) were excluded. A pre-designed semi structured schedule was used to collect the demographic details (age, sex, place of residence), clinical presentation, site of cancer, type of cancer treatment (chemotherapy, radiotherapy, or both), HIV status, and any comorbid conditions. Clinical specimens such as blood, sputum, throat swabs, and bronchoalveolar lavage were collected at the start and during treatment. Samples were processed using standard techniques for bacterial and fungal identification and speciation. The bacterial pathogens were identified by their colony morphology, gram staining, biochemical tests and/or using BD PhoenixTM100 automated system. Antimicrobial susceptibility testing of the isolates was done using BD PhoenixTM100 automated system and/or by conventional Kirby-Bauer disk diffusion method. The results were interpreted as per the Clinical and Laboratory Standards Institute guidelines 2022. Fungal isolates were identified by preliminary macroscopic examination of fungal colony on SDA, microscopic examination using KOH wet mounts and lactophenol cotton blue tease mount for molds and for yeast identification BD PhoenixTM100 automated system was used. The data generated was entered into a pre structured data entry form on Microsoft Excel spreadsheet and analyzed using EPI Info31.

A total of 100 patients were included in the study, of which 86 patients were suffering from respiratory tract and 14 from oral cavity cancer with male predominance in both. The sex distribution, risk factors and comorbid conditionsassociated and management of respiratory tract and oral cavity cancer are presented in table 1. Table: 1 Demographic details, risk factors, co-morbid conditions and management of respiratory tract and oral cavity cancer patients. Respiratory tract Oral Cavity Age in years (IQR) Sex % (n) Male 87%(75) 93%(13) Female 13%(11) 7% (1) Risk factors Smoking % (n) 78%(67) 57%(8) Tobacco Chewing % (n) Nil 7%(1) Smoking & tobacco chewing n(%) 1%(1) 21%(3) Alcohol intake n(%) 53%(46) 64%(9) Alcohol & smoking n(%) 51%(44) 64%(9) Comorbidity n(%) 23%(20) Hypertension 12%(10) 0 Type II diabetes 7%(6) 0 Tuberculosis 3%(3) 0 Asthma 1%(1) 1 Management Radio-chemotherapy 45%(33) 45%(5) Chemotherapy 44%(32) 55%(6) Radiotherapy 11%(8) Nil Among patients of respiratory tract cancer, 70% (n=60) were above 60 years of age, 26% (n=23) were in the age group of 50-59 years and 4% (n=3) were below 50 years of age where as among oral cavity cancer 50% (n=7)were above 60 years of age, 36% (n=5) were below 50 years of age and 14% (n=2) were between the age group of 50-59 years. Use of tobacco (smoking/chewing) was observed among 79% and 85% of respiratory tract and oral cavity cancer respectively. Non-small cell carcinoma was observed among 78% (67) followed by small cell carcinoma 9% (8) and lymphoma and mesothilioma 1% each in patients with respiratory tract cancer and histology was unknown in 11% (n=9). In oral cavity cancer squamous cell carcinoma was the most common (n=10;72%) followed by spindle cell carcinoma (n=1; 7%) and unknown histology in 21% (n=3). The most common symptom for patients with respiratory tract cancer was shortness of breath 43% (37) followed by chest pain 41% (35), cough 38% (33) and hemoptysis 21%(18) where as among oral cavity cancer patients difficulty in swallowing {35%(6)}was followed by non-healing ulcer {18%(3)}.Local or systemic metastasis was seen in 28% (n=24) of the respiratory tract and 21% (n=3) of the oral cavity cancer patients. The distribution of bacterial and fungal organisms isolated from the samples of respiratory tract and oral cavity cancer patients is depicted in table number 2& 3 respectively. Table 2: Bacterial and fungal organisms isolated from the samples of respiratory tract cancer. Organisms Bacteria (n=80) Fungus (n=18) Type Gram positive (n=28) Gram negative (n=52) Yeast (n=14) Mold (n=4) Staphylococcus species Streptococcus pneumoniae Escherichia coli Klebsiella species Serratiamarcescens Pseudomonas aeruginosa Acinetobacterbaumanii Other non-fermenters Candida albicans Aspergillusfumigatus Blood(n=43) 22 0 6 1 0 2 4 8 0 0 