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Coagulopathy in two patients with cystic fibrosis treated with ciprofloxacin
Journal of Cystic Fibrosis 6 (2007) 209 – 211 www.elsevier.com/locate/jcf
Coagulopathy in two patients with cystic fibrosis treated with ciprofloxacin Gillian C. Moore a,⁎, Jan Redfern a , Caroline R. Shiach b , Kevin Webb a , Andrew M. Jones a a
Manchester Adult Cystic Fibrosis Unit, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK b Department of Haematology, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK Received 26 April 2006; received in revised form 13 August 2006; accepted 18 August 2006 Available online 12 October 2006
Abstract We report two cases of prolonged blood clotting times as demonstrated by a raised international normalised ratio and elevated activated partial thromboplastin time in patients with cystic fibrosis taking ciprofloxacin. The potential mechanisms of a coagulopathy of this picture as an adverse drug reaction with ciprofloxacin are discussed along with the possible clinical consequences for patients with cystic fibrosis. © 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Ciprofloxacin; Coagulopathy; INR; APTT
1. Introduction Ciprofloxacin is a commonly prescribed oral antibiotic for patients with cystic fibrosis (CF) due to its efficacy in treatment of Pseudomonas aeruginosa infection [1,2]. Ciprofloxacin is documented to induce a coagulopathy, namely, a raised international normalised ratio (INR), in patients taking warfarin [3]; however, it has been reported that at the usual oral ciprofloxacin dose of 500 mg twice daily this effect is usually not significant [4]. The proposed mechanism of this action is by inhibition of the IA2 isoform of cytochrome P450 enzyme [5]. There are no published reports of a raised INR in patients taking ciprofloxacin who are not on anti-coagulant medication. 2. Case reports 2.1. Case 1 A 29-year-old woman with CF and chronic P. aeruginosa infection was admitted with features of distal intestinal
⁎ Corresponding author. Tel.: +44 161 291 2154; fax: +44 161 291 2080. E-mail address: [email protected] (G.C. Moore).
obstruction syndrome. She had a past history of a right internal jugular venous thrombosis related to the insertion of a permanent venous access device and a right-sided common femoral deep vein thrombosis secondary to a temporary venous access line. On the advice of the haematology team, she was using 1.5 mg/kg subcutaneous enoxaparin daily as she had difficulty complying with the regular monitoring of INR required with previous warfarin therapy. During the admission her spirometric values worsened and she was treated with intravenous (IV) ciprofloxacin 400 mg twice daily and nebulised tobramycin. Two days after commencing ciprofloxacin her INR was 3.4 compared to a baseline INR of 1.0. This was confirmed on sending a repeat sample. In addition, the APTT was 41.2 s compared to a baseline of 22.1 s. Renal and synthetic liver function tests were normal throughout the admission. The IV ciprofloxacin was changed to IV ceftazidime. Twenty-four hours later, her INR had settled to baseline values (1.3) and her APTT was back within the normal range (26.0 s). Enoxaparin was continued in view of her prothrombotic history and she was discharged home 5 days later after her abdominal symptoms improved. The possibility of a raised INR secondary to ciprofloxacin therapy was reported via a “yellow card” system to the Medicines and Healthcare Products Regulatory Agency (MHRA).
