A descriptive study of vancomycin use at Red Cross War Memorial Children’s Hospital, Cape Town

Background Antimicrobial stewardship principles guide the clinical use of antimicrobials, including vancomycin, but paediatric vancomycin prescribing practices have not been evaluated in South Africa. Objectives To document the use, prescribing practices and monitoring of intravenous vancomycin and the spectrum of bacteria isolated on microbiological culture in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children’s Hospital (RCWMCH). Method A retrospective audit of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed. Results All 158 vancomycin prescription episodes for 143 children were included. Overall usage of intravenous vancomycin was 63 days of therapy per 1000 patient days (interquartile range [IQR]: 38–72). The median starting dose was 15 mg/kg per dose (IQR: 14–15) and median daily dose was 45 mg/kg per day (IQR: 43–60). Vancomycin was prescribed as empiric (127/158, 80%) and directed (31/158, 20%) treatment. The median duration of treatment for the directed group (7 days) was longer than the empiric group (4 days) (p = 0.001). Vancomycin serum trough concentrations were performed in 65/98 (66%) episodes where vancomycin treatment exceeded 3 days, with only 16/65 (25%) of these samples obtained before the fourth dose. Prolonged antibiotic treatment of 14 days or more was not associated with Gram-positive bacteria on culture (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 0.17–4.2). Conclusion Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions. Contribution The study identified multiple opportunities for improved vancomycin prescribing and monitoring. Further research and implementation of improved prescribing practices could contribute to the preservation of vancomycin as an effective antibiotic.


Introduction
Children in low-and middle-income countries (LMICs) are leading consumers of antibiotics globally, 1 and little progress has been made in mitigating the risk of antimicrobial resistance by improving stewardship in this setting. 2The World Health Organization (WHO) has classified 180 antibiotics used in human health into Access, Watch and Reserve categories.This classification is based on spectrum of activity, frequency of use and resistance potential.Vancomycin is a Watch antibiotic and should be prioritised for stewardship and surveillance for resistance. 3Vancomycin's mechanism of action against Gram-positive bacteria is by inhibition of bacterial cell wall synthesis.It remains the treatment of choice for infection caused by β-lactam-resistant Gram-positive bacteria such as Enterococcus faecium, β-lactam-resistant Streptococcus pneumoniae and methicillinresistant Staphylococcus aureus (MRSA). 4,5pharmacist-led, multicentre, antimicrobial stewardship (AMS) initiative, across 47 private hospitals in South Africa, showed that 1 in every 15 antibiotic prescriptions required intervention when dosing errors and excessive duration were common.6 An audit on the impact of stewardship on vancomycin use in children indicated that non-approved indications for

A descriptive study of vancomycin use at Red Cross War Memorial Children's Hospital, Cape Town
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http://www.sajid.co.zaOpen Access prescription, dosing errors and prolonged duration of treatment were problems. 7Real-time intervention and feedback on prescriptions of vancomycin have reduced overall vancomycin use and improved the safety and quality of care in tertiary hospitals. 8,9hievement of adequate plasma and tissue vancomycin concentrations is essential for an optimal clinical response.The effectiveness of vancomycin to treat invasive infections due to Gram-positive bacteria is associated with the area under the concentration-time curve from 0 h to 24 h divided by the minimum inhibitory concentration (AUC 24 /MIC ratio) of the organism being targeted.For MRSA with a vancomycin MIC of 1 mg/L, an AUC 24 /MIC ratio > 400 is recommended. 10he 2011 Clinical Practice Guidelines produced by the Infectious Diseases Society of America (IDSA) recommended targeting vancomycin trough concentrations of 15 mg/L -20 mg/L, which correlates with an AUC 24 /MIC ratio > 400, in adults with severe bacterial infections.The effectiveness and safety of targeting trough concentrations of 15 mg/L -20 mg/L in children were not established at the time and a dose of 15 mg/kg per dose administered intravenously sixhourly was recommended. 11Pharmacokinetic modelling suggests that a trough concentration of 7 mg/L -10 mg/L may be sufficient to achieve an AUC 24 /MIC of > 400 in over 90% of children with MRSA infection. 12Although optimal dosing and the role of therapeutic drug monitoring (TDM) in paediatric practice remain uncertain, 11,13 current IDSA guidelines recommend individualised targeting of an AUC 24 /MIC ratio of 400-600 (assuming a vancomycin MIC of 1 mg/L) to achieve clinical efficacy while improving safety. 5Individualised AUC 24 /MIC targeting is not readily available in LMICs but has been successfully used as an entry point for stewardship elsewhere. 14ediatric prescribing practices of vancomycin have not been evaluated in South Africa.To identify potential AMS intervention opportunities related to vancomycin usage and to aid better patient outcomes, the authors aimed to document the use, prescribing practices and monitoring of intravenous vancomycin, and to describe the spectrum of bacteria isolated on microbiological culture and their antibiotic susceptibility profile in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children's Hospital (RCWMCH) in Cape Town, South Africa.