Sputum(n=27) 3 2 7 6 0 1 0 2 6 0 Swab(n=20) 0 1 3 6 1 5 0 0 4 0 BAL(n=8) - - - - - - - - 4 4 Total (n=98) 25 3 16 13 1 8 4 10 14 4 Table 3: Bacterial and fungal isolates isolated from the samples of Oral cavity cancers. Organisms Bacteria (n=12) Fungus (n=3) Type Gram positive (n=3) Gram negative (n=9) Yeast (n=3) CoNS Escherichia coli Klebsiellapneumoniae Pseudomonas aeruginosa Acinetobacterbaumanii C. albicans C. tropicalis Blood(n=4) 3 0 0 0 1 0 0 Swab(n=11) 0 2 3 3 0 2 1 Total (n=15) 3 2 3 3 1 2 1 Infection (bacterial & fungal) was observed among 77% (77/100) of the respiratory tract and oral cavity cancer patients. Predominant bacterial isolates were gram negative (66%) where as among fungal isolate it was Candida albicans (76%) In patients of respiratory tract and oral cavity cancer among gram positive Staphylococcusspecies were the predominant isolates 89% and 100% respectively. Whereas among gram negative E.coli 31% was predominant isolate in respiratory tract cancer and Klebsiellapneumoniae (33%) and Pseudomonas aeruginosa (33%) were the predominant isolate in oral cavity cancer. The susceptibility pattern of the bacterial pathogens isolated from samples of respiratory tract cancer patients is depicted in figure 1 and 2. In the present study, Staphylococcus species isolated from respiratory tract cancer patients showed least sensitivity to erythromycin 32% and maximum sensitivity to linezolid 100%.Among the gram negative Escherichia coli was least susceptible to ciprofloxacin, levofloxacin, tetracycline, ceftazidime and cefotaxime 37% each and highest to amikacin, imipenem and gentamicin 81% each. Klebsiella species showed susceptibility of less than 53% (amoxycillin + clavulanic acid 15%, for gentamicin and piperacillin + tazobactam53% each).The susceptibility shown by Pseudomonas aeruginosa was least to ceftazidime 50% and maximum to amikacin, imipenem and meropenem 100% each. Acinetobacterbaumaniiwas the most resistant pathogen showing multi drug resistance. Other non-fermenter organisms showed susceptibility of 10% to aztreonam and 70% to gentamicin. Among the oral cavity cancer patients Staphylococcus species were least sensitive to tetracycline, doxycycline, clindamycin and erythromycin 33% each and 100% sensitive to linezolid. Escherichia coli was 100% sensitive to imipenem, meropenem and piperacillin + tazobactam. Klebsiellapneumoniaeshowed sensitivity of less than 66% to all the antibiotics. The susceptibility shown by Pseudomonas aeruginosa was least to ciprofloxacin, levofloxacin, cefepime and aztreonam 66% each and maximum to amikacin, gentamicin, imipenem, meropenem, ceftazidime and piperacillin + tazobactam 100% each. Acinetobacterbaumaniiwas the most resistant pathogen showing multi drug resistance. The distribution of pathogens isolated from patients undergoing chemotherapy, radiotherapy and radio-chemotherapy for the treatment of respiratory tract cancer is depicted in table number 4. Table 4: Distribution of pathogens isolated from patients undergoing chemotherapy, radiotherapy and radio-chemotherapy for the treatment of respiratory tract cancer. Organisms isolated from respiratory tract cancer (n=98) After chemotherapy n=36 After radiotherapy n=6 After radio-chemotherapy n=42 Not under active treatment n=14 Staphylococcus species (n=25) 14(39%) 0 8(19%) 3(21%) Streptococcus pneumoniae (n=3) 0 1(17%) 2(5%) 0 Escherichia coli (n=16) 7(19%) 0 8(19%) 1(7%) Klebsiella species (n=13) 3(8%) 1(17%) 6(14%) 3(21%) Serratiamarcescens (n=1) 0 0 1(2%) 0 Pseudomonas aeruginosa (n=8) 1(3%) 0 5(12%) 2(15%) Acinetobacterbaumanii (n=4) 2(6%) 0 1(2%) 1(7%) Other non-fermenters (n=10) 1(3%) 1(17%) 6(14%) 2(15%) Candida albicans (n=14) 7(19%) 2 (32%) 4(11%) 1(7%) Aspergillusfumigatus (n=4) 1(3%) 1(17%) 1(2%) 1(7% Overall bacterial infections were predominant as compared to fungal infections. However, during treatment (chemotherapy, radiotherapy, radiochemotherapy) majority of the infections occurred after radiochemotherapy 43% followed by after chemotherapy 37%and 6% after radiotherapy alone. However patients who did not receive any treatment 14% had bacterial or fungal infections. However in patients of oral cavity cancer after chemotherapy and radio-chemotherapy 6 episodes of infections were observed in each, whereas in patients not under active treatment only 3 episodes were reported. Here also bacterial infections {Staphylococcusspecies, Klebsiellapneumoniae, Pseudomonas aeruginosa 20% (n=3) each, Escherichia coli 13% (n=2),, and Acinetobacterbaumanii 7%(n=1)} were predominant over fungal{Candida albicans 13% (n=2), Candida tropicalis 7%(n=1)}

