key: cord-0336203-p7ld8zpw
authors: Naseef shtaya, H. A. H.; Mohammad, U.; Al-Shami, N.; Sahoury, Y.; Abukhalil, A. D.; Farraj, M.
title: Bacterial and Fungal Co-Infections among ICU COVID-19 Hospitalized Patients in a Palestinian Hospital: Incidence and Antimicrobial Stewardship
date: 2021-09-15
journal: nan
DOI: 10.1101/2021.09.12.21263463
sha: d96d60da73f335f140e9d35de681f2c08c0ca4ef
doc_id: 336203
cord_uid: p7ld8zpw

Diagnosis of co-infections with multiple pathogens among hospitalized COVID-19 patients can be jointly challenging and very essential for appropriate treatment, shortening hospital stay and preventing antimicrobial resistance. This study proposes to investigate the burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single centre cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. The study included 321 hospitalized patients admitted to the ICU between June 2020 and March 2021 aged [≥]20 years, with a confirmed diagnosis of COVID-19 via RT-PCR conducted on a nasopharyngeal swab. The patient's information was gathered using graded data forms from electronic medical reports. The diagnosis of bacterial and fungal infection was proved through the patient`s clinical presentation and positive blood or sputum culture results. All cases had received empirical antimicrobial therapy before the ICU admission, and different regimens during the ICU stay. The rate of bacterial co-infection was 51.1%, mainly from gram-negative isolates (Enterobacter species and K.pneumoniae). The rate of fungal co-infection caused by A.fumigatus was 48.9%, and the mortality rate was 8.1%. However, it is unclear if it had been attributed to SARS-CoV-2 or coincidental.

