Bloodstream Infections with Opportunistic Pathogens in COVID-19 Era: A Real Challenge Necessitates Stringent Infection Control

Introduction

Bacterial and fungal bloodstream infection (BSI) during intensive care unit (ICU) stay has been reported in other outbreaks of severe acute respiratory syndrome (SARS), but there is limited data on BSI by opportunistic infections available in the context of SARS-CoV-2 pandemic.^[1] Many authors have recognized the importance of superinfection, but definitive data are still lacking.

The role of the host response to infection by SARS-CoV-2 in coronavirus disease 2019 (COVID-19) disease has been used as a potential target for therapy, and several immunomodulatory treatments have been proposed throughout the outbreak.^[2] Steroid therapy use, with varying doses and regimens, and the use of specific biologic drugs such as tocilizumab may lead to profound immune suppression,^[3] and use of broad-spectrum antibiotics and multiple antibiotics, sometimes for a prolonged period, may lead to the emergence of drug-resistant pathogens.^[4] On the other hand, inadequate infection prevention and control (IPC) measures, including improper hand hygiene before and in between patients contact, lack of bundle care while dealing intravenous (IV) lines, and deployment of new staff without adequate training, may be attributed to the emergence of drug-resistant strains and cross-infections among COVID-19 patients admitted in ICU and non-ICU wards.^[5,6]

Materials and Methods

This was a prospective, cross-sectional study conducted in the Department of Microbiology, Peerless Hospitex Hospital and Research Center Ltd. for a period of 6 months, spanning from September 2020 to February 2021. A total of 150 patients admitted in both COVID-19 and non-COVID-19 Intensive therapy units, ICU, and non-ICU wards were enrolled in the study. The study obtained permission from the institutional ethical committee, vide letter number—PHH and RCL/CREC/FM02 dated 9th September 2021. The relevant demographic characteristics and risk factors were assessed and analyzed, including age, gender, duration of hospitalization, presence of prior antibiotic treatment, clinical comorbidities, duration of exposure to central venous access, device days, history of indwelling devices, and clinical outcome. Laboratory testing for infection control was mainly targeted at three major areas—antibiotic susceptibility testing, detection and identification of infectious disease (ID) pathogens, and finally, genotyping methods. Stringent strategies have been implemented to prevent and control the spread of multidrug-resistance organisms (MDROs) like carbapenem-resistant Enterobacteriaceae (CRE), Multidrug-resistant Acinetobacter & Pseudomonas species, Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), etc. and to minimize the risk of cross-infection to other patients, staff and visitors. For rapid identification of patients or environmental sources colonized with these MDROs, active surveillance (like CRE, VRE, and MRSA surveillance) was carried out from rectal swabs, feces, nostrils, groin, and armpits for high-risk patients admitted in ICUs, as per Centers for Disease Control and Prevention (CDC) guidelines. For timely management of patients, the detection of antimicrobial drug-resistant genes was carried out by different phenotypic (EDTA Carbapenem inactivation method, Modified Carbapenem inactivation method) and genotypic methods like real-time polymerase chain reaction (RT-PCR). Non-molecular-based approaches like Enzyme-linked fluorescence assay to detect C. difficile toxin in stool, rapid immunochromatographic card tests, and immune- blot assays were also used.

Results

Out of the total of 150 patients admitted during the study period, 54 patients with suspected clinical sepsis developed a laboratory-confirmed bloodstream infection (LCBI) on one or more occasions. A total of 54 opportunistic nonduplicate isolates were detected from 54 LCBI patients over 6 months from September 2020 to February 2021. The study population constituted 44 (81.48%) males and 10 (18.5 %) females. The median age of infected patients was 62 years (interquartile range: 52.5–72). The mean length of hospital stay was 8 ± 1 day (range: 3–62 days) and the mean length of ICU stay was 6.4 ± 2 days (range: 3–31 days).