In our study out of 100 patients enrolled, 86 suffered from respiratory tract cancer and 14 from oral cavity cancer. Male predominance was observed among both respiratory tract (87%) and oral cavity cancer(93%) as observed by Noronha et al16 and Raj et al17 in their respective studies. The higher incidence of these two cancers among males may be attributed to more substance abuse in males as compared to their female counterparts. The median age of the patients among respiratory tract cancer patients was 65 years ranging from 40-80 years and whereas or oral cavity cancer it was 59 years (30-79 years) as also observed by other authors16,17. Cancer is a disease of senescence and with age there is continual shortening of telomeres during repeated cell replication cycles, and hence greater chance of DNA damage.18 In the present study for respiratory tract cancer, non-small cell lung carcinoma (NSCLC) was the predominant (78%) type of carcinoma and for oral cavity cancer, squamous cell carcinoma (SCC) was the predominant (72%) type of carcinoma. Thai et al19 in the year 2021 also observed non-small cell lung cancer (85%) as the predominant type of carcinoma in respiratory tract cancer patients. The predominance of squamous cell carcinoma (88.9%) in oral cavity cancer patients was also studied by Zhang et al20 (2016). In our study the symptoms observed were shortness of breath 43%, chest pain 41%, cough 38% and hemoptysis 21% which are similar to the observations made by Collins et al.21 It was observed that local/systemic metastasis was in 28% (n=24) respiratory tract and among 21 % (n=3) of oral cavity cancer patients. Collins et al21 reported that about one third of the total patients of respiratory tract cancer develop local or systemic metastasis to bones, liver, adrenal glands, lymph nodes, brain, and spinal cord whereas Kalyani et al22 in the year 2021 found 18% distant metastasis in oral cavity cancer. Tobacco use in the form of smoking and/or chewing was observed in 79% respiratory tract cancer patients and Collins et al21also observed similar finding (79%). Tobacco contains about 4000 chemical substances, of which approximately 60 are known carcinogens which attribute to the pathogenesis of respiratory tract cancer.23 When comparing the two cancers we found that use of tobacco and alcohol was higher in oral cavity cancer patients i.e., 86% and 64% respectively. Tobacco use in various forms (Bidi, Khaini, Gutka) is a major risk factor for carcinoma seen in 66.66% of the patients in a study conducted by Raj et al17 in the year 2017. This can be explained by the synergistic effect of alcohol and tobacco in the etiology of oral and oropharyngeal SCC.24 The predominant organism causing bacteremia in patients with respiratory tract cancer was Staphylococcus species 51% which is in concordance with a study conducted by Vento et al25 where 60–70% of cases of bacteraemia in respiratory tract cancer patients were caused by gram-positive cocci predominantly coagulase-negative staphylococci, viridans streptococci, and Staphylococcus aureus. The prevalence of gram-positive bacteria in these patients may be due to suppressed immune response which enables colonization followed by infection caused by endogenous microflora while using indwelling catheters and devices during treatment.26 The fungal infections seen in respiratory tract cancer patients were due to Candida albicans 14% and Aspergillusfumigatus in 4%. Similar observations were made by Vento et al25 where most systemic yeast infections were due to Candida albicans. Invasive candidiasis is generally preceded by colonisation of mucosal surfaces .In the same