1 hospital stay and preventing antimicrobial resistance. This study proposes to investigate the 31 burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single centre 32 cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. The 33 study included 321 hospitalized patients admitted to the ICU between June 2020 and March 2021 34 aged ≥20 years, with a confirmed diagnosis of COVID-19 via RT-PCR conducted on a 35 nasopharyngeal swab. The patient's information was gathered using graded data forms from 36 electronic medical reports. The diagnosis of bacterial and fungal infection was proved through 37 the patient`s clinical presentation and positive blood or sputum culture results. All cases had 38 received empirical antimicrobial therapy before the ICU admission, and different regimens during 39 the ICU stay. The rate of bacterial co-infection was 51.1%, mainly from gram-negative isolates 40 (Enterobacter species and K.pneumoniae). The rate of fungal co-infection caused by A.fumigatus 41 was 48.9%, and the mortality rate was 8.1%. However, it is unclear if it had been attributed to Introduction 51 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263463 doi: medRxiv preprint 2 Severe Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) is a highly contagious novel viral 52 pathogen that provokes an immediate spread among hospitalized patients with Community- 53 Acquired Pneumonia (CAP) (1); extending from mild symptoms approximately in 84% of patients 54 to life-threatening hypoxic conditions necessitating admittance into the Intensive Care Unit (ICU) 55 and oxygen support (2). Additionally, it causes multi-organ failure that involves sepsis and 56 thromboembolic complications, which progresses into an acute kidney and cardiac injury (3). On 57 March 11 th, 2020, the World Health Organization (WHO) deemed COVID-19 a pandemic disease; 58 due to its unusual transmission speed and the wide-scale of infection (4) . 59 The bacterial and fungal co-infections are frequently recurring due to respiratory viral diseases. 60 For example, most deaths in the Spanish flu pandemic in 1918 were due to subsequent bacterial 61 infection (5). It raises a concern as it hinders COVID-19 management, worsens prognosis, and 62 might increase the fatality rate. The reported prevalence of bacterial co-infection varies between 63 studies (6). 64 Throughout the pandemic, evaluation of gathered specimens from hospitalized COVID-19 65 patients reported the most prevalent organisms, which induce the co-bacterial infection; these 66 were S. aureus, S. epidermidis, H. influenzae, Streptococcus spp., E. coli, K. pneumoniae and P. 67 aeruginosa (7). Therefore, many COVID-19 treatment protocols include empirical antibiotic 68 therapy to cover suspected organisms. Relatively, in a systematic review, thirty studies were 69 summarized including 3834 COVID-19 patients. Overall only 7% of the hospitalized patients were 70 confirmed to have bacterial co-infection with one or more pathogens, primarily in seriously ill 71 patients (8). On the contrary, fungus infections in COVID-19 patients are neglected or delayed 72 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. and were elusive to have the actual prevalence of fungal co-infection and yet to be explained in 73 extent. Few studies were conducted in this regard; a systematic review meta-analysis research 74 was carried out in China on 2780 confirmed SAR-CoV-2 participants from nine relevant articles. 75 After fungal culturing at admission, 0.12%-0.15% of the cases were positive for fungal infection 76 and Asian patients were more likely to acquire fungal co-infection. The infecting fungi include 77 Aspergillus, Candida, Cryptococcus neoformans, Pneumocystis, or other fungal species (9). 78 The exact mechanism of microbial co-infection is inadequately understood. Virologists assumed 79 that the viruses attach and penetrate the host's airway epithelial cells creating an inflammatory 80 response desensitizing Toll-like receptors leading to cellular apoptosis in numerous mechanisms. 81 In addition, it debilitates the body's defense, induces cellular dysfunction and death (10). 82 Viruses aid in proliferation, colonization, and invasive infection of opportunistic nosocomial 83 pathogen or respiratory tract normal flora; via hindering the innate immune response, 84 compressing airway mucus, and disrupting the cilia. Thereby, this will allow for the spread and 85 adhesion to more sites (3). Furthermore, various researches highlighted the synergy regulations 86 among viruses and bacteria; both are jointly advantageous, aggravating clinical outcomes. If this 87 cooperation is confirmed, then the management with antibiotics becomes further reasonable 88 (11) . 89 The COVID-19 disease has been chiefly linked to high levels of inflammatory markers, such as 90 elevated levels of C-reactive protein and procalcitonin. Accordingly, the similarity between Sar-91 CoV-2 and bacterial infections in radiological infiltrates and laboratory findings makes it 92 challenging in daily medical practice to provide a precise diagnosis (12). However, according to 93 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263463 doi: medRxiv preprint 4 current studies, most COVID-19 patients did not have bacterial or fungal co-infections upon 94 admission or through the hospital stay, even though they received antibiotics upon admission or 95 before diagnosis (13) . Furthermore, lack of specific antiviral agents and the overload to the 96 health services capacity, saturated laboratories used to identify the causative microbial and 97 diagnosis uncertainty to rule out super-infections; those factors advocated escalation of 98 antimicrobial consumption in the pandemic (14) . As a result, clinicians are obliged to prescribe 99 broad-spectrum multi-antibiotic regimens; to treat all the possible infected pathogens. bacteria or fungi were included in the study, and patients with negative cultures were excluded. 113 The study was approved by the Scientific Research Ethics Committee of Birzeit University and by 114 Beit-Jala hospital. 