1569-1993/$ - see front matter © 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2006.08.002
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G.C. Moore et al. / Journal of Cystic Fibrosis 6 (2007) 209–211
2.2. Case 2
3. Discussion
An 18-year-old woman with CF and chronic P. aeruginosa infection presented to outpatients with a 1-week history of a coryzal illness and mildly increased dyspnoea. She was given a course of oral ciprofloxacin 1 g bd and rifampicin 300 mg bd. She was not taking any anticoagulant drugs and had previously tolerated this antibiotic combination without problems. Five days after starting ciprofloxacin and rifampicin she re-presented with vomiting. Blood tests revealed a markedly raised urea and creatinine (urea 17.6 mmol/l, creatinine 768 μmol/l), an INR of 2.6 and APTT of 45.1 s. These compared to baseline values of urea 3.9 mmol/l and creatinine 83 μmol/l taken 8 weeks previously. Her liver function tests were normal, paracetamol levels were undetectable and she was haemodynamically stable. There were no other clinical signs of sepsis and no organisms grown on repeated sets of blood cultures. Ciprofloxacin and rifampicin were discontinued. She was seen by the nephrologists who felt that her worsening renal function represented interstitial nephritis secondary to ciprofloxacin toxicity rather than pre-renal failure. Over the next week, she made a good clinical improvement and was monitored with daily measurements of coagulation and urea and electrolytes (Fig. 1). Her INR was normal (1.0) at discharge. At discharge urea was 15.1 mmol/ l and creatinine 265 μmol/l. These slowly returned to baseline 3 weeks after discharge. Her APTT returned to values within the normal range 72 h after the antibiotics were terminated. The incident was reported to MHRA as a complication of ciprofloxacin and rifampicin therapy.
In both cases, there was an increase in both the INR and APTT that coincided with starting ciprofloxacin that was reversible on discontinuation of the drug. This is an important side effect and has not previously been reported in patients who are not taking warfarin. On reviewing reporting of adverse drug reactions for ciprofloxacin to the MHRA [6], there are a total of 5643 adverse drug reactions reported for ciprofloxacin of which 70 were fatal. Amongst these are 34 reported cases of acute renal failure of which 3 were fatal. Four cases of acquired coagulopathy are reported, none of which were fatal. The aetiology of this picture of coagulopathy noted with ciprofloxacin is unknown. A case of factor VIII inhibitor possibly caused by ciprofloxacin has been reported [7], as has acquired transitory von Willebrand syndrome [8] and a case of prolonged bleeding time [9]. Two incidents of acquired factor V inhibition and antiphospholipid antibodies after treatment with ciprofloxacin have been reported [10]. Patients with CF tend to receive higher doses of ciprofloxacin than other patients due to enhanced activity of certain cytochrome P450 enzymes and increased renal clearance [11], and these increased doses could increase the chance of adverse drug reactions. It is also possible that both patients had borderline low levels of vitamin K due to exocrine pancreatic insufficiency related to cystic fibrosis [12] and possibly that ciprofloxacin further reduced gastrointestinal vitamin K absorption leading to a temporary vitamin K-deficient state and explaining the raised INR and APTT. We postulate that selective deficiencies of vitamin K-dependent clotting factors were a possible causative link for the coagulopathy and that factor VII in particular is implicated due to the relatively quick
Fig. 1. Trends in creatinine and INR in case 2.
G.C. Moore et al. / Journal of Cystic Fibrosis 6 (2007) 209–211
return of INR to baseline in both cases after stopping ciprofloxacin. In both patients, there were no adverse clinical consequences from the temporary prolongation of the INR. However, massive haemoptysis is a recognised complication of CF with an average annual incidence of just under 1% and a lifetime incidence of 4.1% [13]. In patients with haemoptysis, an unexpected coagulopathy could have significant clinical consequences. Unfortunately, in neither case, clotting factor assays were undertaken. If a similar effect is seen in the future, measurement of clotting factor levels would be helpful. In conclusion, we present two cases of a prolonged INR and APTT in patients with CF on ciprofloxacin therapy. In one case, the patient was on enoxaparin in view of a previous prothrombotic history and in the other case the patient also developed an interstitial nephritis. These co-morbid factors may have predisposed the patients to developing the coagulopathy that we have reported. However, in the first case, the significant rise in INR cannot be explained by longterm enoxaparin therapy and in the second case the nephritis would not explain the marked prolongation of APTT and INR. In addition, the coagulopathy reversed promptly in both cases when the ciprofloxacin was stopped. The aetiology of this mechanism is unclear and would benefit from further investigation. Due to the frequency of ciprofloxacin prescription, it is important to be aware of this potential adverse drug reaction in clinical practice in caring for patients with CF. We would encourage reporting further similarly observed reactions through MRHA in addition to measurement of clotting factor levels to enable further details regarding the aetiology of this effect to be obtained. References [1] Taccetti G, Campana S, Fastini F, Mascherini M, Doring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J Sep 2005;26(3):458–61.
