Intermittent vs Continuous Infusion Of Vancomycin In Neonates Anisa Patel – Neonatal Pharmacist Yorkhill Hospital, Glasgow Anand D1 Lucas C3, Thomson AH,2,4 We recently changed the way in which administer vancomycin to our neonates and this morning I’m going to present an audit which compared intermittent versus continuous infusion vancomycin in neonates

Background Coagulase negative Staph (CoNS) is a major cause of late onset sepsis in NICU Vancomycin is usually 1st choice antibiotic Efficacy depends on achieving and maintaining optimal concentrations throughout the treatment period Avoid toxic / sub-therapeutic levels

Previous audit of Intermittent Guidelines June 2009 to June 2010 Initial trough Overall (n = 160 ) (n = 984) < 12 mg/L 41% 38% 12 – 15 mg/L 20% 20% 15 – 20 mg/L 29% 27% > 20 mg/L 10% 15% Recommended target range has increased from 8 -12 mg/L to 12 - 15 mg/L This is a snapshot 1 year audit of all initial and overall vancomycin levels measured in the neonatal unit of Yorkhill between June 2009 and 2010. The data shows that only 20% of levels were within our recommended target trough range of 12-15mg/L. Causing further concern was the high proportion of levels that were sub therapeutic, around 40%.

Cyclical problem Current guidelines do not achieve target troughs High workload prescribing taking bloods processing samples interpreting levels Frequent dosage alterations and associated monitoring Therapeutic levels difficult to maintain So we had a bit of a cylical problem with vanc in our unit. Our intermittent dosing guidelines did not consistently achieve target trough levels from the outset – which meant that we were often amending doses which meant frequent monitoring – exact dosing and sampling times were not always possible – so we were often amending doses in response to inaccurate levels – which lead back to frequent dose alternations and associated monitoring. So we had a high workload with regards to vancomycin in terms of prescribing, taking blood samples from patients, processing these samples and interpreting the results and we were still struggling to maintain therapeutic levels despite all this effort. Doses amended in response to unreliable levels Exact dosing and sample times not always possible

Continuous vs Intermittent - evidence in adults At least as effective Rybak et al 2009 Subtherapeutic concentrations are less likely and they may cause a lower rate or slower onset of nephrotoxicity Hutschala et al, 2009, Ingram et al, 2009 Flat profile means sampling time is less critical, concentrations are easier to monitor and doses are easier to adjust. Binning et al, 2003 Continuous infusions used successfully in adult patients within GG&C for several years. So why would switching to continuous infusions help the situation. Well there is good evidence in adults to show that…….

Additional potential benefits Time dependent antibiotic so flat profile is ideal. New guideline which aims for current recommended levels Wider target range due to flat profile. Levels with routine morning bloods - fewer blood samples from patients. Standard strength syringes from pharmacy Other potential benefits are that vanc is a time dependent antibiotic so a flat concentration profile makes pharmacokinetic sense, a new guideline could be implemented which would aim to achieve current recommended levels from the outset and levels could be taken with routine bloods meaning fewer blood samples from patients. We would also be able to provide standard strength syringes from pharmacy, reducing workload for nursing staff.

Objectives To compare the effectiveness of intermittent and continuous vancomycin infusions in achieving target concentrations in neonates To assess the implications for clinical practice So, the objectives of the audit were to….

Methods Survey to assess current UK practice 50 level 3 neonatal units Majority used vancomycin 1st line for late onset sepsis All administered by multiple, intermittent infusions No consensus on dosing guidelines 4 units used continuous as well as intermittent infusions Pawlotsky et al, 10 – 40 mg/kg/day So just to quickly go over the methods of the audit. Firstly, a phone survey of 50 levels 3 units across the country was carried out in order to gauge current practice within the UK and this revealed that all of these units administered vancomycin as multiple intermittent infusions and that there was no consensus on dosing or target levels. 4 units also used continuous infusions and based their dosing on a paper by Pawlotsky et al which recommended doses of 10 – 40mg/kg/day.

Methods Audit comparing intermittent and continuous infusion guidelines over a 4 month period. Included all patients admitted to NICU RHSC between March and June 2011 treated with vancomycin Month 1: Data collection on intermittent guideline Month 2: Training on new continuous infusion guideline Month 3: Implementation of guideline Month 4: Data collection on continuous infusions So the audit compared intermittent and continuous infusion guidelines over a 4 month period and included all patients admitted to Yorkhill’s NICU between March and June of this year who required treatment with vancomycin. During month 1…..

The New Continuous Infusion Guideline Loading dose: 15 mg/kg over 1 hour then maintenance continuous infusion Serum Creatinine (mmol/L) Corrected Gestational Age (weeks) Dose Infusion rate < 40  37 60 mg/kg/day 0.6 ml/kg/hr  37 40 mg/kg/day 0.4 ml/kg/hr 40 - 60 all 30 mg/kg/day 0.3 ml/kg/hr > 60 20 mg/kg/day 0.2 ml/kg/hr This is the continuous infusion guideline that was implemented. It advises a loading dose of 15mg/kg to ensure therapeutic levels are achieved quickly and then a maintenance infusion dose based on the baby’s creatinine and also the corrected gestational age at the time treatment (a factor not taken into account by our previous intermittent guideline). A dose of 20 – 60mg/kg/day is selected based on these 2 factors.

