Burkholderia cepacia complex nosocomial outbreaks in India: A scoping review

Materials & Methods

The study followed PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The PRISMA-ScR 22 points checklist (Supplementary Table) has been referred to while formulating this review. Databases such as ‘PubMed’ (https://pubmed.ncbi.nlm.nih.gov), ‘Embase’ (https://www.embase.com) and ‘Web of Science’ (https://clarivate.com) were utilized. Literature published between 1993 and September 2024 and only in English was included in this review. Furthermore, the references cited in the included studies were assessed (Figure). The combination of search terms used was as follows: (Burkholderia cepacia complex OR Burkholderia species OR Pseudomonas cepacia; MeSH Terms) AND (outbreak; MeSH Terms) AND (India; MeSH Terms) (Supplementary Material). Search terms like contaminated drugs or pharmaceuticals were not used as they would limit the search results.

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Figure.

Flowchart outlining the review process for including the studies.

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Included were prospective, retrospective and cohort studies assessing Bcc outbreaks due to any source in Indian hospital settings. However, conference abstracts and case reports (less than 3 patients infected) were excluded. Studies that only reported the outbreak up to the point of identification, without investigating potential sources, were also excluded. This was based on the rationale that without investigating the possible source, no valid conclusions can be drawn; neither would it substantially contribute to infection prevention strategies for avoiding such nosocomial outbreaks. We thoroughly documented essential details, encompassing outbreak features, patient population, nature of infections, investigation for infection source, and the implementation of infection prevention and control (IPC) strategies to manage the outbreak. ‘Extrinsic contamination’ of medical products is defined as the introduction of contamination during product utilization, while ‘intrinsic contamination’ refers to contamination occurring before use, specifically at the level of manufacturing²¹.

Three reviewers (AS, SM, and LS) charted the data to extract data from the included studies. The table was created in two parts. First, the general characteristics of the published studies were charted with the following information: author, year of outbreak, city/State of India, number of patients affected, patient population, source of outbreak, type of Burkholderia species identified, infection type, and what method of molecular typing, if used, was done. The charted data was then rearranged according to a common denominator: the outbreak’s source. Source categories were pharmaceutical preparations, medical products, environment, medical devices, and no source identified. The second table compiled the data of studies that successfully identified the source of the outbreak, and the relevant infection prevention and control (IPC) strategies used to curb the outbreaks. The assessment of potential bias and heterogeneity was not conducted. Basic statistical methods like percentages were used to summarize and communicate key trends in the data.

Results

For this analysis, our search identified 22 published studies of hospital-acquired Burkholderia cepacia complex outbreaks across India, which met our criteria (Table I)^{12,15,16,19,20,22-38}. Ten outbreaks were reported from southern States of India^{12,19,22,23-29} (6 from Tamil Nadu, 2 from Karnataka, 1 from Puducherry, & 1 from Kerala), six outbreaks were reported from western States^{15,16,20,30-32} (5 from Maharashtra & 1 from Rajasthan), five from northern States^33-37 (2 from Delhi, 1 each from Haryana, Chandigarh and Jammu & Kashmir) and one from the eastern State of West Bengal³⁸.

Discussion

This scoping review provides a comprehensive description of Bcc outbreaks in Indian hospital settings for the first time, encompassing all possible sources. This review highlights that these outbreaks majorly affect ICUs (57.1%). Patients in medical, surgical and trauma ICUs and those in paediatric wards and NICUs typically have lengthy hospital stay. They are subjected to various interventions, and their reliance on invasive medical devices and many broad-spectrum antibiotics makes them prone to bloodstream infections among others³⁹. Outbreaks affecting ICUs were associated with different sources, including chlorhexidine solutions, amikacin and diltiazem vials, dextrose and normal saline solutions, ultrasound gels, and suction apparatus. Bacteremia was noted to be the most common presentation, possibly stemming from a breach in the skin via in-situ central lines and catheters, contaminated IV medication and solutions, ultrasound gels used for routine scanning, and open wounds, among other routes. Burkholderia cepacia was observed to be the predominant species among the isolates, as conventional methods of bacterial culture and biochemical reactions for identification limit many laboratories in India. Other less commonly isolated species were observed to be B. multivorans, B. contaminans and B. cenocepacia.