115 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Co-infection is a sequela that occurs during or after the primary causative pathogen or its 132 treatment. The isolated bacteria or fungi obtained from COVID-19 patients should be clinically 133 relevant and not microbiota or contaminants. All the microbiological samplings were conducted 134 upon the hospital`s entry and before the ICU admittance, and only patients holding positive 135 bacterial or fungal outcomes were admitted into the unit. In combination with decision-making, 136 a scope of standards should meet to provide permission on who necessitates access. Essentially, 137 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. cystine 1200 mg /day, which began from their hospital`s entrance to the exit. 158 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Bacterial co-infection was recorded in 51.1% of cases, with higher mortality rates among 224 Enterobacter infected patients; this may be due to its known drug resistance. It should be noted 225 that normal oral flora colonization or contamination may occur, particularly in the sputum 226 specimens. In general, the empirical treatment with Ceftriaxone or Ampicillin/Sulbactam showed 227 minimal benefits to the clinical status. However, we observed a better prognosis with Ceftriaxone 228 than Ampicillin/Sulbactam. The mortality rate also varied from 4% with Ceftriaxone vs. 17.3% 229 with Ampicillin/Sulbactam; this association needs more investigation. 230 Once the bacterial co-infection is confirmed and the patient is admitted into the ICU, the wide-231 spectrum antimicrobial regimens are administered. Unfortunately, there is no available data to 232 compare COVID-19 patients who received antibacterial agents with those who did not; to 233 determine the therapeutic efficacy. However, Piperacillin with Tazobactam and Levofloxacin 234 resemble Meropenem and Vancomycin in the clinical outcomes and management rate. Counter 235 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263463 doi: medRxiv preprint 13 to a study that reveals a higher rate of mortality and organ failure regarding Meropenem (13) . 236 Furthermore, after the recovery and discharge from the hospital, all outpatients have been 237 prescribed Azithromycin, which also has antiviral activity and may decrease the incidence of 238 acute organ failure (13) . 239 Earlier examinations illustrated that multiple antibiotic administrations did not alter the disease 240 results or had joined with higher deaths (18). In our study, it appeared to induce a good prognosis. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In our study, 100% of the patients were severe-critical ill. Therefore, it is required to differentiate 258 between them and mild-moderate patients and prioritize the ICU admittance. (23) . Furthermore, current smokers have higher ace-2 276 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263463 doi: medRxiv preprint gene expression than non-smokers; this gene is responsible for ACE-2 receptors production, 277 which COVID-19 attaches to and penetrates the cells, thus raising the chance of infection (24). 278 Our study did not find an association between smoking habits and the duration of ICU stay or 279 clinical prognosis. 280 Numerous investigations found that older COVID-19 patients aged ≥50 years were correlated 281 with higher risk for severe signs, atypical presentation, the opportunity for co-infections and 282 higher fatality rates compared to patients with <50 years of age, and the rate usually increases 283 rapidly with age; it is not surprising due to the drop in natural immunity by age, associated 284 comorbidities and it is believed that older people are prone to adverse drug reactions. In general, 285 people of different ages are prone to get infected with the COVID virus (25) (26). A review 286 reported a twice higher fatality rate in males compared to females; it has stated that male 287 patients may have higher ACE-2 enzyme activity, directed by male sex hormones, contributing to 288 more risk for SARS-CoV-2 infection and worsening clinical outcomes (27). Additionally, the 289 smoking rate is higher in males. 290 Effects of comorbidities such as hypertension, diabetes mellitus, coronary heart disease and 291 Cancer were compared between survivors and non-survivors. All of those comorbid conditions 292 have a significantly greater fatality rate in non-survivors; because they have decreased natural 293 immunity and are poly-pharmacy patients (28) (29). In our study, there was no association 294 between age, gender or comorbidities with the clinical outcomes and ICU stay duration. 295 Previous reports had described mild anemia in COVID-19 patients at the ICU; due to severe 296 inflammation which consumes iron (30), the innate immune system limits the bioavailability of 297 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. iron; to diminish viral replication and infection. Accordingly, iron absorption from the diet is 298 reduced, and the liver generates hepcidin which blocks carrying iron out of the cell. Accordingly, 299 iron supplementation may exacerbate the disease and increase the inflammatory process (31). 300 However, no solid investigations were performed on the relation between iron and clinical results 301 in COVID-19 patients. In our study, 62.6% of the patients had received IV iron supplement for 302 three days, based on a randomized clinical trials, and 99% of them had improved and stayed for 303 a shorter time (1-6 days) in the ICU; which provided a good immunity enhancing. Therefore, there 304 is a strong association between low serum levels of iron and an increased infection rate and 305 morbidity. 306 COVID-19 produces oxidative stress irregularity, and this process has been enhanced by 307 glutathione reduction. Thiones are synthesized in a multi-step process in which N-acetyl-cysteine 308 is part of it. Thiones are also ACE-2 blockers, thereby diminishing SARS-CoV-2 penetration into 309 the cell. In a placebo-controlled study, NAC administration had reduced plasma inflammatory 310 biomarker levels via several mechanisms. Besides antioxidant activity, NAC has vasodilator 311 activity, especially in the intravenous route. In addition, it has mucolytic properties, inhibits RNA 312 virus replication, and has confirmed protective effects against comorbid conditions, including 313 cardiovascular diseases (32). In our study, patients had received NAC 1200 mg/day during the 314 hospital stay, and even after discharge, those showed a better prognosis and improvement in 315 their health status. 316 This research has some limitations: first, it is a cross-sectional study holding obstacles restricting 317 the potential bias and difficulty proofing the relation between the exposure and the outcome. 318 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Other, it is a single-centre, and its results could vary in another setting. Comprehensively, those 319 conclusions present data supporting a conservative antibiotic administration for severely unwell 320 COVID-19 infected patients. Our examination regarding the impacts of employing antifungals to 321 manage COVID-19 patients can work as a successful reference for future COVID-19 therapy. CoV-2 or coincidental; little of available data. Finally, Antimicrobial stewardship, appropriate 330 patient assessment, and selecting the appropriate antimicrobial agents for the right patient at 331 the right time will decrease hospital stay, mortality, and health care costs. 332 333

