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Antibiotics in patients on chemotherapy; aspects on pharmacokinetic and pharmacodynamic interactions with antineoplastic drugs

Nyhlén, Anna LU (2002)
Abstract (Swedish)
Popular Abstract in Swedish

Dagens behandling av cancer, inklusive blodmaligniteter, har blivit mer effektiv genom andvändning av potenta, cytostatiska läkemedel. Cytostatika medför att patienternas normala infektionsförsvar försvagas och att risk finns för livshotande infektioner, särskilt i perioder av neutropeni(lågt antal vita blodkroppar). Det är viktigt att dessa patienter vid infektionstecken får fullgod antibiotikabehandling då de inte själva kan bidra med kroppens eget försvar på ett optimalt sätt. Fullgod antibiotikabehandling innebär att adekvat antibiotika ges med tanke på vilka bakterier som vanligen förorsakar infektioner hos dessa patienter, och att doseringen av valt antibiotika är optimal.... (More)
Popular Abstract in Swedish

Dagens behandling av cancer, inklusive blodmaligniteter, har blivit mer effektiv genom andvändning av potenta, cytostatiska läkemedel. Cytostatika medför att patienternas normala infektionsförsvar försvagas och att risk finns för livshotande infektioner, särskilt i perioder av neutropeni(lågt antal vita blodkroppar). Det är viktigt att dessa patienter vid infektionstecken får fullgod antibiotikabehandling då de inte själva kan bidra med kroppens eget försvar på ett optimalt sätt. Fullgod antibiotikabehandling innebär att adekvat antibiotika ges med tanke på vilka bakterier som vanligen förorsakar infektioner hos dessa patienter, och att doseringen av valt antibiotika är optimal. Avhandlingsarbetet belyser olika aspekter på antibiotikas kinetik hos cytostatikabehandlade och dynamiska interaktioner mellan antibiotika och cytostatika. Resultat: 1) Om man kortar doseringsintervallet för de undersökta anibiotika meropenem och ceftazidim till 6 timmar får man en längre tid över MIC, vilket är målet för dessa immunsvaga patienter. Alternativt kan kontinuerlig infusion av antibioitka ges. 2) Även patienter med symtom på svår tarmpåverkan efter cytostatika kan rekommenderas sedvanlig dos av trimetoprim-sulfa som profylax. 3) De aktuella antibiotikas bakteriedödande effekt var i de flesta fall densamma med och utan cytostatika. Enstaka observationer gjordes av synergistiskt ökad bakteriedödande effekt mellan kombinationerna tobramycin och 5-FU samt tobramycin och doxorubicin mot stafylokocker. De studerade kombinationerna av antibiotika (meropenem, ceftazidim, tobramycin) och cytostatika (5-FU, doxorubicin, etoposide) kan administreras tillsammans utan risk för att antibiotikas effekt påverkas negativt. 4) ciprofloxacin + 5-FU och meropenem + 5-FU gav upphov till synergistiskt förlängd postantibiotisk effekt mot S. epidermidis. 5-FU avbröt produktionen av slem hos de påverkade stammarna, och detta kan ha bidragit till den förlängda postantibiotiska effekten. 5) Tarmfloran påverkades i de flesta fall inte i samband med att patienterna fick cytostatika. Dock ökade bakteriearten Bacteroides och jästsvamp signifikant i antal hos enstaka patienter i samband med cytostatikabehandling. Större studier behövs för att kunna dra slutsatser som kan användas kliniskt. (Less)
Abstract
The aims of these studies were to investigate the pharmacokinetics of two beta-lactam antibiotics in patients with fever and cytostatic-induced neutropenia and the influence of cytostatic-induced gastrointestinal damage on the absorption of co-trimoxazole. Furthermore to study the pharmacodynamic interactions between antibiotics and antineoplastic drugs and the impact of antineoplastic drugs on the intestinal microflora.



Methods: Kinetic data were obtained by model-independent methods for the beta-lactam antibiotics and by population-based methods for co-trimoxazole. Bacterial killing curves and postantibiotic effects (PAE) of different antibiotics alone and in combination with antineoplastic drugs were studied in vitro.... (More)
The aims of these studies were to investigate the pharmacokinetics of two beta-lactam antibiotics in patients with fever and cytostatic-induced neutropenia and the influence of cytostatic-induced gastrointestinal damage on the absorption of co-trimoxazole. Furthermore to study the pharmacodynamic interactions between antibiotics and antineoplastic drugs and the impact of antineoplastic drugs on the intestinal microflora.



