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Healthcare-associated bloodstream infections caused by bacterial and fungal contamination of intravenous fluids and medicines in healthcare facilities in low- and middle-income countries: a scoping review

Antimicrobial Resistance & Infection Control volume 14, Article number: 24 (2025) Cite this article

Abstract

Introduction

We reviewed culture-confirmed healthcare-associated outbreaks linked to bacterial and fungal contamination of intravenous fluids and medicines (further “infusates”) in low-income countries and lower and upper middle-income countries (LIC, Lower-MIC and Upper-MIC). We assessed the scope, impact, risks, and gaps in knowledge.

Methodology

Literature search including PubMed, Web of Science, Worldwide Database for Nosocomial Outbreaks, Global Health, and Google Scholar. National essential medicine lists (NEMLs) of sub-Saharan countries were searched for listing of pediatric infusates.

Results

Between 1975 and 2023, 50 articles were retrieved. Median (range) number of patients affected was 12 (3–185); 74.2% (761/1025) of all patients affected were children. All patients presented with bloodstream infections; median case fatality ratio was 21.1% (0.0–87.5%). Upper-MIC, Lower-MIC and LIC accounted for 21, 25 and 4 articles, respectively. Most frequently affected wards were neonatal and adult intensive care units (19 and 6 articles). The 50 articles revealed 59 contaminated infusates: IV fluids (n = 37), including TPN (n = 10, of which 8 were from Upper-MIC), and IV medicines (n = 22), comprising amongst others propofol (n = 4) and Water for Injection (n = 3). The 63 isolates included Enterobacterales (46.0% (29/63) of isolates), non-fermentative Gram-negative bacteria (NFGNB, 47.6% (30/63)), fungi (4.8%, 3/63)) and Bacillus circulans (1.6% (1/63)). Among the Enterobacterales, the genera Serratia, Klebsiella, and Enterobacter represented 82.8% (24/29) of isolates. Burkholderia cepacia was the most frequent NFGNB (53.3% (16/30) isolates). Excluding TPN, 18 IV fluids and 7 IV medicines (representing half (51.0%, (25/49) of these infusates) were incorrectly used as multidose vial. A third (33.9%, 20/59) of infusates in 40.0% (20/50) of articles was intrinsically contaminated. In LIC and LMIC, staff in neonatology units turned to in-ward preparation of infusates because of lack of access to pediatric IV formulations and sizes. Less than a third (31.8%, 18/44) of the NEMLs listed neonatal IV premixtures.

Conclusion

Infusate contamination is a serious, underreported risk especially for children in LICs and Lower-MIC. Outstanding issues are access to pediatric infusates and preventing in-ward preparation of IV medicines in LIC and Lower-MIC, and safe preparation and administration of TPN in Upper-MIC.

Introduction

Healthcare-associated infections (HAI) are acquired while receiving treatment in a healthcare facility (HCF) [1]. In acute-care hospitals, for every 100 patients, 7 patients in high-income countries (HIC) and 15 in low- and middle-income countries (LMIC) will acquire at least one HAI. Among patients admitted to the intensive care unit, 30% can be affected by HAIs, with the incidence being 2–20 times higher in LMIC compared to HIC, especially among neonates [2].

The HCF environment contains multiple reservoirs of bacteria and fungi that can cause HAIs. Reservoirs include medical devices, patient care devices and water. They function as sources for pathogens, which can be transmitted to the patient’s mucous membranes and skin, and subsequently colonize and infect the patient [3,4,5,6].

Patients admitted to HCF may require intravenous (IV) fluid for rehydration, medication, and parenteral nutrition. Children require pediatric doses of IV medicines and fluids, and neonates in addition require specific IV formulations (Box 1) [7, 8]. Like other fomites, infusates can be contaminated with bacteria and fungi and be reservoirs of pathogens that may cause HAI [3].

Box 1 Terms and definitions related to intravenous fluids and medicines used in this review
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Despite the heavy burden of HAIs and the challenges of IV therapy, bacterial and fungal infusate contamination and its contribution to HAI are not known and have rarely been reported from LMIC. A review published in 2007, focusing on viral, bacterial, and fungal contamination of infusates and blood products, included almost twice as many articles from HIC compared to LMIC [3]. Based on our field observations and inspired by conversations during a course on Antimicrobial Resistance [9], we conducted a scoping review about HAI caused by bacterial and fungal contamination of IV fluids and medicines in HCF in LMIC. The purpose of this study was to identify the scope and impact of these contaminations, highlight potential gaps in knowledge, and inform strategies for prevention and control in LMIC.

The research questions of this review are as follows:

  1. 1.

    What were the known frequency and burden of outbreaks caused by bacterial and fungal infusate contamination in HCF in LMIC?

  2. 2.

    Which products and pathogens were involved?

  3. 3.

    Which were the risk factors for contamination and transmission?

  4. 4.

    Which interventions were made to contain these outbreaks and to mitigate the risks of infusate contamination?

  5. 5.

    What are the outstanding issues about contamination of infusates in LMIC?

