Stability of antibiotics in peritoneal dialysis fluids

181 Pages·2014·6.8 MB·English

STABILITY OFANTIBIOTICS INPERITONEALDIALYSIS FLUIDS
by
SandraElizabethHohnes, B.Pharm
submittedin fulfilment oftherequirements for the degree of
MasterofPharmacy
'"ti/ * "t'
UniversityofTasmania
March 1990
u
Thisthesiscontains nomaterialwhichhasbeenacceptedfortheawardofanyother
higher degree or graduatediplomainanytertiaryinstitution.
To the best ofmy knowledge andbelief,this thesis contains no material previously
published or written byanother person,except when due reference is made in thetext
ofthe thesis.
SandraHolmes
m
SUMMARY
Literaturereview
A literature review of the stability of antibiotics in peritoneal dialysis fluids was
conducted. The information obtained was collated and presented in a format which
would serve as a useful working reference for hospital pharmacists. It was found that
the stability ofantibiotics inperitoneal dialysisfluids had receivedlittle attention in the
literature. The review highlighted the lack of information on the stability and
compatibility ofmany of the antibioticsandantibioticcombinations commonly used for
the treatment of peritonitis. Despite increasing interest in intraperitoneal antifungal
chemotherapy, there was no information on the stability of antifungal agents in
peritonealdialysis fluids.
Stabilitystudies
A studyof thestabilityof theantifungal agent, miconazole, inperitonealdialysisfluid
was conducted. Greaterthan 10% loss ofthe initialmiconazoleconcentration occurred
within 4 hours when this drug was added to peritoneal dialysis fluid and stored in
polyvinyl chloride (PVC) bags at 20°C. Similar admixtures were stable for at least
3days when stored in glass ampoules under the same conditions. These findings
indicatedthat the loss of miconazole observedin PVC bags was dueprimarily to an
interaction with the container, rather than chemical decomposition in solution.
Approximately 28% ofthe miconazole lost from the solution was recovered from the
plastic by methanolic extraction, representing sorption of miconazole by the PVC
container. In theclinicalsituation, therapidlossofmiconazolefromperitonealdialysis
fluid storedinPVCbags, would demandthatsuch admixtures bepreparedimmediately
priorto administration.
IV
A study of the stability of both components of the antibacterial combination,
co-trimoxazole, in peritoneal dialysis fluid was conducted. Greater than 10% loss of
the initial trimethoprim concentration occurred within 3 days when admixtures of
co-trimoxazole in peritoneal dialysis fluid were stored in PVC bags at 20°C. The
concentrationoftrimethoprimin similaradmixtures stored in glass ampoules under the
sameconditions,remained virtuallyunchangedfor9days. This suggested thatthe loss
oftrimethoprimobservedin admixtures storedinPVC bags, mayhavebeen due to an
interactionwith thecontainer.
Greater than 10%loss of the initial sulphamethoxazoleconcentration occurred within
2 daysin admixtures storedinPVC bags. Similarlossesoccurred in admixtures stored
in glass ampoules, suggesting thatthemechanism ofthislosswasprimarilychemical
decomposition in solution. Further evidence for this proposition, was the time
dependent increase in concentration of an unknown decomposition product in
admixtures stored in both plastic and glass containers. It was suspected that this
compoundwas a derivativeofsulphamethoxazole, howeverit was demonstrated that it
was not sulphanilicacid or 5-methyl-3-isoxazolamine, which havepreviously been
identifiedasdecompositionproducts ofsulphamethoxazoleunderacidconditions.
This study found that the shelf-life of admixtures of co-trimoxazole in peritoneal
dialysis fluid stored in PVC bags at 20°C, was limited by the stability of the
sulphamethoxazole component. The data conservatively indicated a shelf-life of
approximately 12hours, since greater than 10% lossoftheinitialsulphamethoxazole
concentrationhadoccurredinthis timeinoneofthe admixtures examined.
ACKNOWLEDGEMENTS
I sincerely thank Dr. Stephen Aldous for his advice and encouragement during the
course of this research. I am also grateful for the advice ofDr. Alan Polack, and
extendmy appreciation to allmembers of staffofthe School ofPharmacy, University
ofTasmania, for theirinterestandassistancein this work.