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[2] Canton R, Cobos N, de Gracia J, Baquero F, Honorato J, Gartner S, et al. Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect Sep 2005;11(9):690–703. [3] Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin–warfarin coagulopathy: a case series. Am J Hematol Jan 2000;63(1):28–31. [4] Bianco TM, Bussey HI, Farnett LE, Linn WD, Roush MK, Yong YW. Potential warfarin–ciprofloxacin interaction in patients receiving longterm anticoagulation. Pharmacotherapy 1992;12(6):435–9. [5] Fuhr U, Anders EM, Mahr G, Sorgel F, Staib AH. Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrob Agents Chemother May 1992;36 (5):942–8. [6] http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_ PAGE&nodeId=742 Accessed 05/02/06. [7] Miesbach W. Rituximab in the treatment of factor VIII inhibitor possibly caused by Ciprofloxacin. Thromb Haemost May 2005;93 (5):1001–3. [8] Castaman G, Lattuada A, Mannucci PM, Rodeghiero F. Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor. Am J Hematol May 1995;49(1):83–6. [9] Pilmore HL, Walker RJ. Prolonged bleeding time during ciprofloxacin therapy. J Clin Pharm Ther 1995;20:45–6. [10] Miesbach W, Voigt J, Peetz D, Scharrer I. Massive bleeding symptoms in two patients with factor V inhibitor and antiphospholipid antibodies after treatment with ciprofloxacin. Med Klin (Munich) Jun 15 2003;98 (6):339–43. [11] Rey E, Treluyer GM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet Oct 1998;35(4):313–29. [12] Wilson DC, Rashid M, Durie PR, Tsang A, Kalnins D, Andrew M, et al. Treatment of vitamin K deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr Jun 2001;138(6):851–5. [13] Flume PA, Yankaskas JR, Ebeling M, Hulsey T, Clark LL. Massive hemoptysis in cystic fibrosis. Chest Aug 2005;128(2):729–38.
Coagulopathy in two patients with cystic fibrosis treated with ciprofloxacin Gillian C. Moore a,⁎, Jan Redfern a , Caroline R. Shiach b , Kevin Webb a , Andrew M. Jones a a
Manchester Adult Cystic Fibrosis Unit, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK b Department of Haematology, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK Received 26 April 2006; received in revised form 13 August 2006; accepted 18 August 2006 Available online 12 October 2006
Abstract We report two cases of prolonged blood clotting times as demonstrated by a raised international normalised ratio and elevated activated partial thromboplastin time in patients with cystic fibrosis taking ciprofloxacin. The potential mechanisms of a coagulopathy of this picture as an adverse drug reaction with ciprofloxacin are discussed along with the possible clinical consequences for patients with cystic fibrosis. © 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Ciprofloxacin; Coagulopathy; INR; APTT
1. Introduction Ciprofloxacin is a commonly prescribed oral antibiotic for patients with cystic fibrosis (CF) due to its efficacy in treatment of Pseudomonas aeruginosa infection [1,2]. Ciprofloxacin is documented to induce a coagulopathy, namely, a raised international normalised ratio (INR), in patients taking warfarin [3]; however, it has been reported that at the usual oral ciprofloxacin dose of 500 mg twice daily this effect is usually not significant [4]. The proposed mechanism of this action is by inhibition of the IA2 isoform of cytochrome P450 enzyme [5]. There are no published reports of a raised INR in patients taking ciprofloxacin who are not on anti-coagulant medication. 2. Case reports 2.1. Case 1 A 29-year-old woman with CF and chronic P. aeruginosa infection was admitted with features of distal intestinal
⁎ Corresponding author. Tel.: +44 161 291 2154; fax: +44 161 291 2080. E-mail address: [email protected] (G.C. Moore).