study25, aspergillosis was caused by Aspergillusfumigatus or A. flavus. Aspergillosis is invariably acquired from colonised air-conditioning or construction sites or may arise from conidia that colonise the respiratory tract, especially in patients with a smoking habit or compromised airways.26 The pathogens isolated from the oral cavity cancer patients were 60% gram-negative bacteria and 20% gram-positive bacteria. This finding is in concordance with a study done by Soni et al27 where gram-negative bacteria was found in 63.6% and Staphylococcus aureus in 8%. The fungal pathogens isolated were 20% which is similar to a study done by Lalla et al13 where it was 37.4%. This increased risk of candidiasis is likely due to the salivary hypofunction resulting from radiation therapy.13 Overall, a total of 92 bacterial isolates were obtained from respiratory tract and oral cavity cancer patients of which 61 (66%) were gram-negative and 31 (34%) gram-positive bacteria. The gram-positive bacteria (34%) isolated were 100% sensitive to linezolid whereas 41% Staphylococcus species showed methicillin resistance (MRS). Our findings are in concordance with a study conducted by Bhat et al28 where none of the gram-positive bacteria were resistant to linezolid and 41% of S. aureus were methicillin resistant. Macrolide susceptibility seen in the present study was 55% whereas that observed by Bhat et al28 was 32%. E. coli (30%), followed by Klebsiellapneumoniae(26%) and Pseudomonas aeruginosa (18%) were the most common gram-negative bacteria identified in the present study. Other non-fermenter organisms contributed 26% altogether. High susceptibility rates were observed among the GNB isolates to imipenem, meropenem and piperacillin/tazobactam. Susceptibility of gram-negative isolates to fluoroquinolones and aminoglycoside in the present study was observed in 47% and 66%, respectively and 54% and 63%, in a study done by Bhat et al28. The same study showed carbapenem susceptibility in 84% Escherichia coli which was 78%in the present study. Acinetobacterbaumanii(4%) was multidrug resistant as also observed by Bhat et al28. In the present study, there was predominant growth of gram-negative bacilli (64%) followed by gram-positive bacteria (24%) and fungal isolates (12%) among respiratory tract cancer patients under radiochemo therapy as also observed by Akinosoglou et al29.All six patients of oral cavity cancer who were subjected to chemotherapy showed growth of microorganisms, predominantly gram-positive bacteria (Staphylococcus species) 32% whereas those subjected to radio-chemotherapy (n=5) showed predominant growth of gram-negative bacteria 67%. These findings are in concordance with a study conducted by Panghal et al30. The prevalence of bacterial infections following chemotherapy and radio-chemotherapy may be because of the damage done to the body’s immune system by radiations and chemotherapy and lesser use of routine prophylactic oral antibiotics.30 Candida albicansisolated following radio-chemotherapy in oral cavity cancer patients was 33% which is similar to the findings of Panghal et al.30 The reason for colonization of C. albicans in the oral cavity of radio-chemotherapy treated cancer patients is induction of hyposalivation by radiation which encourages oral candidal colonization that often leads to oral candidiasis.30 Limitations: Limitations include the limited sample size, lack of fungal and molecular resistance characterization.

In the present study, overall, in both oral cavity and respiratory tract cancer patients, gram-negative bacteria were the most common pathogens isolated. Bacterial and fungal infections were observed to be more prevalent after radio-chemotherapy followed by chemotherapy and radiotherapy. The isolated bacteria showed a wide range of antimicrobial susceptibility pattern with gram-positive bacteria being most sensitive to linezolid and gram-negative bacteria to aminoglycosides and carbapenems. AcinetobacterbaumaniiandKlebsiellapneumoniaeisolated in the present study were the most multi-drug resistant bacteria.

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