Study design, setting and identification of study participants
A retrospective descriptive study of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed.The RCWMCH is a 272-bed referral hospital that serves children aged 13 years and younger from the Western Cape province and occasionally from surrounding provinces.All children treated with intravenous vancomycin during the study period were eligible for inclusion and excluded only if records were missing or the prescription chart could not be located in the hospital folder.Study participants were primarily identified from the RCWMCH pharmacy database.
In addition, the intensive care unit (ICU) discharge summary database was searched, as vancomycin used to treat children admitted to the ICU is obtained from ICU medication stock and not issued directly from the pharmacy on an individual patient basis.).Categorical variables were described using absolute values and percentages with the associated 95% confidence intervals (CIs); continuous variables were described using median and interquartile range (IQR) for non-normally distributed data.Comparison of the vancomycin daily dose between treatment groups was done using the Wilcoxon rank sum test.To examine whether participants with a Gram-positive organism on culture had increased odds of being prescribed vancomycin for more than 14 days compared to those with negative cultures, odds ratio (OR) were calculated using the STATA immediate command.P-values of less than 0.05 were used to denote statistical significance.

Study definitions
An infection episode was considered community-acquired (CAI) if vancomycin was started within 48 h of admission to hospital and considered hospital-acquired (HAI) if vancomycin treatment was started more than 48 h after hospital admission or within 30 days of discharge from a previous admission. 16vancomycin prescription was considered empiric treatment if commenced before culture and antibiotic susceptibility results were available, and all prescriptions for which cultures remained negative or no cultures were submitted to the laboratory.A vancomycin prescription was considered directed when an organism susceptible to vancomycin was identified by culture and AST, and vancomycin was considered the preferred treatment option.
Vancomycin usage was expressed as days of therapy per 1000 patient days (DOT/1000 PD) defined as the number of days that study participants were treated with intravenous vancomycin (regardless of the dose) per 1000 inpatient days including all patients admitted in the hospital during the study period. 17ncomycin TDM was considered appropriate if a serum trough concentration was performed before the fourth dose for treatment exceeding 3 days, based on the time to reach steady state. 18Trough concentrations of 10 mg/L -20 mg/L were considered therapeutic based on guidelines followed within the study period. 16,18

Ethical considerations
Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee (approval number HREC Ref: 498/2020) and the RCWMCH research committee (RCC 241/WC_202008_114).A waiver of consent was granted on the basis that the study only used anonymised archived data.The study was done in accordance with the Declaration of Helsinki.

Results
A total of 158 vancomycin prescription episodes for 143 children were included (Figure 1), of which 67 (47%) were male and 76 (53%) were female.The median age at admission was 7 months (IQR: 1-77) and the median weight was 7 kg (IQR: 3-19).Twenty-two (15%) of participants were term neonates and 26/143 (18%) had been born premature with a corrected gestational age below 44 weeks.Monthly usage stratified by use in and outside of the ICU is illustrated in Figure 2.

Vancomycin usage
The

Duration of treatment
The median duration of vancomycin treatment was 5 days (IQR: 3-7 where vancomycin was prescribed for 14 days or more, Gram-positive organisms were cultured.Similarly, in episodes where vancomycin was prescribed for less than 14 days, 28/143 (20%) isolated Gram-positive bacteria from culture.Thus, the odds of having a Gram-positive organism on culture when treated with vancomycin for 14 days or more compared to the odds when treated for less than 14 days were similar (OR: 1.02, 95% CI: 0.17-4.2,p = 0.59).