VI
CONTENTS
CHAPTER 1 STABILITYOFANTIBIOTICS INPERITONEALDIALYSISFLUIDS 1
1.1 Introduction 1
1.1.1 Anoverview ofperitonealdialysis 1
1.1.2 Continuous ambulatoryperitoneal dialysis(CAPD) 7
1.1.2.1 Advantages ofCAPD 7
1.1.2.2 Problems associatedwith CAPD 9
1.1.2.3 Treatmentofperitonitis 14
1.1.3 Stabilityofantibiotics inperitonealdialysis fluids 15
1.2 Aims 18
1.3 Methods 18
1.3.1 Literaturereview 18
1.3.2 Collation andpresentationofthe data 18
1.4 Results 22
1.5 Discussion 22
CHAPTER2 STABILITYOFMICONAZOLEINPERITONEALDIALYSISFLUID 25
2.1 Introduction 25
2.1.1 Fungalperitonitis: characterisation andincidence 25
2.1.2 Riskfactorsforfungalperitonitis 26
2.1.3 Treatmentoffungalperitonitis 27
2.1.4 Stabilityofantifungalagents inperitonealdialysisfluids 29
2.1.5 Miconazoleinthetreatmentoffungalperitonitis 30
2.2 Aims 30
2.3 Methods 32
2.3.1 Materials 32
2.3.2 Analysis ofmiconazole 32
2.3.2.1 Instrumentation 34
vu
2.3.2.2 Operatingparameters 34
2.3.2.3 Calibrationcurve 34
2.3.2.4 Samplepreparation 36
2.3.3 Stability-indicatingcapabilityoftheassay 36
2.3.4 Stabilityofmiconazole in peritonealdialysis fluid storedin PVCbags 37
2.3.5 Stability ofmiconazoleinperitoneal dialysisfluid storedin glass
ampoules 37
2.3.6 Sorptionofmiconazole byaPVCcontainer 38
2.4 Results 39
2.4.1 Stability-indicatingcapability oftheassay 39
2.4.2 Stabilityofmiconazoleinperitonealdialysis fluidstoredinPVC bags 42
2.4.3 Stabilityofmiconazoleinperitonealdialysisfluidstoredin glass
ampoules 42
2.4.4 Sorptionofmiconazole byaPVCcontainer 44
2.5 Discussion 44
CHAPTERS STABILITYOFCO-TRIMOXAZOLEINPERITONEALDIALYSISFLUID 52
3.1 Introduction 52
3.2 Aims 54
3.3 Methods 54
3.3.1 Materials 54
3.3.2 Analysis ofco-tiimoxazole 56
3.3.2.1 Instrumentation 56
3.3.2.2 Operatingparameters 56
3.3.2.3 Calibrationcurves 58
3.3.2.4 Samplepreparation 58
3.3.3 Stability-indicatingcapabihtyofthe assay 61
3.3.4 Stabilityofco-tiimoxazoleinperitonealdialysis fluid storedinPVC
bags 61
vm
3.3.5 Stability of co-trimoxazoleinperitonealdialysis fluid storedin glass
ampoules 62
3.3.6 Identification ofadecompositionproductin co-trimoxazole/peritoneal
dialysisfluid admixtures 63
3.3.6.1 Comparisonwithknowndecompositionproducts 63
3.3.6.2 DirectprobeMSanalysis 65
3.3.6.3 Extractionofcolumneffluentfractions: GCMS analysis 65
3.3.6.4 Extractionwithdichloromethane: HPLC andGCMS analysis 66
3.4 Results 66
3.4.1 Stability-indicatingcapabilityoftheassay 66
3.4.2 Stability ofco-trimoxazoleinperitonealdialysis fluid storedinPVC
bags 68
3.4.3 Stabilityof co-trimoxazoleinperitoneal dialysis fluid storedin glass
ampoules 71
3.4.4 Identificationofadecompositionproduct in co-trimoxazole/peritoneal
dialysis fluid admixtures 74
3.4.4.1 Comparisonwithknowndecompositionproducts 74
3.4.4.2 Directprobe MS analysis 81
3.4.4.3 Extractionofcolumn effluent fractions: GCMS analysis 81
3.4.4.4 Extractionwith dichloromethane: HPLC andGCMS analysis 81
3.5 Discussion 84
REFERENCES 88
APPENDIX 1 Stabilityof antibioticsinperitonealdialysis fluids
APPENDIX2 Miconazoleconcentrations inperitonealdialysis fluid admixtures
storedin PVCbags and glass ampoules
APPENDIX3 Sulphamethoxazole andtrimethoprimconcentrations inperitoneal
dialysisfluid admixturesstoredinPVCbags and glass ampoules
CHAPTER 1
STABELTTYOFANTIBIOTICS INPERITONEALDIALYSIS FLUIDS
1.1 Introduction
1.1.1 An overviewofperitoneal dialysis
In 1923,Ganterreported animprovementin theconditionof a uremic guineapig after