Materials and Methods

Terms and Definitions of Infusates

Box 1 explains the terms and definitions used in the present review. In brief, the term infusates refers to both IV fluids and IV medicines. IV fluids are grouped as dextrose, saline and total parenteral nutrition (TPN), and IV medicines also include Water for Injection used for reconstitution. Single dose vials (SDV) are designed for a single injection, whereas multidose vials (MDV) are designed to deliver more than one dose; the latter contain antibacterial substances (preservatives). Premixtures are commercially prepared products; admixtures are mixtures of IV fluids and/or IV medicines which are prepared in the HCF, either in the pharmacy or in the ward. The term multiple-use single dose vial (mSDV) was coined for this review: mSDV comprise single dose IV medicines and IV fluids which are—against the manufacturer’s instructions—used for administration of multiple doses. Intrinsic (primary) contamination refers to contamination during the manufacturing process, while extrinsic (secondary) contamination refers to contamination during transport, storage, preparation, and administration of infusates.

Eligibility Criteria

The inclusion criteria were original articles addressing culture-confirmed HAI (outbreaks and single patient cases) related to bacterial and fungal contamination of infusates in HCF in LMIC. Reports from HIC, reports that conducted only a clinical-epidemiological investigation with no environmental cultures, experimental studies, veterinary studies, and reviews were excluded. Studies that reported the contamination of medicine vials with nebulizing solutions, intraocular solutions, intra-articular injections, and intramuscular injections were also excluded, as was the bacterial or fungal contamination of blood products.

Search Strategy

Peer-reviewed studies were searched via PubMed, Web of Science, Global Health, Google Scholar, and via the Worldwide Database for Nosocomial Outbreaks [10]. The PubMed search terms used were: (nosocomial infection OR hospital-acquired infection OR HAI OR bacterial contamination OR fungal contamination) AND (admixtures OR intravenous fluid OR multidose vial OR single-dose vial). These keywords were adapted for the other databases. Additionally, we conducted a search without Boolean operators, using the following terms: ‘intravenous fluid contamination,’ ‘intravenous medication contamination,’ ‘saline contamination,’ and ‘dextrose contamination.’ A snowball search was performed by examining the reference list and the “cited by” lists of the retrieved papers. Additional libraries and grey literature databases like ProQuest Dissertation were searched. Publications in English, French, Spanish, or German were considered, and no publication date limit was set.

The country's income level was retrieved from the World Bank website [11] based on the article’s publication year. The categories used in the review include low-income countries (LIC), lower middle-income countries (Lower-MIC), and upper middle-income countries (Upper-MIC).

Data Extraction

The articles retrieved were screened first by title and abstract using Rayyan systematic review screening software [12]. Next, full-text screening of the articles that were retrieved in the first step was performed to determine eligibility. Data extraction was done by the first author (JN) and verified by the second author (PH); discrepancies were resolved by discussion with the fourth author (JJ). General data extracted for LMIC were year of publication, country, income level, and HCF level. Outbreak-related data extracted for review question 1 (frequency and burden) were clinical ward, number of patients and case fatalities, age and sex, clinical presentation and co-morbidities, and outbreak duration. For review question 2 (products and pathogens), the genus and species of clinical and environmental pathogens, their clonal relatedness and (if available) antimicrobial susceptibility data were extracted. For question 3 (risk factors for contamination and transmission), results of the clinical-epidemiological and microbiological investigations, procedure review, interviews with staff and observations were extracted. For question 4 (interventions), interventions were extracted. The bacterial and fungal nomenclature was verified [13]. Further in this manuscript, the updated genus and species names are used, with the superseded names used in the articles written in Table 1.

Table 1 Synthetic overview of the outbreaks of bacterial and fungal contamination of infusates in healthcare facilities in low- and middle-income countries
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Data Analysis

The extracted data were compiled in an Excel spreadsheet (Microsoft, Redmond, WA, USA). Gram-negative bacteria were grouped as Enterobacterales and non-fermentative Gram-negative bacteria (NFGNB). Unless otherwise specified, results were presented for outbreaks and case reports combined (commonly “outbreak reports”). Most results were presented with the number of outbreak reports as the denominator; where appropriate, numbers of different infusate products or pathogens were used as the denominator. Medians were expressed with ranges.

Additional Search of National Model List of Essential Medicines

Given the problem of access to age appropriate IV infusate formulations and sizes for children and neonates reported from sub-Saharan Africa, we searched the national lists of essential medicines (NEML) of sub-Saharan countries. These NEML should reflect the WHO Model List of Essential Medicines for Children (9th Edition, 2023), with adaptations according to national needs [8]. The purpose of the NEML is to guide country-wide prioritization, procurement, and supply of medicines. In addition, NEML can serve as a foundation for national treatment guidelines [14]. We reviewed the NEMLs of sub-Saharan African countries to determine whether premixtures of combined saline-dextrose IV fluids (Box 1) were included. The NEML were retrieved by a desktop search from online resources and through professional contacts of the Institute of Tropical Medicine network [15].

