European Journal of

Eur J Clin Phannacol (1987) 33:435-436

Clinical Pharmacology
@ Springer-Verlag 1987

A Clinically Significant Interaction Between Ciprofloxacin

and Theophylline
A. H. Thomson t 2 G. D. Thomson 2, M. Hepburn 1, and B. Whiting 1
1Department of Materia Mediea, University of Glasgow, and 2Department of Pharmacy, Stobhill General Hospital, Glasgow, UK

Summary. We report a case of theophylline toxicity tion with ciprofloxacin [2] is controversial. We re-
following the co-administration of ciprofloxacin. port an increase in theophylline concentrations dur-
Total theophylline clearance fell from 2.3 l-h -1 to ing ciprofloxacin therapy which necessitated dis-
0.81.h -1 when ciprofloxacin was added to the continuation of theophylline for 3 days and which
treatment regimen and returned to 2.11. h - i after ci- led to a significant reduction in the dose of the-
profloxacin was discontinued. ophylline.

Key words: theophylline, ciprofloxacin; drug inter-

action Case Report

A 92-year-old man was admitted with a chest infec-

tion and an acute exacerbation of chronic obstruc-
tive airways disease. He was initially given nebu-
An increase in theophylline concentrations has been lized salbutamol, aminophylline 225 mg three times
reported with a number of quinolone antibacterial daily, and amoxycillin 500 mg three times daily. His
drugs [1], but the clinical significance of the interac- serum theophylline concentration 9 h after the dose

40

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:~ 20 // ............ 1

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Fig. L Theophylline dosages and

25TID) ',,,,',," '~0'0mg BO 400 mg 8B
I .........l'~°°~g "°~tyi plasma theophylline concentrations
• Opr°ftoxadn t before, during, and after treatment
with ciprofloxacin
0 4 8 12 16 20 24 28 32
Time tdays)
436
on the third day was only 7.5 mg-1 -~ (usual thera-
peutic range 10-20 rag.1-1) and the dose of theo-
phylline was therefore increased to 400 mg twice
daily. Analysis 3 days later confirmed that a satis-
factory concentration had been achieved (15 mg.
I -a) and this dose was continued. After 1 week the
antibiotic was changed to ciprofloxacin 500 mg
twice daily because evidence of infection persisted:
a Gram -re organism of the Acinetobacter species
was isolated from the sputum and ciprofloxacin was
the only antibiotic which could be administered or-
ally to which this organism was sensitive.
Over the next few days the patient became in-
creasingly agitated and confused, eventually being
given chlorpromazine to control his symptoms. The
possibility of theophylline toxicity was considered,
and this was confirmed by a serum concentration of
37 mg.1-1. Theophylline was discontinued and the
fall in concentrations was monitored over the next
few days (Fig.l). An elimination half-life of 23 h
and a theophylline clearance of 0.8 l-h -~ were esti-
mated [3] from these measurements. This compares
with an estimated clearance of 2.3 1.h -1 and an
elimination half-life of 8 h at the start of therapy.
His agitation and confusion subsided as the theo-
phylline concentrations fell, and therapy was re-
started after 3 days with a dose of 200 mg daily. The
course of ciprofloxacin had been completed by this
time and the drug was stopped. Theophylline con-
centrations were measured regularly over the next
few days and a gradual return to the previous dose
requirements was observed (Fig. 1). After 16 days he
was restabilized on a dose of 400 mg twice daily,
with an estimated clearance at this time of 2.1 1-h.
Comment.
Quinolone derivatives have previously been demon-
strated to influence the disposition of theophylline
in healthy volunteers [4] and increased serum con-
centrations of theophylline have been observed in
patients receiving combinations of theophylline
with ciprofloxacin, enoxacin, or pefloxacin [1]. The
increase in theophylline concentrations observed by
Wijnands et al. [1] was around 23% with a corre-
sponding decrease in clearance of around 30%. This
A. H. Thomson et al.: Ciprofloxacin - Theophylline Interactions
contrasts with the two- to three-fold increase in con-
centrations and the 64% reduction in clearance ob-
served in this patient. Maesen and colleagues [2] re-
ported no adverse clinical effects when ciprofloxac-
in and theophylline were combined in 20 patients,
but they had no theophylline measurements and an
increase in plasma concentration cannot be ex-
cluded. Interestingly, Raoof et al. [5] reported a
mean increase in theophylline concentration of
10 mg. 1-~ in 31% of patients treated with ciproflox-
acin, and stated that this was a particular problem
in elderly patients, as demonstrated in the present
case. Following discontinuation of ciprofloxacin
therapy the clearance of theophylline gradually im-
proved, and dosage requirements returned to base-
line within 2-3 weeks of discontinuation of ciprof-
loxacin. In conclusion, we suggest that theophylline
concentrations should be monitored both during
and after treatment in all patients receiving ciprof-
loxacin and the dose adjusted accordingly. This is
of particular importance if the patient is elderly.
References
1. Wijnands WJA, Vree TB, Van Herwaarden CLA (1986) The in-
fluence of quinolone derivatives on theophylline clearance. Br
J Clin Pharmacol 22:677-683
2. Maesen FPV, Teengs JP, Baur C, Davies BI (1984) Quinolones
and raised plasma concentrations of theophylline. Lancet II:
530
3. Kelman AW, Whiting B, Bryson SM (1982) OPT: a package of
computer programs for parameter optimisation in clinical
pharmacokinetics. Br J Clin Pharmacol 14:247-256
4. Nix DE, DeVito JM, Whitbread MA, Shentag JJ (1987) Effect
of multiple dose oral ciprofloxacin on the pharmacokinetics of
theophylline and indocyanine green. J Antimicrob Chemother
19:263-269
5. Raoof S, Wollschlager C, Khan F (1986) Treatment of respira-
tory tract infections with ciprofioxacin. J Antimicrob Chemo-
ther 18 [Suppl. D] 139 145
Received: July 21, 1987
accepted in revised form: August 10, 1987
Dr. A. H. Thomson
Clinical Pharrnacokinetics Laboratory
Department of Materia Medica
Stobhill General Hospital
Glasgow G21 3 UW
UK