Dosing strategies in relation to vancomycin serum trough concentrations
For samples obtained before the fourth dose, the median vancomycin serum trough concentration was 14 mg/L (IQR: 6-18).
Positive cultures were obtained in 58/146 (40%) vancomycin prescription episodes and the median vancomycin treatment duration in these episodes was 6 (IQR: 2-8) days.Vancomycin was the appropriate antibiotic choice and prescribed as directed treatment in 22/58 (38%) prescription episodes and 9/58 (15%) episodes where CONS were identified and of which the clinical significance was uncertain.For 19/58 (33%) episodes, vancomycin was stopped within 5 days as culture either identified an organism for which vancomycin was not the appropriate antibiotic choice or the organism was not deemed clinically significant.
Vancomycin was continued beyond 5 days in 8/58 (14%) when the organism identified was either not susceptible to vancomycin or vancomycin was not considered the preferred treatment option.These included the following: 3/8 (37%) episodes where Gram-negative bacteria were isolated from blood and pus in suspected NEC 2 and from a tracheal aspirate in febrile neutropaenia 1 ; 3/8 (37%) episodes where methicillin-susceptible S. aureus was identified from sputum in an episode of VAP, from a pus swab from a wound infection following cardiac surgery, and from blood culture in febrile neutropaenia, respectively; 1 (1/8, 13%) episode in which Candida albicans was isolated from blood culture in an episode of VAP; and 1 (1/8, 13%) episode in which Streptococcus agalactiae was isolated from blood culture in an episode of NEC.

Adverse events
Four ADEs were documented in the clinical records.One episode was associated with a hypersensitivity reaction; three had acute kidney injury (AKI) attributed to vancomycin with all having preexisting chronic kidney disease (advanced membranous nephropathy, lupus nephritis and hepatorenal syndrome).Two participants with documented AKI also received furosemide and amikacin, respectively.Whether co-administration of these drugs contributed to AKI is uncertain.Vancomycin TDM and dose adjustment were performed throughout the course of therapy for participants with ADE.Vancomycin was stopped in two (50%) episodes and continued despite the ADE in two (50%) episodes.