Results

Overview of the Articles Retrieved

A total of 50 articles were included, comprising 48 outbreaks and 2 case reports; 17 were retrieved by snowball search (Fig. 1). Upper-MIC, Lower-MIC and LIC represented 21, 25 and 4 articles respectively (Fig. 2). The articles originated from a total of 17 countries (Fig. 3), including 2 articles from South Africa, which were published before the country shifted from the Lower-MIC to the Upper-MIC category [16, 17].

Fig. 1
figure 1

Flow chart of the literature search for outbreaks related to bacterial and fungal contamination of intravenous fluids and medicines in healthcare facilities in low-and middle-income countries

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Fig. 2
figure 2

The number and timeline of reviewed articles reporting outbreaks related to bacterial and fungal contamination of intravenous fluids and medicines in healthcare facilities in upper middle-income countries (n = 21), lower middle-income countries (n = 25) and low-income countries (n = 4)

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Fig. 3
figure 3

Geographic distribution of the reviewed articles (n = 50) reporting outbreaks and case reports of bacterial and fungal contamination of intravenous fluids and medicines in healthcare facilities in low- and middle-income countries (lower- and upper middle-income countries) according to the UN Geoscheme [18] and by the World Bank Classification by income level at the year of publication [11]. Numbers represent the number of reviewed articles. In South Africa, 2 articles [16, 17] were published before it shifted from the lower middle-income category to the upper middle-income category

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Frequency and Burden of the Outbreaks

More than half (28/50, 56.0%) of the outbreaks occurred in tertiary care hospitals, and 9 occurred in > 1 HCF (Supplementary Table 1). The main clinical wards affected (information available for 48 articles, Table 1) were neonatal intensive care units (n = 19), adult intensive care units (n = 6), and hematology—oncology (n = 5); 32 and 20 outbreaks affected children and adults respectively, for a total of 1025 patients, 761/1025 (74.2%) of whom were children. The median number of patients affected (case reports excluded, data for 44 outbreaks) was 12 (3–185); 9 outbreaks reported > 30 patients. All outbreaks presented as bloodstream infections, and clinical isolates were obtained from blood cultures. The median case-fatality ratio (case reports excluded, data for 33 outbreaks) was 21.1% (range of 0.0–87.5%). The median duration (data from 43 outbreaks) was 8 weeks (1 day–156 weeks), and 27 (62.8%) outbreaks had a duration of > 1 month, of which 16 (34.8% (15/43) of all outbreaks) extended beyond 3 months.

Epidemiological and Microbiological Methods Used

A clinical-epidemiological investigation was mentioned in 33/50 (66.0%) outbreaks. In another 12 (24.0%) outbreaks, the presumed reservoir and transmission were obvious from the start, e.g. by close in time clusters of bloodstream infections after administration of a particular infusate [17, 19,20,21,22,23,24] or by the distinct presence of an IV catheter among the affected patients [25,26,27,28,29,30,31]. Eleven (22.0%) investigations conducted a formal exposure analysis, 4 of them in a case–control design [22, 32,33,34,35,36,37,38,39,40,41] (Supplementary Table 1).

Selection of samples for environmental microbiology investigation (data available for 45 outbreaks) was limited to IV infusates in 13 investigations [22, 24,25,26, 30, 34, 35, 37, 40, 42,43,44,45]. In 19 other investigations, infusate analysis was part of a broader environmental investigation comprising high touch surfaces, shared equipment and surfaces, liquids, and instruments close to the patient. In 16 investigations, healthcare workers’ hands were sampled. Other human samples were throat and nose swabs from healthcare workers [17, 46, 47], and urine [24, 48] and rectal swabs or stool samples from both patients and health care workers [32, 33, 49, 50]. In 3 investigations of contaminated TPN, the preparation area in the pharmacy including equipment and TPN compounds were assessed [19, 33, 51].

Microbiological methods varied widely but mostly consisted of direct plating on agar media sometimes combined with enrichment broths (Supplementary Table 1; for an overview of microbiological methods, see Supplementary Box 1). In 8 investigations, only enrichment broths were used [17, 27, 37, 40, 41, 48, 52, 53]; filtration was done in 6 investigations [16, 34, 35, 41, 51, 54]. Quantitative cultures of infusates were performed in 2 studies, reporting viable bacterial counts of 103/ml for Burkholderia cepacia in Water for Injection [26] and > 25*105/ml of Serratia liquefaciens in saline [55]. Identification was done by conventional biochemical testing; in recent studies MALDI-TOF analysis was used [21, 31, 38, 41, 47, 56]. If performed, methods of antimicrobial susceptibility testing were not fully detailed and, in some articles, only partial information about antimicrobial resistance was available [24, 39, 41, 57].

In one third (17/50, 34.0%) of the articles, assessment of relatedness between environmental and clinical isolates was based on identification and the antimicrobial susceptibility results only [22, 23, 25, 26, 30, 33, 36, 41, 42, 44, 46, 52, 53, 55, 57,58,59]. Clonal relatedness was further assessed by phenotypic testing (biotyping) [17, 19, 28, 32, 49, 60], Pulsed Field Gel Electrophoresis [29, 34, 35, 43, 45, 47, 49, 54, 60,61,62,63], nucleic acid amplification-based typing tests [19, 27, 28, 37, 38, 50, 64], and whole genome sequencing [21, 31, 39, 40, 65]. More than three-quarters (37/50, 74.0%) of outbreak investigation teams also conducted a review of procedures, site observations and interviews of the healthcare workers (Supplementary Table 1).