COVID -19: a brief history and treatments in development

Secondary bacterial infections 362 associated with influenza pandemics

COVID-19: 364 don't neglect antimicrobial stewardship principles!

Few bacterial co-infections but frequent empiric antibiotic use in the 369 early phase of hospitalized patients with COVID-19: results from a 370 multicentre retrospective cohort study in The Netherlands

Detection of Bacterial Coinfection in COVID-19

Patients Is a Missing Piece of the Puzzle in the COVID-19 Management in

Fungal co-376 infection in COVID-19 patients : evidence from a systematic review and 377 meta-analysis

Postviral Complications: Bacterial Pneumonia. Clin

Antibiotics and antimicrobial resistance in the COVID-383 19 era: Perspective from resource-limited settings

Recommendations for antibacterial 388 therapy in adults with COVID-19 -an evidence based guideline

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted

Clinical characteristics and 391 antibiotics treatment in suspected bacterial infection patients with COVID

COVID-19: An emerging threat to antibiotic stewardship in the emergency 395 department

Antibiotic prescription during the COVID-398 19 pandemic: A biphasic pattern

Mortality rates of patients with COVID-19 in 400 the intensive care unit: A systematic review of the emerging literature

Fungal Co-infections Associated with Global 403 COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China

Clinical features of 85 fatal cases of 407 COVID-19 from Wuhan: A retrospective observational study

Clinical course and outcomes 411 of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a 412 single-centered, retrospective, observational study

COVID-19 and the clinical 415 hematology laboratory

Value of leukocytosis and elevated C-reactive protein in 418 predicting severe coronavirus 2019 (COVID-19): A systematic review and 419 meta-analysis

All rights reserved. No reuse allowed without permission

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted

The 424 effect of smoking on COVID-19 severity: A systematic review and meta-425 analysis

Current smoking is not 427 associated with COVID-19

Potential Factors for Prediction of

Disease Severity of COVID-19 Patients

COVID-19 in older adults: What 434 are the differences with younger patients?

An 436 Assessment on Impact of COVID-19 Infection in a Gender Specific Manner

Age, and Comorbidities with Mortality in COVID-19 Patients: A 440 Systematic Review and Meta-Analysis

Clinical 442 characteristics, laboratory outcome characteristics, comorbidities, and 443 complications of related COVID-19 deceased: a systematic review and meta-444 analysis

Patient blood management during the COVID-19 pandemic: a 448 narrative review

Anemia and iron metabolism in COVID-452 19: a systematic review and meta-analysis

Acknowledgements: 334 We would like to express our appreciation to the health worker at Beit-Jala Governmental 335 Hospital, Palestine, for their support and cooperation.

Availability of data and materials 337 

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263463 doi: medRxiv preprint