Postgrad Med J
1999;75:571-573 ( September )
Adverse drug reaction of the month
Ciprofloxacin-induced bone marrow depression
Tarun Kumar Dutta, Bhawana A Badhe
Jawaharlal Institute of Postgraduate Medical Education and Research,
Pondicherry 605 006, India
Accepted 18 February 1999
Ciprofloxacin, a broad-spectrum fluoroquinolone antibacterial agent, is
generally considered to be a safe drug. However, occasionally it may have
life-threatening complications. Two instances of bone marrow failure
following use of ciprofloxacin are reported. In one case, the bone marrow
reverted to normal following withdrawal of the drug. In the other case, the
patient succumbed to irreversible bone marrow depression leading to severe
thrombocytopenia and uncontrolled bleeding. This could have been an
idiosyncratic reaction.
Keywords: ciprofloxacin; bone marrow depression; adverse drug reaction
Ciprofloxacin, a drug belonging to the quinolone group of antibiotics, is
routinely used for treatment of typhoid fever in endemic areas following the
widespread development of chloramphenicol-resistant typhoid fever in these
areas. The advantages have been the overall safety and tolerance profile of
the drug and scarce reports of resistance.1 Nevertheless, it now appears
that the use of this drug may occasionally be life-threatening. We present
two instances of use of ciprofloxacin in suspected cases of enteric fever
(later proved to be non-typhoid cases) associated with life-threatening bone
marrow depression and pancytopenia. In one instance the bone marrow
depression reverted to normal with stoppage of ciprofloxacin therapy, in the
other instance, however, the patient succumbed to the bone marrow
depression.
Case 1
A 24-year-old man, a resident doctor of this institute, was admitted on 25
August 1996 with high-grade fever and chills and rigors for 4 days and
jaundice for one day. On examination the patient was found to be febrile and
icteric. There were no other positive physical findings. A provisional
diagnosis of malaria or viral hepatitis was made. However, the patient had
been fully immunised against hepatitis B infection, and examination of his
blood failed to reveal malaria parasite. He was empirically given
chloroquine, but the fever did not subside and he was started on 500 mg of
ciprofloxacin (Minopharm Laboratories, Hyderabad, India) orally bid on the
third day of his hospital stay with a fresh provisional diagnosis of typhoid
hepatitis. A haemogram done before starting ciprofloxacin showed haemoglobin
9.4 g/dl, total leucocyte count (TLC) 8.7 × 109/l, differential count of
neutrophils 87%, eosinophils 1%, basophils 0%,
lymphocytes 12%, monocytes 0%, platelets 181 × 109/l and reticulocytes 0.3%
(table 1). Blood tests 2 days after starting ciprofloxacin were negative for
typhoid fever, HIV infection, and HBsAg. Urine examination for leptospira
was also negative. A chest X-ray revealed a pneumonic patch in the right
upper lobe. His liver function test showed a total bilirubin of 10 mg/dl,
direct 3.1 mg/dl. Urine was positive for bile pigments. Crystalline
penicillin was added to the treatment in view of the possibility of
pneumonia. A repeat haemogram 2 days after starting ciprofloxacin revealed
haemoglobin 8.9 g/dl, TLC 2.1 × 109/l and a differential of neutrophils 48%,
lymphocytes 36%, eosinophils 16%, platelets 167 × 109/l and reticulocytes
0.1%. Three days later (1 September 1996), his haemogram showed further
deterioration (table 1) and a peripheral smear revealed pancytopenia.
Presuming that the pancytopenia was drug related and since the patient had
become afebrile and his jaundice had subsided, both drugs were stopped. His
blood counts continued to be low, however, and he developed gingival bleed
and purpuric spots on the right cubital fossa, left forearm and thigh over
the next week. Examination of the patient's bone marrow revealed
hypocellularity with increased lymphocyte count suggesting bone marrow
failure (table 2). He was given two units of blood (350 ml/unit) and four
bags of platelet
concentrate during this period.