Products and Pathogens

In the 50 articles, 59 infusate products were involved; 4 articles reported > 1 contaminated infusate [34, 39, 52, 66] (Table 1). Overall, 37 IV fluids were involved, including TPN (n = 10), saline (n = 10, including 2 heparinized saline admixtures), other IV fluid admixtures (n = 3), dextrose (n = 7), IV premixtures (n = 4), Ringer’s lactate (n = 1) and unspecified IV fluids (n = 2). Contaminated TPN products were reported from Brazil, Türkiye, Venezuela, Malaysia, Mexico, and South Africa [17, 19, 21, 33, 43, 50, 63, 64, 66], i.e. all but 2 were from upper-MIC at the time of reporting.

Two out of 3 admixtures were made in the ward by mixing saline with dextrose and saline with dextrose and potassium chloride as an IV fluid admixture for neonates; they were contaminated with Klebsiella pneumoniae and Klebsiella oxytoca respectively [25, 58]. Saline-heparin admixtures were used in 2 outbreaks (contaminated with Acinetobacter baumannii and Serratia marcescens respectively) [28, 29]; the remaining admixture was made in a cardiology unit and contaminated with Pseudomonas fulva [62].

Twenty-two IV medicines were counted, including propofol (n = 4), Water for Injection (n = 3), calcium gluconate (n = 2), diltiazem (n = 2), bromopride, caffeine citrate, fentanyl, furosemide, gentamicin, granisetron, heparin, immunoglobulin, metronidazole, ondansetron, and a steroid (1 product each).

Excluding TPN, 18 IV fluids and 7 IV medicines (in total half (51.0%, (25/49) of infusates) were incorrectly used as multidose vial: the IV fluid products were used amongst others for flushing intravascular catheters (n = 6) and reconstituting antibiotics (n = 5); another (n = 6) were used in pediatrics and neonatology, though their specific use was not specified (Table 2). The IV medicines which were used as mSDV comprised immunoglobulin, propofol and the antibiotics (gentamicin and metronidazole).

Table 2 Outbreaks related to bacterial and fungal contamination of infusates in healthcare facilities in low- and middle-income countries: products involved, and pathogens isolated
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A total of 63 microorganisms were cultured; in 4 infusates, more than one species was cultured [26, 35, 40, 66]. Enterobacterales and NFGNB accounted for 46.0% (29/63) and 47.6% (30/63) isolates, respectively (Table 1). The remaining isolates were fungi (n = 3), i.e., Candida albicans associated with TPN, Saprochaete capitata associated with a non-specified fluid and Sarocladium kiliense associated with ondansetron [42, 50, 65] and Gram-positive bacteria (n = 1) i.e., Bacillus circulans associated with intrinsically contaminated calcium gluconate [32].

The 29 Enterobacterales isolates grew in 29 infusates: TPN (n = 8), other IV fluids (n = 15), and IV medicines (n = 6, immunoglobulins, propofol and steroids); 16 of them were used as mSDV including the IV medicine immunoglobulin and propofol. The genera Serratia, Klebsiella, and Enterobacter species accounted for 82.7% (24/29) of the infusates contaminated by Enterobacterales. The 30 Non fermentative Gram-negative bacteria (NFGNB) isolates were cultured from 29 infusates: 11 IV fluids (2 admixtures and 7 IV fluids used as mSDV, 2 premixtures of 5% saline dextrose and IV lipid), TPN (n = 2), and 16 out of 22 medicine vials including Water for Injection, and 3 TPN infusates. The most frequent bacteria among the NFGNB were Burkholderia cepacia complex (among which Burkholderia contaminans); they grew from 16 infusates. Of note, among the 16 outbreaks with a duration > 3 months, 12 were associated with 18 NFGNB isolates (B. cepacia (n = 10), Acinetobacter sp. (n = 3), Ralstonia pickettii (n = 2), Ralstonia solanacearum, Phytobacter diazotrophicus, Rhizobium radiobacter [16, 19, 31, 35, 37, 39, 41, 44, 45, 52, 62, 66] with 2 outbreaks having growth of more than one organism from the infusates [35, 66].

In all articles clonal identity between clinical isolates and those of the environmental reservoir was demonstrated; coexisting clones were observed for Klebsiella pneumoniae and Burkholderia cepacia [39]. Among the articles with well-described antibiotic susceptibility results, there were third-generation cephalosporin-resistant Enterobacterales (Klebsiella spp. n = 5, Enterobacter hormaechei, n = 1, Proteus mirabilis n = 1) and New Delhi producing carbapenem-resistant Leclercia adecarboxylata (n = 1) [21, 34, 36, 43, 48, 61, 63, 67].