Identifying the outbreak source is crucial for implementing effective infection control measures. We observed that investigators in one-fourth of the outbreaks could not identify the source. This may be due to challenges in identifying the bacterium, not having access to a special Bcc isolation medium or insufficient knowledge about potential reservoirs of Bcc, resulting in inadequate sampling during surveillance. However, we could determine that about 45.4 per cent of the reported studies were associated with pharmaceutical preparations (including sterile intravenous medications, solutions and disinfectants). Incriminated products were contaminated IV antiemetics granisetron and palonosetron, topical anaesthetic eyedrops, rubber stopper of multidose amikacin vials, IV fluids like 5% dextrose, normal saline, caffeine citrate vials, diltiazem vials, cetrimide and chlorhexidine solution and chlorhexidine mouthwash. We noted two outbreaks among cataract and keratoplasty surgery patients presenting with acute-onset postoperative endophthalmitis. A variety of perioperative and intraoperative sterile products used during eye surgeries are known to cause cluster endophthalmitis, such as intraocular lens solution, balanced salt solution, and others⁴⁰. Topical anaesthetic eye drops were identified as the source of one of these outbreaks. The ability of Bcc to utilise a wide variety of organic compounds as carbon and energy source is a testament to the fact that it grows and thrives in sterile drug solutions, which are difficult to catabolize. Members of Bcc can oxidise aromatic and nitroaromatic compounds present in drugs, with the help of monooxygenase and dioxygenase enzymes. In pharmaceutical manufacturing, Bcc is believed to spread through water, raw materials and equipment surfaces, resulting in contamination of nonsterile products like mouthwashes, nasal saline solutions etc.,¹⁰ as was seen in a Bcc outbreak by Bilgin et al⁴¹ associated with contaminated chlorhexidine mouthwash. Once they contaminate the biocide, the most worrisome property of Bcc bacteria is their ability to grow and proliferate in these compounds. Resistance to disinfectants and antiseptics can be intrinsic or acquired. Various mechanisms include the presence of a highly charged lipopolysaccharide layer acting as a barrier; efflux pumps, notably of the resistance-nodulation-cell division (RND) transporter family acting against biocides like benzalkonium chloride and chlorhexidine gluconate^42,43, biofilm formation, and mutations in genes encoding cell wall, outer membrane proteins and porins. Bcc has been shown to contaminate analgesic gels and intravenous fentanyl in other reported outbreaks^44,45. The presence of Bcc in drugs and solutions degrades the active compound and also contributes to the formation of toxic metabolites, potentially transmitting infection to vulnerable populations¹⁰.

Contamination is often linked to breaches in IPC measures rather than intrinsic drug contamination, leading to delays in control efforts. This review shows that medical products like ultrasound gel should also be considered as possible source of infection during Bcc outbreak, as was seen in 18.1 per cent of the reported studies. USG scanning is routinely performed in intensive care, trauma and surgical units. Bcc species can degrade the stabilizing agent of ultrasound gels, that is, parabens (p-hydroxybenzoic acid esters), and hence contaminate the gel⁴⁶. Intrinsic contamination of ultrasound gel has been reported when recovered from unopened vials²⁷. We observed environmental contamination of water supply and distilled water as source of infection in 13.6 per cent of the included studies. The adaptive properties of Bcc hypothesized to facilitate growth in water include tolerance to limited nutrition, interaction with other bacteria, morphological switch to coccobacilli and temperature variations^18,42.