theintermittentinfusionandremoval ofsalinesolution fromtheperitonealcavity. He
noted that after an intraperitoneal (i.p.) dwell time of one hour, the urea-nitrogen
concentration in the fluid approximated that in the blood. Ganter also reported an
improvementin the condition ofa uremic woman afterthe instillation of 1.5L ofsaline
solution into theperitonealcavity, and thatthei.p.infusionof3L ofsaline solution in a
patientwithdiabeticcomaproducedareversaloftheunconsciousstate. Followingthese
observations, Ganterproposed thattheperitoneal membrane allowed thepassage oftoxic
substances from the bloodinto theperitoneal cavity (1).
During the period from 1923 to 1948, 101 patients were reported as having received
some form of peritoneal dialysis. Of the 63 patients who suffered reversible renal
disease, 32 were treated successfully with this dialysis technique. During this
pioneeringperiodofperitoneal dialysis, three complications accountedfor the majority
ofdeaths; (i)pulmonaryoedema, (ii)uremia, and (iii)peritonitis. At this timeperitoneal
dialysis was largely confinedto animalexperimentation andthe treatmentofacuterenal
failure in humans. It was also used successfullyfor the treatmentofhypercalcaemiaand
various poisonings. The high incidence of peritonitis, and the failure to develop a
successfulperitoneal access device, leadto the abandonmentofattempts to establishlong
termperitonealdialysis (1,2).
2
In 1963, Boen commenced treatment ofapatientusing peritoneal dialysis in which the
dialysis fluid was introduced into the peritoneal cavity using a repeated puncture
technique. Effective control of the uremic state was obtained using an intermittent
dialysis regime consisting of three or four dialysis sessions per week, each session
lasting approximately 10 hours and using approximately 40 L of fluid. This regime
became known as intermittent peritoneal dialysis. Using the repeated puncture
technique, Boen's patient was maintainedon intermittent peritoneal dialysis for three
yearsprior to a successfulkidneytransplant, andthefeasibility of long term peritoneal
dialysis for the management of end-stage renal disease was therefore established.
Tenckhoff, Boen's co-worker, confirmedthe success ofthis procedureby maintaining a
patientonintermittentperitonealdialysis forthreeandahalfyearsinahomesetting. In
1966, Lasker et al also reported success with the repeated puncture technique in
5 patients (1, 3).
Peritonealaccessdevices
Althoughtherepeated puncture technique wasassociatedwith alowriskofinfectionand
enabled the feasibility oflong term peritoneal dialysis to be established, the procedure
was both unpleasant for the patient and demanding on staff, who would have to carry
outtheprocedureatleastthreetimesweeklyforeachpatient. Attentionwasonceagain
turned to the developmentofalong termperitoneal access device. In 1968, Tenckhoff
designeda siliconerubber catheterwithtwodacroncuffswhich wereintended toanchor
the catheter to the abdominal wall, and to close the sinus tract around the catheter,
therebypreventing bacterial intrusion. Thiscathetergained widespread acceptance and
was the most important factor in promoting long term peritoneal dialysis in other
centres (1). Many other catheter designs have evolved. A modified version of
Tenckhoffsdoublecuffcatheter, with acatheteradaptermadeoftitaniumandaluerlock
configuration between the adapter and theplastic extension tubing, is in widespreaduse
today (4).