Risk factors for Contamination and Transmission (Tables 1, 2, Supplementary Table 1)

In 40.0% (20/50) outbreaks representing a third (33.9%, 20/59) infusates, were intrinsically contaminated; they included one saline and one 5% saline-dextrose premixture, 4 TPN infusates, as well as 14 IV medicines. Seven products (TPN (n = 4), bromopride, calcium gluconate and ondansetron) were implicated in multi-institutional outbreaks involving 3–15 hospitals in Brazil, Mexico, and South Africa [17, 21, 35, 37, 43, 65, 66]. One investigation of intrinsically contaminated TPN assessed the compounding facility: air leaks in the compounding chamber were noted, as well as errors in cleaning and hand hygiene practices [17]. In another outbreak caused by Ralstonia solanacearum associated with intrinsically contaminated saline bottles, the packaging of the infusates in the stock room had air bubbles, water drops, and leaks suggestive for contamination [31].

For the 30 remaining outbreaks, one had no detailed data about environmental sampling and 9 articles did not address nor discuss the potential pathway of the contamination of the infusate. Ten reports explicitly mentioned handborne transmission as the probable transmission pathway, and in 4 investigations, hands of healthcare workers grew Gram-negative bacteria matching the index organisms, i.e., Enterobacter cloacae, Pluralibacter gergoviae, K. pneumoniae and P. mirabilis respectively [36, 48, 49, 54]. Of note, in 2 other investigations, Gram-negative bacteria unrelated to the index pathogen were found on the healthcare workers’ hands [17, 58]. In 13 articles, potential handborne transmission was mentioned indirectly (“handling”, “preparation of TPN”, “breaches in asepsis”).

A third (34.0%, 17/50 of the articles, mostly from LIC and Lower-MIC, mentioned unsafe practices such as the use of infusates as mSDV [20, 23, 24, 34, 36, 39, 55, 57, 63, 68], not respecting the period after opening [20, 54, 68], cloth tape used to cover the tops of single-use, preservative-free ampoules between uses [34], not disinfecting the IV rubber ports on fluid bags and lines [61, 68], withdrawing medication from medicine vials using a previously used syringe with a new needle [23,24,25, 39, 55, 57], air venting (inserting a needle in semirigid containers (Box 1)) [25], pooling of residual volumes of admixed antibiotics [39], and not reprocessing the infusion pump after use [68]. Further, infusates were prepared and stored in the clinical ward and at room temperature, even close to the sink [34, 39, 47, 58, 64]. In several cases, these unsafe practices were caused by non-compliance with HCF procedures or manufacturer’s instructions [36, 41, 47]. Further, several articles reported poor hand hygiene [34, 36, 39, 41, 47, 48, 61, 64] and environmental cleaning [17, 41, 64] as well as sharing equipment [55] and use of IV catheters without clinical indication [41].

Factors cited as root-causes of the IPC failures included economical constraints, understaffing, high workload, and time pressure related to a performance-based payment system [47, 48, 58, 62, 64]. The main reason behind the practices of making admixtures and using mSDV in neonatal wards (mentioned in 6 articles) was the lack of access to pediatric IV fluid formulations (including premixtures) and volumes [30, 34, 36, 39, 46, 58].

Interventions

Forty-three (86.0%) out of 50 articles reported interventions. For the intrinsic contamination of the infusates, recall and withdrawal of the products controlled the outbreak. Interventions made to prevent contamination of TPN included the provision of a biosafety cabinet in the pharmacy, installing a medicines' preparation room [64], installing automated TPN preparation [50], and increasing the frequency of sterility testing of prepared TPN [33]. For IV fluids and medicines, mSDV were replaced by single-use medicine vials [20, 24, 28, 46, 56, 68]. Where this was not possible, risk mitigation was sought by adequate disinfection of the sample port of the mSDV and reducing the period-after-opening [27, 54, 61]. Further, storage of infusates in the refrigerator and keeping the medication preparation trolley away from the sink was implemented [39].

Cohorting of the infected neonates was done in 5 outbreaks, caused respectively by Burkholderia contaminans, P. mirabilis, P. gergoviae, Klebsiella aerogenes and Serratia marcescens ([38, 48, 54, 61, 64]. Many articles reported reinforcement of hand hygiene practices and/or environmental cleaning [29, 33, 34, 36, 38, 48, 49, 55, 58, 61, 62]. Education and in-service training of healthcare workers were implemented in 8 articles [34, 39, 46,47,48, 61, 62, 64].

Additional Search of National Model List of Essential Medicines

In the Sect. 26 about “Solutions containing water, electrolyte and acid–base disturbance”, the WHO Model List of Essential Medicines for Children mentions the premixtures of half-normal saline—5% dextrose and normal saline—5% dextrose IV fluids. Sizes (volumes) are not mentioned (Box 1) [8]. The NEML list of 44/48 sub-Saharan countries was retrieved. Less than a third (14/44, 31.8%) of these NEML mentioned one of both saline—dextrose premixtures, and only 8 among them (18.8% of all 44 countries) mentioned the half-saline—5% dextrose recommended for neonates (Supplementary Table 2).