Discussion
To the best of the authors knowledge, this is the first description of vancomycin usage and prescribing practices in South African children.Intravenous vancomycin prescription occurs throughout RCWMCH, with ICU unsurprisingly accounting for most usage (51%) during 2019.Comparable vancomycin usage has not been published from healthcare facilities treating children in South Africa.
Vancomycin was prescribed exclusively for HAI and mostly as empiric treatment (80%) and less often as directed treatment (20%) with cultures routinely obtained prior to prescriptions in most (92%).Clinical indications for using vancomycin at initiation of empiric antibiotic treatment included intra-abdominal infection and NEC (26%), HAP and VAP (24%) and SSTI (19%).For directed treatment, indwelling venous catheter-associated infection (24%), HAP and VAP (19%), and intra-abdominal infection and NEC (23%) were common.Vancomycin prescription for inappropriate or non-approved indications was less frequent than previously described in other settings. 7sing of vancomycin was variable with only 53% of prescriptions adhering to a starting dose of 15 mg/kg per day and only 22% adhering to the recommended total daily dose of 60 mg/kg per day. 19More than two-thirds of prescriptions were for < 60 mg/kg per day.Dosing frequency was most often eight-hourly (56%) or six-hourly (27%) with dosing less frequently than eight-hourly due to prematurity or renal dysfunction.
The significant difference in treatment duration between empiric and directed treatment episodes suggests that vancomycin is stopped sooner once cultures are negative than in cases where cultures and AST confirm an infection where vancomycin is the appropriate treatment.However, among the 15 episodes (9%) where vancomycin treatment continued for 14 days or more, empiric treatment accounted for 80% of prescription episodes.These findings are in keeping with studies from other countries indicating that inappropriate prescribing and empiric treatment are common, with differences among age groups contributing to dosing complexity. 20,21,22e optimal dosing of vancomycin and the role of TDM in paediatric practice remain uncertain 11,12 and may soon be replaced with model-informed precision dosing where available. 23Infectious Diseases Society of America guidelines 5 recommend AUC 24 /MIC targeting, whereas guidelines aiming for vancomycin serum trough concentrations of 10 mg/L -20 mg/L are still followed at RCWMCH. 19Serum trough concentration monitoring was only performed in 60% of prescription episodes overall and in 66% of episodes treatment for longer than 3 days.Only 21% of TDM samples were obtained before the fourth dose, lower than the 40% reported in a study from France that evaluated 154 vancomycin prescriptions. 24With the very variable dosing found in the study overall, it is surprising that the median vancomycin serum trough concentration in the 20 episodes with samples obtained before the fourth dose was 14 mg/L (recommended range 10 mg/L -20 mg/L) 19 although the variability was wide (IQR: 6-18).It was difficult to interpret the serum trough concentrations that were < 10 mg/L or > 20 mg/L, as well as the appropriateness of dose adjustments done in response to these results.Although AUC 24 /MIC monitoring is not currently available, its future utilisation as an AMS tool may improve vancomycin dosing and safety, which is particularly important as ADEs are likely underreported at RCWMCH. 14e microbiological results revealed that approximately two-thirds of positive cultures occurred where an indwelling device was present.This finding suggests that improved compliance with infection prevention and control (IPC) could reduce the need for vancomycin prescription.Although blood culture yielded MRSA in 47% of isolates, it is reassuring that no isolates were nonsusceptible to vancomycin.The rate of MRSA in was lower than the 72% and 65% in hospital-acquired BSI due to S. aureus recorded in previous paediatric studies done in Cape Town. 25,26ke many others in LMIC settings, RCWMCH lacks the capacity to implement prospective audit and real-time feedback to prescribers, and discontinuation or de-escalation to narrower spectrum antibiotics based on culture and AST results where appropriate.Among episodes with negative cultures, vancomycin was discontinued in 41% within 3 days and 73% within 5 days of starting treatment.However, among 58 episodes with positive cultures, 8 (14%) continued vancomycin treatment despite the identification of an organism that was not susceptible to vancomycin or where vancomycin is not the preferred treatment option.
This study has several limitations.It was performed at a single centre and paper-based medical record review with missing documents resulted in a high exclusion rate (23%).Uniform local guidance on vancomycin prescribing is limited and variable, and the appropriateness of vancomycin treatment based on the documented clinical syndrome could not be assessed.Clinical indications were only collected when vancomycin was initiated, as information on indications for continued prescribing was not available.Furthermore, outcome data were not available and the impact of vancomycin prescription errors on outcomes could not be accurately assessed.As a result of the diversity in prescribing practices among different institutions, results may not be applicable elsewhere.

Monitoring antimicrobial consumption and instituting effective AMS interventions remain a challenge in areas
where electronic prescribing is not yet feasible.This study emphasises the need to develop and implement uniform guidelines for the prescription and monitoring of vancomycin along with appropriate de-escalation practices as urgent AMS interventions.Similar guidance is important for all other antimicrobials prescribed at RCWMCH.Ongoing education of prescribers and compliance with IPC practices are essential.Future research should focus on defining methods to improve prescribing practices and evaluate future AMS interventions.

Conclusion
u a r y F e b r u a r y M a r c h A p r i l M a y J u n e J u l y A u g u s t S e p t e m b e r O c t o b e r N o v e m b e r D e c e m b e r DOT/1000 PD Months ICU Non-ICU Total DOT/1000 PD, days of therapy per 1000 patient days; ICU, intensive care unit.

FIGURE 2 :
FIGURE 2: Monthly usage of vancomycin over the study period (2019) in ICU & non-ICU wards at the Red Cross War Memorial Children's Hospital.

FIGURE 1 :
FIGURE 1: Participants and vancomycin prescription episodes included in the study.

TABLE 2 :
Microbiological profile of organisms isolated from positive cultures.
Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions in the study.Antimicrobial stewardship interventions targeting uniform guidance and http://www.sajid.co.zaOpen Access concurrently improving IPC compliance may contribute to the preservation of vancomycin at RCWMCH.