In total, 125 (83.3%) out of 150 patients were admitted to intensive care units (ITU and ICU), and the rest to nonintensive care wards. Various risk factors were observed among 54 patients with BSI caused by opportunistic pathogens, including a prolonged length of hospital stay of more than 7 days, central venous access, and exposure to mechanical ventilation for more than 5 days among others, in comparison to the noninfected cases (n = 96). Risk factors for cases and matched controls are listed in ►Table 1.

Microbiological Workup

A total of 54 nonduplicate clinical isolates were obtained from blood samples of these patients admitted to ITU, ICU, and non-ICU general wards. The mean time from admission to culture positivity was 8.5 days. The incidence of opportunistic pathogens causing BSI is depicted in ►Table 2.

Out of 54 BSI isolates, Burkholderia cepacia topped the list accounting for 13 cases, followed by Elizabethkingia meningoseptica that accounted for 10 cases. The third important group was the non-albicans Candida species, of which C. auris isolates were recovered from seven patients. Remaining were shared among VRE and other nonfermenting gram-negative bacilli (Chryseobacterium indologenes; Aeromonas species; Stenotrophomonas maltophilia, and Alcaligenes faecalis). All clinical isolates obtained from the same genus showed similar morphological appearance and growth characteristics on microbial culture.

After a thorough root cause analysis, we concluded that such occurrence could probably be due to improper hand hygiene, improper use of gloves between patients, prolonged storage of RO water in jars for more than 48 hours that could have helped waterborne pathogens to grow, common NS being used for inotrope preparation, improper bundle care related to intravenous lines, more incidence of femoral lines, especially in COVID-19 patients, and deployment of new nursing staff without adequate training of IPC measures.

Antimicrobial susceptibility testing revealed that all the isolates under the same genus exhibited a similar antibiogram.

As a part of intensive source tracking and control, we screened a total of 105 environmental samples at periodic intervals. Three used normal saline samples from ICU patients grew nonlactose fermenting, late oxidase-positive, and gram-negative bacilli, which were subsequently identified as B. cepacia by Vitek 2 system.

Three RO water samples in a jar (used for a humidifier)—one each from ITU, ICU, and Netaji ward also showed growth of B. cepacia. All six isolates from environmental sources showed similar growth characteristics with that of clinical isolates and shared a similar antibiogram. In total, we could identify 17 isolates out of 105 environmental samples tested. Details of the isolates from surveillance samples are summarized in ►Table 3.

The mortality rate was alarmingly high among patients with BSI caused by opportunistic pathogens, especially with Elizabethkingia meningoseptica, Stenotrophomonas maltophilia, B. cepacia, and Candida guilliermondii. Details of mortality analysis are depicted in ►Table 4.

After a few consecutive cases, detailed systematic and rigorous infection control practices were initiated to prevent the further spread of these opportunistic bugs. Initially, the infected patients were isolated and cohorted using physical barriers within the cubicle. Every cubicle was disinfected by fogging using Silvicide (0.01% w/v silver nitrate and 10% w/v hydrogen peroxide) vapor. Intensive terminal cleaning of cubicles, bed rails, and bedside objects was done with Virex 256 (quaternary ammonium compounds). Thorough cleaning of the curtains, bedding, and linen was done using appropriate heat disinfection with hospital-graded detergents. Strict hand hygiene with plain or antimicrobial soap and water or alcohol-based hand rub was reinforced. Enhanced barrier precautions, that is, the use of personal protective equipment was encouraged if contact with patients or objects surrounding patients was anticipated, and dedicated instruments (e.g., stethoscope/blood pressure cuff) was also allocated, as it has been seen to disrupt the spread of MDROs among the patients with devices. Rational use of gloves and interchanging of gloves between two patients while handling lines and suctioning was strictly followed by doctors, nurses, and paramedics. Infection control nurses were vigilant to monitor the same meticulously. The unnecessary use of gloves was discouraged in non-COVID-19 wards. A thorough training was given to all HCWs, especially in COVID-19 wards, to ensure bundle care of IV lines. The common use of saline bottles for flushing and preparation of inotrope and other medications was strictly prohibited. It was decided to use 100 mL normal saline bottles for each patient individually for preparation of medication and flushing, etc. by adhering to infection control practices. Reuse was restricted to the same patient and no syringe was to be reused (for the same patient) for more than 24 hours. All IV fluids, TPN, and medications were scrupulously checked and administered with significant caution. Feed preparation was strictly monitored. Thorough cleaning of water tanks with pipelines and chlorination was immediately done and then regularly monitored at regular intervals.