Discussion

Frequency and Burden

The present review aggregated 50 culture-confirmed infusate-related outbreak and case reports which occurred in HCF in LMIC. All outbreaks presented as bloodstream infections, over long durations, and with high case-fatality ratios. The neonatology ranked first among the affected wards, in line with the high burden of HAI in neonatology wards in LMIC [69, 70]. The long duration of outbreaks reflects the typical insidious course and difficult detection of HAI outbreaks [6, 71, 72]. The risk of overlooking outbreaks is even larger in the case of “endemic” organisms, such as Klebsiella sp. [69].

The 50 retrieved articles probably represent an under-representation from LMIC, as noted previously [3]. It points to a substantial under-reporting and under-detection [69, 73]. For the LIC and Lower-MIC, a main problem for detection and monitoring is the low availability of clinical bacteriology: in a recent survey across 14 countries in sub-Saharan Africa, only 1.3% of diagnostic laboratories declared to perform bacteriology analysis [74]. Further, more than half of the outbreaks were described from tertiary care and referral hospitals. The frequency and burden of infusate-related HAI is probably much higher in remote and rural areas in LMIC, where Water, Sanitation and Hygiene (WASH) standards are low [75], and where the poor storage and distribution practices along the supply system may create conditions for product contamination or accelerated degradation [76].

Products and Pathogens

Among the infusate products, IV fluids were most represented, and most of them were used as mSDV. TPN (10 outbreaks) is well-known for its risk of contamination. Among the contaminated IV medicines, contaminated propofol and fentanyl were previously reported from HIC [3, 77]. In line with their nutrient requirements, Enterobacterales and yeasts were the most frequent organisms found in contaminated TPN; similarly, the 3 saline-dextrose admixtures reported from the neonatal wards were contaminated with Klebsiella spp. [25, 39, 58]. In a review of neonatal outbreaks in Africa, half of the 20 outbreaks were due to Klebsiella pneumoniae [78]. Among the IV fluids (n = 37), both NFGNB and Enterobacterales were isolated, the latter most probably reflecting hand contact during their preparation or manipulation of admixtures and mSDV [79]. P. gergoviae (isolated from dextrose IV fluid in a neonatology unit [54]) is naturally resistant to preservatives and a well-known contaminant of cosmetics and soaps [80].

NFGNB have very low nutrient requirements. B. cepacia complex (reported from 16 infusates) is naturally resistant to preservatives and is the most frequent bacterial species found in contaminated water-based pharmaceuticals [81, 82]. Ralstonia species (5 infusates) are slender rods capable of bypassing sterilization filters used in pharmaceutical filling processes [83]. Third-generation cephalosporin and carbapenem-resistant Enterobacterales (reported from 8 outbreaks) are listed as Critical Group Pathogens on the WHO Bacterial Priority Pathogens List for the containment of antimicrobial resistance [84].

Risk Factors for Contamination and Transmission

Preparation and administration of IV medication are error prone [85, 86]. Use of mSDV is a major risk for infusate contamination [3]. In the articles reviewed, half of the infusates (TPN extracted) were used as mSDV, for IV catheter flushing, medicine reconstitution, and pediatric IV fluid administration. The heparin-saline solution used for peripheral IV catheter flushing [28, 29] ranked first among the outbreaks listed in the previous review [3] and the WHO explicitly warns against mSDV for IV catheter flushing [87]. In addition, multiple unsafe practices during preparation and administration were reported, also in recent studies [39, 41]. Some of the observed practices occur frequently in LMIC, such as air-venting of rigid infusion containers (Box 1) [88,89,90,91].

The saline–dextrose IV fluid admixtures for neonates (Box 1) were prepared in the ward, where they also were divided in into smaller bag sizes [30, 39, 58]. In HICs, preparing IV medicines in the ward is more at risk for contamination than compounding in the pharmacy [92, 93], even if compounding pharmacies themselves are not exempt from risk of contamination [94]. This risk is probably much higher in HCF in LMIC, given the high environmental contamination [95]. Likewise, storage in the ward and in the vicinity of sinks are also risks for contamination [3, 96, 97]. The general IPC deficiencies contribute to the risk of infusate contamination, either directly (hand hygiene) or indirectly (recontamination of hands due to poor environmental cleaning). The above-mentioned risk factors were also reported from other LMIC articles related to infusate outbreaks and contamination [34, 89, 90, 98,99,100,101]. Many of these studies also revealed nursing care challenges [34, 102], in part related to overcrowding and understaffing [103, 104].

Interventions

Most interventions listed in the selected articles were in line with recommendations and good practice statement issued by healthcare associations [87, 91, 97, 105,106,107]. They should be implemented according to the WHO multimodal improvement strategy [108] and in pace with implementation of standard IPC practices and quality patient care. Key elements of these recommendations are not using mSDV [29], strictly using SDV for one patient and one injection [34, 36, 46, 55, 61], limiting MDV to single-patient use [34], creating dedicated medicine preparation areas [34, 39], and transitioning to closed IV infusion systems [89]. Access to age-appropriate formulations (premixtures) and sizes, syringe and infusion pumps will eliminate the need for admixing and aliquoting infusates in neonatology and pediatrics. Unnecessary infusates should be banned [109] and the IV route must be reserved for selected clinical conditions and for periods as short as possible [87, 89, 93].