Methods: Kinetic data were obtained by model-independent methods for the beta-lactam antibiotics and by population-based methods for co-trimoxazole. Bacterial killing curves and postantibiotic effects (PAE) of different antibiotics alone and in combination with antineoplastic drugs were studied in vitro. Faecal samples were obtained from patients with acute leukaemia on different cytostatic regimens before, during and after treatment and were cultured quantitatively and qualitatively.



Results and Discussion: The faster elimination of meropenem and ceftazidime in our patients compared to historical controls results in shorter times above MIC for the most common pathogens. A dose interval of 6 h seems safer than the commonly used 8 h interval, since serum concentrations should stay above MIC for most of a dose interval in these immunocompromised patients. No correlation was found between the degree of cytostatic-induced gastrointestinal damage and the bioavailability of co-trimoxazole, indicating that the dose of co-trimoxazole needs not be adjusted in these patients.Antibacterial effect and PAEs of the combinations of antibiotics and antineoplastic drugs did not differ markedly from the effects of the antibiotics alone. In the presence of 5-FU and doxorubicin, the antibacterial effect of tobramycin was increased against S. aureus. The PAEs of meropenem and ciprofloxacin against S. epidermidis were synergistically prolonged by 5-FU. This might be due to inhibition of slime production in these strains by 5-FU. The antineoplastic regimens caused only minor changes of the intestinal microflora. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • unknown], [unknown
organization
publishing date
type
Thesis
publication status
published
subject
keywords
antibiotics, neutropenic, antineoplastic agents, pharmacokinetics, pharmacodynamics, PAE, interactions, synergy, Microbiology, bacteriology, virology, mycology, Mikrobiologi, bakteriologi, mykologi, virologi
pages
153 pages
publisher
Ulla Wetterlundh, Dep. of Infectious Diseases, University Hospital of Lund, SE-22185 Lund, Sweden,
defense location
N/A
defense date
2002-03-15 10:15
language
English
LU publication?
yes
id
0f5dc8cf-7a07-4d66-800a-2fb55c2ab52e (old id 464362)
date added to LUP
2007-10-03 14:18:57
date last changed
2016-09-19 08:45:08
@misc{0f5dc8cf-7a07-4d66-800a-2fb55c2ab52e,
  abstract     = {The aims of these studies were to investigate the pharmacokinetics of two beta-lactam antibiotics in patients with fever and cytostatic-induced neutropenia and the influence of cytostatic-induced gastrointestinal damage on the absorption of co-trimoxazole. Furthermore to study the pharmacodynamic interactions between antibiotics and antineoplastic drugs and the impact of antineoplastic drugs on the intestinal microflora.<br/><br>
<br/><br>
Methods: Kinetic data were obtained by model-independent methods for the beta-lactam antibiotics and by population-based methods for co-trimoxazole. Bacterial killing curves and postantibiotic effects (PAE) of different antibiotics alone and in combination with antineoplastic drugs were studied in vitro. Faecal samples were obtained from patients with acute leukaemia on different cytostatic regimens before, during and after treatment and were cultured quantitatively and qualitatively.<br/><br>
<br/><br>
Results and Discussion: The faster elimination of meropenem and ceftazidime in our patients compared to historical controls results in shorter times above MIC for the most common pathogens. A dose interval of 6 h seems safer than the commonly used 8 h interval, since serum concentrations should stay above MIC for most of a dose interval in these immunocompromised patients. No correlation was found between the degree of cytostatic-induced gastrointestinal damage and the bioavailability of co-trimoxazole, indicating that the dose of co-trimoxazole needs not be adjusted in these patients.Antibacterial effect and PAEs of the combinations of antibiotics and antineoplastic drugs did not differ markedly from the effects of the antibiotics alone. In the presence of 5-FU and doxorubicin, the antibacterial effect of tobramycin was increased against S. aureus. The PAEs of meropenem and ciprofloxacin against S. epidermidis were synergistically prolonged by 5-FU. This might be due to inhibition of slime production in these strains by 5-FU. The antineoplastic regimens caused only minor changes of the intestinal microflora.},
  author       = {Nyhlén, Anna},
  keyword      = {antibiotics,neutropenic,antineoplastic agents,pharmacokinetics,pharmacodynamics,PAE,interactions,synergy,Microbiology,bacteriology,virology,mycology,Mikrobiologi,bakteriologi,mykologi,virologi},
  language     = {eng},
  pages        = {153},
  publisher    = {ARRAY(0xb8e3088)},
  title        = {Antibiotics in patients on chemotherapy; aspects on pharmacokinetic and pharmacodynamic interactions with antineoplastic drugs},
  year         = {2002},
}