The hand hygiene compliance rate was measured on monthly basis. An increase in hand hygiene compliance from 79.8 to 87.8 % was observed over 6 months from September 2020 to February 2021. Central line insertion was closely monitored, and maintenance was regularly assessed and recorded in a standard proforma as per CDC guidelines. Central line bundle care compliance was assessed and recorded daily and special training was given to HCWs to increase compliance with aseptic procedures and techniques. There was an increase in central line bundle care compliance from the baseline rate of 75.6 to 89.8 % observed over 6 months from September 2020 to February 2021 (►Fig. 1).

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Fig. 1

Improved hand hygiene compliance and central vascular catheter (CVC) bundle care compliance (in percentages) after thorough training.

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All concerned staff and HCWs participated in infection control meetings held regularly, to discuss measures and recommendations to control this unusual surge of BSI by opportunistic pathogens. After assiduous, exhaustive, and timely efforts along with efficient source tracking and control activities, a drastic reduction in cases of BSI by opportunistic pathogens was observed over the next couple of months, and cases with isolation of these characteristic strains reduced to near zero after March 2021 (►Fig. 2).

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Fig. 2

Decrease in bloodstream infection (BSI) by opportunistic pathogens following implementation of infection prevention and control (IPC) measures. Y axis indicates number of isolated opportunistic pathogens. ICU, intensive care unit; VRE, vancomycin-resistant Enterococcus.

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There was a gradually decreasing trend of COVID-19 cases in the city at the end of the study period. Thus, to find out a correlation between a decrease in opportunistic pathogen-mediated BSI and decreasing number of COVID-19 cases in the city, we performed a statistical analysis, which revealed that decreased opportunistic BSIs were not attributed to decreasing trend of COVID-19 cases in the city (►Fig. 3). Pearson correlation coefficient between the month-wise number of opportunistic blood-borne pathogens and total active COVID-19 cases reported in Kolkata were calculated. The calculated R was 0.7356. However, the p-value was found to be 0.095619. The result was not significant at 0.05 levels. Thus, it indicates that no relationship was present between the two variables.

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Fig. 3

Graph showing number of bloodstream infection (BSI) and total number of coronavirus disease 2019 active cases (x1000) in Kolkata (TACK), X-Axis: 1-Sep, 2020, 2-Oct, 2020, 3-Nov, 2020, 4-Dec, 2020,5-Jan, 2021, 6-Feb, 2021.

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Discussion

In recent times, opportunistic bacterial and fungal pathogens, such as B. cepacia, Elizabethkingia meningoseptica, other nonfermenting gram-negative bacilli, and Candida non-albicans species are being detected in the bloodstream with increased frequency, especially from COVID-19 patients.^[7,8]

Nonfermenting gram-negative bacilli like B. cepacia, Elizabethkingia meningoseptica, and Stenotrophomonas maltophilia are primarily environmental bacteria residing mainly in water and aqueous solutions.^[9] They cause opportunistic infections in immune-compromised subjects including those on prolonged broad-spectrum antibiotic and steroid therapy. Although they may be transmitted from one patient to another through improperly disinfected hands of caregivers and aerosols, those are not the common routes of spread. The organisms have to be introduced into the bloodstream through contaminated syringes or from IV hubs to colonize the IV lines or cause BSIs.^[10]

In our study, prolonged ICU stay, central venous access, exposure to mechanical ventilation, immune-compromised condition, and use of biologics were found to be significant risk factors of BSI, which corresponds to observations of other workers.^[11-13] Although higher age, diabetes mellitus, and steroid use appear as important risk factors for BSI, in this study we did not find any significant difference with the control population. Paradoxically, neutropenia appeared to be a significant risk factor, predominantly seen with control as compared to cases (29.3% in control vs 9.3% in cases).