Outbreak Investigation Methods

Most of the outbreak reports used clinical-epidemiological information to orient the environmental sampling. Broad sampling (done in 19/45 of the documented outbreak investigation) may detect co-existing reservoirs and provide clues to transmission. Sampling healthcare workers’ hands (done in outbreaks) has low priority in the context of high environmental contamination and suboptimal handwash facilities; it is most effective if focused on onychomycosis, artificial fingernails, or rings [69, 110]. In the outbreak setting caused by Gram-negative bacteria, microbiological testing of healthcare workers’ or patients’ throat and nose samples (done in 3 outbreaks) has no place. Likewise, assessing patients’ stool samples for the index organisms (done in 4 outbreaks) has little additional value in the context of an ongoing outbreak; it can be considered in the case of screening for carriage of multidrug resistant organisms when the possibility of isolating or cohorting patients is present [69, 111]. However, it entails a risk of stigma and cultural offensiveness and must be balanced against the required expertise, means and costs [111].

The spread plate culture method is within reach of the standard microbiology laboratory and provides information about bacterial counts (Supplementary Box 1). In the case of Enterobacterales and nutrient-rich infusates, counts can be very high (exceeding 105/ml) [55, 98, 112] and even such high contaminations are not detectable by the naked eye [113]. Species identification and antibiotic resistance pattern provide instant clues to the relatedness of clinical and environmental isolates [6] but ideally should be further studied by molecular analysis. Burkholderia cepacia is frequently polyclonal [37, 114], and distinct clones of Klebsiella, Serratia and Enterobacter may coexist [67, 115,116,117]. Given its high resolution and the database libraries, Whole Genome Sequencing provides sub-species identification, resistome analysis and information about in-hospital epidemiology, as presently shown for the Klebsiella and B. cepacia outbreaks in a neonatology unit in The Gambia [39].

Outstanding Issues and Research Questions

As discussed above, the underrepresentation of reports from LMIC—in particular LIC and Lower-MIC—despite anecdotal reports is a main issue. A recent review highlighted a significant publication gap between LMIC and HIC, revealing that HIC produce nearly 9 times more publications than LMIC [118]. Strengthening the capacity of researchers and healthcare professionals in LMICs to document and publish their findings can be achieved through mentorship opportunities [119], fostering networks and collaborations), engaging policymakers, funders, and hospital management [120].

Further, despite the overall low number of outbreak reports, a variation according to country income was noted. The 4 outbreaks reported from LIC occurred in pediatrics and were related to in-ward prepared and administered admixtures and mSDV fluids [30, 39, 55, 58]. In addition, LIC and many Lower-MIC reported serious shortcomings in standard IPC practices. By contrast, Upper-MIC reported all but one of the contaminated TPN infusates and were also experiencing large multi-institutional outbreaks of intrinsically contaminated IV medicines, in line from what was also seen in outbreaks related to contaminated antiseptics and disinfectants in HIC [72]. Further, they could afford high-cost interventions to assure safe TPN preparation [33, 50, 64]. Upper-MIC countries also scored consistently higher as to the implementation of IPC and WASH compared to Lower-MIC and LIC [2]. Further studies should explore these differences as they can orient and prioritize IPC interventions.

It is probably unknown to many in the global health community, including policymakers, that contaminated infusates represented the cause of a quarter (5/20) of neonatal outbreaks in sub-Saharan Africa [69]. The need for pediatric IV infusates has been raised 20 years ago based on microbiological and observational studies in Mexico and Egypt [34, 99, 121] and it was still expressed very recently by the presently assessed outbreak reports from sub-Saharan Africa [30, 39]. This situation is not unique to infusates. The NEML serve as a basis for the procurement and supply of medicines in public HCF. Ideally, these medicines should be available in the appropriate quality, quantity, and dosage forms to meet the needs of the population including children [122]. Some positive initiatives are underway: for instance, a priority list of antibiotics for pediatric medicines optimization was published in 2023 [123].

Given the probable underreporting but heavy burden of the neonatal outbreaks, the extent of the scarcity of pediatric formulations in LIC should be explored. The low adoption of the saline–dextrose 5% IV fluid premixtures in the NEML of the sub-Saharan countries and the low access to these products may explain the frequent practice of in-ward preparation of infusates. Large-scale access to pediatric IV infusates will require commitment of numerous (inter)national stakeholders, a stable supply chain and a healthy market, with local production enabled by transfer of technology and quality know-how through public–private partnerships [89, 124]. Moreover, suspicion or evidence of intrinsic contamination should be accompanied by timely communication to the supplier, the National Regulatory Authority (NRA), and the national Pharmacovigilance (PV) Centre. The supplier and NRA may assess if the concerned product batch presents and organize a national batch recall if indicated. The PV center can identify poor dispensing practices consistently resulting in safety incidents and support the update of guidelines at national level.