Haemogram on 7 September 1996 revealed haemoglobin 9.7 g/dl, TLC 1.5 ×
109/l, platelets 51 × 109/l and reticulocytes 0.5%. However, thereafter the
blood counts started rising and the haemogram 7 days after stopping
ciprofloxacin showed haemoglobin 10.6 g/dl, TLC 2.9 × 109/l and platelets
113.1 × 109/l. The haemogram became totally normal by 15 September 1996 (see
table 1). He became totally asymptomatic and recommenced work in this
institute. As the blood counts fell soon after starting ciprofloxacin, the
pancytopenia and bone marrow depression were attributed to ciprofloxacin
(repeat bone marrow examination to confirm recovery was not done for ethical
reasons, although it was clear that the recovery was complete).
Case 2
A 25-year-old man was admitted with a history of high-grade fever and chills
for 3 weeks, melaena for 5 days, and bleeding gums, haematuria,
haematochezia and purpuric rashes for 3 days. Prior to entry to this
institute, he had been treated as a case of malaria with chloroquine; in the
absence of a response, he was treated for enteric fever/septicaemia in a
private nursing home (10 days before entry) where he was given injections of
ciprofloxacin (Cadila Healthcare, Ahmedabad, India), initially for 3 days,
then gentamicin, metronidazole, and procaine penicillin for 7 days (cefoperazone
was also added on the last four days).
At the onset of illness, his blood counts had revealed a haemoglobin of 12
g/dl, TLC 9.2 × 109/l, differential count of neutrophils 52%, lymphocytes
47% and monocytes 1%. Peripheral smear had revealed a normal blood picture.
His blood cultures were twice sterile. He had had the first episode of
bleeding in the form of melaena after 5 days on ciprofloxacin. His total
leucocyte count had fallen to 3.2 × 109 /l after 8 days on ciprofloxacin (2
days before entry to this hospital) and bleeding time was found to be
prolonged (>10 min). His chest X-ray was normal.
On admission to this institute, the patient had severe pallor, bleeding
gums, mild hepatomegaly and purpuric spots all over his body. His haemogram
revealed haemoglobin 6.5 g/dl, TLC 0.4 × 109/l, a differential count of
neutrophils 20%, lymphocytes 80%; platelet count was 7 × 109/l, and
reticulocytes 0%. Peripheral smear revealed severe pancytopenia. His blood
was negative for fibrin degradation product. His peripheral smear was
negative for malaria parasite. Bone marrow examination showed a hypocellular
marrow with predominantly
erythrocytic suppression (myeloid:erythroid ratio 6.5) (table 2) and
megakaryocytic suppression (? idiosyncratic to ciprofloxacin). Ultrasonogram
revealed an organised blood clot in the urinary bladder. Widal test was not
suggestive of enteric fever. The initial diagnosis was drug-induced
hypoplastic anaemia (since enteric fever as a cause of hypoplastic marrow
had been ruled out). The original illness appeared to have been septicaemia.
He was commenced on cephalosporins and aminoglycosides, but despite repeated
fresh blood transfusions continued to bleed from various sites and died 2
days after admission.