B. cepacia (24.1%) was most commonly isolated followed by E. meningoseptica (18.5%); C. auris (12.9%), VRE (9.2%), and A. xylosoxidans (5.5%) among many other opportunistic pathogens in our study. B. cepacia is a well-reported pathogen known to be associated with many hospital outbreaks, attributed to a plethora of sources: antiseptics, disinfectants, and nebulizer solutions^[14] (Memish et al., 2009). In our study, we were able to isolate B. cepacia from six environmental samples, three each from used saline bottles and from RO water that was kept in a jar to be used as a humidifier. Various studies have shown that E. meningoseptica is capable to survive in chlorinated water, disinfectants, the contaminated hand of HCWs, infant formulas, and often colonizing sinks, taps, etc. Contaminated medical devices involving saline solution used for flushing, ventilators, breathing circuits, endotracheal tubes, humidifiers, and intravascular devices have been documented as of serious concern and creating potential reservoirs for healthcare-associated infections.^[14,15] A study conducted by Khan et al showed that the administration of broad-spectrum antibiotics including Colistin was found to be a predisposing factor to cause invasive infection by E. meningoseptica.^[16] In our study, 7 out of 10 patients (70%) suffering from E. meningoseptica bacteremia had a previous history of broad-spectrum antibiotics exposure including Colistin. C. auris is an emerging fungus that can cause invasive infections associated with high mortality and is often resistant to azoles, Amphotericin B, and Flucytosine and sensitive to Echinocandins only. It often colonizes the axilla and groin of hospitalized patients before it can result in invasive infection in hosts. We were able to identify one isolate of C. auris from a groin swab collected from a patient during active surveillance screening in our hospital as per CDC guidelines. In our study, BSI caused by A. xylosoxidans was reported only in three cases, which is similar to the study conducted by Houlihan et al, where it had been reported rarely.^[16] In this study, we also observed no significant correlation between opportunistic BSI and the total number of active COVID-19 cases in our locality.

Most of the opportunistic pathogens isolated from blood were also recovered from different water sources used in the hospital for various purposes. Thus, water contamination is an important factor for these opportunistic BSI. This finding corresponds to the findings of other workers.^[17] A high mortality rate was observed in BSI by opportunistic bugs like E. meningoseptica (80%) and B. cepacia (44%) in our study, as also observed by other authors.^[18] Both hand hygiene compliance (from 79.8 to 87.8 %) and CVC bundle care compliance (from 75.6 to 89.8 %) had improved significantly after thorough training (►Fig. 1), which is similar to the study conducted by Rastogi et al^[19] and these were probably reflected in curbing the rate of BSI following IPC training. In agreement with other studies, coordinated infection control activities such as implementing standard hand hygiene, barrier and contact precautions, cohorting of patients having the same opportunistic infections, environmental surveillance and source tracking, water disinfection, and enhanced and terminal cleaning of the ICUs helped us to decrease BSI rates significantly over next couple of months (March and April 2021) in our hospital (►Fig. 2).

Clonal relatedness could not be established for environmental isolates with that of clinical isolates, due to the lack of multilocus sequence testing facility in our hospital.

Conclusions

BSI due to opportunistic microbes is seen to be on the rise during the COVID-19 pandemic. B. cepacia, E. meningoseptica, C. auris, VRE, and A. xylosoxidans are the common opportunistic pathogens isolated from BSI in our study. Common sources were identified as RO water and used normal saline bottles. Early diagnosis and appropriate therapy, along with intensive and persistent infection control practices, are required for the successful containment of these pathogens and to curb such clusters of opportunistic infections.