To guide interventions, a better understanding of the errors during the IV infusate preparation and administration is needed. Simulation and video-based teaching settings have been successfully used to study errors of infusate preparation and administration [125,126,127]. Further, the human factors behind the unsafe practices should be explored. Recent IPC surveys in sub-Saharan Africa pointed to gaps in IPC risk knowledge and awareness, such as ignorance of the period-after-opening of antiseptics, underestimation of the dangers of tap water and overestimation of the bactericidal power of a refrigerator [128, 129]. An unexpected barrier noted in Mexico was the outspoken preference of pediatricians for calculator-based admixtures over premixtures, as the former were perceived as more scientific [99]. Although not mentioned in the articles, training materials and procedural support for aseptic reconstitution and admixing of infusates is rare. In view of the absence of generic training material, a Spanish team developed practical trainings for medication preparation in the neonatal ward with video demonstrations [125]. At the HCF level, education will rely on in-service training, whereby task-based, bedside and simulation trainings are preferred [130]. Examples of information leaflets and workplace reminders about safe injection practices are available [106]. Further, the risks and risk mitigation of infusate contaminations should be addressed in medical curricula and textbooks [99].

Limitations and Strengths

Most outbreak reports did not fully comply with outbreak reporting guidelines [131]. Part of them were brief reports [23, 29, 43, 60, 63] or focused on molecular analysis [21, 38, 39, 66]. This may have caused a retrieval and selection bias. However, even if the search retrieval reflected only part of the real-life incidence and burden, we believe that—apart from the obviously higher burden—the main findings of the review we believe that would still hold true if more articles had been retrieved. Further, only culture-proven outbreaks were included. As to the strengths, the present review has an additional 41 culture-confirmed reports from LMIC compared to a previous review (nearly 20 years ago) [3]. Further, a detailed inventory of products and products wase made and risk factors and interventions were explored.

Conclusion

Bacterial and fungal contamination of infusates in LMIC is a serious but an underreported and overlooked risk for patients, with—in LIC and Lower-MIC a possible disproportionate impact on young children and neonates. Awareness among healthcare workers and policymakers can prepare for risk-mitigating measures along the production and supply and at the HCF level. HCF in LMIC face different challenges related to the country's income level, with an outstanding need for pediatric infusate formulations (premixtures) and sizes in LIC and Lower-MIC and a better understanding of the human factors behind unsafe practices. Improvement of local practices should be framed and supported by global efforts to correct the current imbalances in availability of adequate resources including appropriate infusates for children.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

AST:

Antimicrobial susceptibility testing

BSI:

Bloodstream infection

CLABSI:

Central line-associated bloodstream infection

EML:

Essential medicines for children

HAI:

Healthcare-associated infections

HCF:

Healthcare facilities

HIC:

High-income countries

IPC:

Infection and prevention control

IV:

Intravenous

LIC:

Low-income countries

LMIC:

Low- and middle-income countries

Lower-MIC:

Lower middle-income countries

MALDI-TOF:

Matrix-assisted laser desorption/ionization

MIC:

Middle-income countries

mSDV:

Multiple-use single dose vials

NFGNB:

Non-fermentative gram-negative bacteria

NEMLs:

National essential medicines lists

OPPP:

Opportunistic pathogens of premise plumbing

SDV:

Single-dose vials

TPN:

Total parenteral nutrition

Upper-MIC:

Upper middle-income countries

WGS:

Whole genome sequencing

WHO:

World health organization

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Acknowledgements

We would like to thank our colleagues from the Institute of Tropical Medicine, Antwerp. In particular, we thank Eva Nijs and Nic Peeters from the institute’s library for their contribution to the literature search, Erika van Eijk for retrieving of the national lists of essential medicines and Eric Florence from the University of Antwerp Hospital and Anne-Sophie Heroes from the institute’s Tropical Bacteriology unit for the critical review of this paper.

Funding

This work was part of J.N.'s Master of Science in Tropical Medicine thesis. J.N. was awarded a scholarship from the Johnson and Johnson Foundation via the Institute of Tropical Medicine, Antwerp.

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  1. Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium

    Jemima Nyandwaro, Peter Hyland & Jan Jacobs

  2. Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium

    Raffaella Ravinetto

  3. Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium

    Jan Jacobs

  4. School of Public Health, University of the Western Cape, Cape Town, South Africa

    Raffaella Ravinetto

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Contributions

Conceptualization was done by J.N. and J.J.; methodology by J.N., P.H., and J.J.; database screening and extraction by J.N., P.H., and J.J.; data analysis by J.N., P.H., and J.J.; writing—original draft preparation by J.N. and J.J.; writing—review and editing by J.N., P.H., R.R., and J.J.; and supervision by J.J.

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Nyandwaro, J., Hyland, P., Ravinetto, R. et al. Healthcare-associated bloodstream infections caused by bacterial and fungal contamination of intravenous fluids and medicines in healthcare facilities in low- and middle-income countries: a scoping review. Antimicrob Resist Infect Control 14, 24 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13756-025-01536-3

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Antimicrobial Resistance & Infection Control

ISSN: 2047-2994

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