ciprofloxacin is widely used in typhoid endemic areas though safe, it may
rarely cause pancytopenia and bone marrow depression ciprofloxacin-induced
bone marrow depression should be suspected when blood counts fall soon after
starting ciprofloxacin
Ciprofloxacin is generally considered to be a safe and well-tolerated drug.3
Its side-effects are mild and not life-threatening, significant side-effects
being seen in <1% cases.3 All side-effects are reversible with
discontinuation of the drug. Hematological adverse effects in particular are
usually mild and are seen in only 0.9-1.8% of cases.4 5 Thus, the drug is
recommended for febrile neutropenias.3 No bleeding or coagulation
abnormality has been noted in the past with this drug.6 Reported
haematological side-effects include
reversible leucopenia7and asymptomatic increase or decrease of platelet
count.4 8 There have been reports of haematological side-effects from an
Indian study by Karande and Kshirsagar, who reported them in 3.8% of cases9;
however, Grover, in another study, reported no haematologic abnormality in
any of his patients.10 Rare haematological side-effects include transiently
acquired Von Willebrand syndrome (reported in two cases).11 In another
report, asymptomatic prolongation of bleeding time was noted in one patient,
but did not occur on re-challenge.6 Bone marrow depression has not
previously been reported to our knowledge.4 5
In the first case, although the provisional diagnosis was typhoid fever,
this was subsequently excluded. Thus, the bone marrow depression could not
be attributed to disease per se. The only drug used before the onset of
pancytopenia, apart from ciprofloxacin, was chloroquine, which is also not
known to cause bone marrow depression.12 Even though the patient recovered
completely with discontinuance of ciprofloxacin, re-challenge with the drug
was not performed for ethical reasons. In the second case, counts were
normal at the onset of
illness, and typhoid was ruled out on the basis of the blood report. Since
the other drugs used in this patient are not known to cause bone marrow
depression, the bone marrow failure was also attributed to ciprofloxacin.
The rapid depression of bone marrow following use of ciprofloxacin suggests
an idiosyncratic reaction. In one case, pancytopenia was observed only 2
days after use of ciprofloxacin, while in the other case, bleeding symptoms
started 5 days after starting ciprofloxacin (even though the drug was
stopped on the fourth day). Thus, it is possible that a single dose may
cause bone marrow depression in rare instances. Further controlled trials
need to be undertaken to confirm this reaction, especially in non-typhoid
cases.
1. Rodrigues C, Mehta A, Andrews R, Joshi VR. Clinical resistance to
ciprofloxacin in salmonella typhi. J Assoc Physicians India
1998;46:323-324[Medline].
2. Mazza JG, ed. Manual of clinical hematology. Boston: Little, Brown and
Company, 2nd edn, 1995;411-441.
3. Davis R, Markham A, Balfour JA. Ciprofloxacin - an updated review of its
pharmacology, therapeutic efficacy and tolerability. Drugs
1996;51:1019-1074[Medline].
4. Schacht P, Arcieri G, Hullmann R. Safety of oral ciprofloxacin. An update
based on clinical trial results. Am J Med 1989;87(5A):98S-102S[Medline].
5. Arcieri GM, Becker N, Esposito B, et al. Safety of intravenous
ciprofloxacin. A review. Am J Med 1989;87(5A):92S-97S[Medline].
6. Pilmore HL, Walker RJ. Prolonged bleeding time during ciprofloxacin
therapy. J Clin Pharm Ther 1995;20:45-46[Medline].
7. Choo PW, Gantz NM. Reversible leukopenia related to ciprofloxacin
therapy.
South Med J 1990;83:597-598[Medline].
8. Jick SS, Jick H, Dean AD. A follow-up safety study of ciprofloxacin
users.
Pharmacotherapy 1993;13:461-464[Medline].
9. Karande SC, Kshirsagar NA. Adverse drug reaction monitoring of
ciprofloxacin in pediatric practice. Indian Pediatr
1992;29:181-188[Medline].
10. Grover JK. Unwanted effects of ciprofloxacin in Indian population.
Indian
J Physiol Pharmacol 1993;37:232-234[Medline].
11. Castaman G, Lattuada A, Mannuccii PM, Rodeghiero F. Characterisation of
two cases of acquired transitory von Willebrand syndrome with ciprofloxacin:
evidence for heightened proteolysis of von Willebrand factor. Am J Hematol
1995;49:83-86[Medline].
12. Webster LT Jr. Drugs used in the chemotherapy of protozoal infections:
malaria. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and
Gilman's
The pharmacological basis of therapeutics. Singapore: Maxwell Macmillan
Publishing Singapore Pvt Ltd, 8th edn. (Maxwell Macmillan International
Edition),
1991;978-998.
------------------------------------------------------------------------------
--
© 1999 by The Fellowship of Postgraduate Medicine |