Development of the Guideline Existing published guidelines & population PK Modified using published recommendations and anecdotal experience within Glasgow and Leeds. Frymoyer et al 2009, Glover et al, 2000 Not used in practice prior to this audit Recommended target range = 15 – 25 mg/L The guideline was initially developed as part of an MSc project using published guidelines and population pharmacokinetics and was then modified using published recommendations and anecdotal experience from Glasgow and Leeds. It had not been used in practice before this audit and aimed for a target range of 15 – 25mg/L.

Results Clinical characteristics 20 courses (15 patients) of intermittent infusions 20 courses (17 patients) of continuous infusions No significant differences in weight or CGA Ivanc Cvanc CGA (weeks) 37.6 (4.8) 38.7 (2.7) Weight (kg) 2.39 (0.95) 2.66 (0.82) Data are presented as mean (SD) Moving on to the results of the audit – there were 20 courses of intermittent vanc infusions during the first data collection period and 20 courses of continuous infusions during the second audit period and there were no significant differences in weight or corrected gestation age of the patients between the two groups.

Results: the first concentration - how well does each guideline work? CI95 = 0.01 to 0.59 75% This graph shows the percentage of initial vancomycin concentrations below, within and above the target range with each with guideline. Analysis of initial levels only, ie before we amended any doses based on levels gives an indication of how well each guideline works. As you can see, with the intermittent guideline, 35% of levels were below the therapeutic range and these subtherapeutic levels were completely eliminated when we switched over to continuous infusions. The percentage of levels above the range was similar in both groups and the proportion of levels within the target range increased from 45 to 75% when we changed to continuous infusions. Because there were only 20 course in either group the sample set is too small say that this is a statistically significant improvement but the Confidence interval suggests that the trend is towards the continuous infusion guidelines being more likely to achieve therapeutic levels 45%

Results: all concentrations - how well did we maintain target levels? p = 0.0001 CI95 = 0.24 to 0.58 77% This graph shows data for all of the concentrations measured during the two data collection periods. This again shows a reduction in the proportion of overall levels above and below the therapeutic range with the continuous infusion guideline vs the intermittent guideline. The percentage of levels increased from 34 to 77% when we change to the continuous guideline and as this was a larger sample set we can conclude from this that target concentrations are maintained more consistently with the continuous infusion guidelines 34%

Results - Microbiology Patients with confirmed CoNS infection 6 in the intermittent group 2 in the continuous group No patients with ongoing CoNS sepsis in either group after vancomycin therapy all CRP measurements reduced no CoNS grown on sequential blood cultures 2nd line rifampicin was never required From a microbiology point of view there were 6 patients in the intermittent group and 2 patients in the continuous group who had confirmed coag negative staph on blood cultures at the start of treatment and none of these patients has ongoing CONS sepsis after vanc therapy in that all CPR measurements reduced, no CONS was grown on sequential blood cultures and we never had to implement second line therapy with rifampicin.

Results – Creatinine concentration No significant increase in creatinine concentration in either group during or after vancomycin therapy Creatinine concentrations fell between the start and end of treatment in 16 out of 20 courses in the Ivanc group 14 out of 20 courses in the Cvanc group From a renal perspective, there was no increase in ……….and in fact creatinine concentrations fell…..

Results Staff Questionnaire & comments 92% - More dose changes with intermittent guideline 100% - preferred continuous infusion “we find it easier to alter the dose with continuous vanc infusions” “continuous infusions mean babies need fewer jags as levels can be done with routine bloods” A questionnaire was handed out to nursing & medical staff in the unit in order to get their opinions on both of the guidelines. 92% of staff felt that there were more dose changes with the intermittent guideline and all of them said that they preferred the continuous guideline. I’ve included a couple of comments made by staff, one doctor said…

Conclusions Administration of vancomycin by continuous infusion is better at maintaining target concentrations in neonates than administration by intermittent infusion. Additional benefits of continuous infusions Fewer blood samples from patients Reduced workload for staff So in conclusion, administration of…..

Further assessment of the continuous infusion guideline First concentration: data collected for 3 months (60 courses) Guideline modified: upper dose reduced from 60 to 50 mg/kg/day First concentration: data collected for a further 2 months (44 courses) % of first concentrations within each range Finally, I mentioned earlier that the data collected on initial levels was not statistically significant due to the small data set so work was done in order to asses the guideline further. First concentration data was collected for a total of 3 months and you can see from the blue bars on the graph that there was still a reduction in subtherapeutic levels and an increase in the proportion of levels within the target range. However, it was disappointing to see that the proportion of levels above the target range had increased with the continuous infusion guideline. With this in mind, the guideline was modified and the upper dose reduced from 60 to 50mg/kg/day and initial level data collected for a further 2 months. As you can see from the yellow bars on the graph, the percentage of levels that were above the target range fell and the proportion of levels within the target range increased from 45% with the intermittent guideline to 85% with the amended continuous infusion guideline, suggesting that the new guideline achieves target levels from the outset as well as maintaining levels within the target range throughout treatment. 84% 65 % 45 %

Questions?