Among the studies where molecular testing was done, MLST was the most common (6/8, 75%) employed method for Bcc typing^{12,16,24,25,33,37}. One study each utilised PFGE³⁸, BOX-PCR and MALDI-TOF as typing methods^22,37. However, 14 studies did not conduct molecular analysis. They concluded their findings based on the phenotypic properties of isolating Bcc bacteria with similar antimicrobial susceptibility patterns, pinpointing a single common source and cessation of the outbreak after removing the source. MLST offers high resolution in distinguishing closely related strains, whereas PFGE is time-consuming and less sensitive in delineating within species. MLST’s digital sequence data aids computational analysis and data storage, contrasting with the visual banding pattern observed in PFGE, making it more subjective to interpretation^47,48. Whole genome sequencing (WGS) has appeared to demonstrate superior discriminatory power in the recent past. WGS has a high cost and is time-consuming, restricting its availability⁴⁹. MALDI-TOF emerges as a promising new technique with a high level of differentiation among species. Studies have shown good accuracy of MALDI-TOF in correctly identifying Burkholderia species and correlating well with molecular methods like PCR, proving a sensitive and rapid alternative^50,51.

Our review noted that most outbreaks where molecular typing was done were linked to a single sequence type. MLST identified a novel ST 824 in clinical and contaminated amikacin vial Bcc isolates¹⁶, establishing an epidemiological link and confirming the outbreak source, marking the first such study in the country. Surprisingly, two reported outbreaks^33,37 involved the isolation of more than one Bcc species, possibly attributed to contamination with multiple Burkholderia species at the source. The average mortality rate documented for nine included studies was 18 per cent, exceeding the 10 per cent mortality rate noted by Hafliger et al⁵². However, many patients affected by Burkholderia cepacia complex infections in these outbreaks were in the ICU. They had multiple comorbidities, making it difficult to attribute mortality solely to the Bcc infection.

Commonly implemented IPC measures were observed, including product withdrawal, manufacturer communication, and regular sterility testing. Some studies also mentioned patient cohorting and hand hygiene regulation³³. Specific measures included using single-use IV fluids, replacing multidose injection vials with ampules, substituting chlorhexidine with alcohol-based solutions, treating water tanks with chlorine, and employing sterile covers for ultrasound probes. We observed that outbreaks were more frequently associated with product contamination than medical devices (4.5%) or environment (13.6%). Similar findings were reported by Hafliger et al⁵² where the environment (8.1%) and devices (17.1%) were far less commonly associated with Bcc outbreaks than contaminated products. Current hospital guidelines inadequately address the proper use of medical and pharmaceutical products, contributing to bacterial growth through factors such as using outdated products, storing for prolonged periods after use, improper storage conditions, and utilizing small dispensable bottles for mass-procured items like alcohol-based antiseptics and USG gels^10,53.

There are a few limitations in our scoping review. First, we focused exclusively on Indian studies. While this narrowed the evidence we could include, it allowed us to examine the role of contaminated pharmaceutical products and related manufacturing practices specific to India. Second, due to the paucity of limited published literature from India, we included case series involving 3-4 patients each and expanded our evidence beyond ICU outbreaks to include wards and daycare units. This review could not fully assess the overall heterogeneity of the included evidence. Third, we included some studies that did not provide detailed information on the infection prevention and control (IPC) measures implemented to contain the outbreak. Fourth, studies where the source of the outbreak could not be pinpointed but were investigated were also included.

Bcc, identified by the U.S. Food and Drug Administration (FDA) as the predominant contaminant in water-based pharmaceuticals, prompts guidance for manufacturers, alerting them of the risk and emphasizing screening before final release of product from the manufacturing unit^54,55. A similar approach incorporated in good manufacturing practices (GMP) could help other countries as well.

Overall, this review highlights the importance of recognizing Burkholderia cepacia complex as an emerging group of bacteria responsible for serious life-threatening hospital-acquired infections leading to outbreaks in the healthcare settings. Identifying the infection source poses challenges due to Bcc’s presence in diverse environments. However, thorough sampling, awareness of its pathogenicity and use of molecular typing methods can aid in this process. Implementing appropriate control measures post-source identification is crucial for outbreak containment.