obstruction syndrome. She had a past history of a right internal jugular venous thrombosis related to the insertion of a permanent venous access device and a right-sided common femoral deep vein thrombosis secondary to a temporary venous access line. On the advice of the haematology team, she was using 1.5 mg/kg subcutaneous enoxaparin daily as she had difficulty complying with the regular monitoring of INR required with previous warfarin therapy. During the admission her spirometric values worsened and she was treated with intravenous (IV) ciprofloxacin 400 mg twice daily and nebulised tobramycin. Two days after commencing ciprofloxacin her INR was 3.4 compared to a baseline INR of 1.0. This was confirmed on sending a repeat sample. In addition, the APTT was 41.2 s compared to a baseline of 22.1 s. Renal and synthetic liver function tests were normal throughout the admission. The IV ciprofloxacin was changed to IV ceftazidime. Twenty-four hours later, her INR had settled to baseline values (1.3) and her APTT was back within the normal range (26.0 s). Enoxaparin was continued in view of her prothrombotic history and she was discharged home 5 days later after her abdominal symptoms improved. The possibility of a raised INR secondary to ciprofloxacin therapy was reported via a “yellow card” system to the Medicines and Healthcare Products Regulatory Agency (MHRA).
1569-1993/$ - see front matter © 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2006.08.002
210
G.C. Moore et al. / Journal of Cystic Fibrosis 6 (2007) 209–211
2.2. Case 2
3. Discussion
An 18-year-old woman with CF and chronic P. aeruginosa infection presented to outpatients with a 1-week history of a coryzal illness and mildly increased dyspnoea. She was given a course of oral ciprofloxacin 1 g bd and rifampicin 300 mg bd. She was not taking any anticoagulant drugs and had previously tolerated this antibiotic combination without problems. Five days after starting ciprofloxacin and rifampicin she re-presented with vomiting. Blood tests revealed a markedly raised urea and creatinine (urea 17.6 mmol/l, creatinine 768 μmol/l), an INR of 2.6 and APTT of 45.1 s. These compared to baseline values of urea 3.9 mmol/l and creatinine 83 μmol/l taken 8 weeks previously. Her liver function tests were normal, paracetamol levels were undetectable and she was haemodynamically stable. There were no other clinical signs of sepsis and no organisms grown on repeated sets of blood cultures. Ciprofloxacin and rifampicin were discontinued. She was seen by the nephrologists who felt that her worsening renal function represented interstitial nephritis secondary to ciprofloxacin toxicity rather than pre-renal failure. Over the next week, she made a good clinical improvement and was monitored with daily measurements of coagulation and urea and electrolytes (Fig. 1). Her INR was normal (1.0) at discharge. At discharge urea was 15.1 mmol/ l and creatinine 265 μmol/l. These slowly returned to baseline 3 weeks after discharge. Her APTT returned to values within the normal range 72 h after the antibiotics were terminated. The incident was reported to MHRA as a complication of ciprofloxacin and rifampicin therapy.
In both cases, there was an increase in both the INR and APTT that coincided with starting ciprofloxacin that was reversible on discontinuation of the drug. This is an important side effect and has not previously been reported in patients who are not taking warfarin. On reviewing reporting of adverse drug reactions for ciprofloxacin to the MHRA [6], there are a total of 5643 adverse drug reactions reported for ciprofloxacin of which 70 were fatal. Amongst these are 34 reported cases of acute renal failure of which 3 were fatal. Four cases of acquired coagulopathy are reported, none of which were fatal. The aetiology of this picture of coagulopathy noted with ciprofloxacin is unknown. A case of factor VIII inhibitor possibly caused by ciprofloxacin has been reported [7], as has acquired transitory von Willebrand syndrome [8] and a case of prolonged bleeding time [9]. Two incidents of acquired factor V inhibition and antiphospholipid antibodies after treatment with ciprofloxacin have been reported [10]. Patients with CF tend to receive higher doses of ciprofloxacin than other patients due to enhanced activity of certain cytochrome P450 enzymes and increased renal clearance [11], and these increased doses could increase the chance of adverse drug reactions. It is also possible that both patients had borderline low levels of vitamin K due to exocrine pancreatic insufficiency related to cystic fibrosis [12] and possibly that ciprofloxacin further reduced gastrointestinal vitamin K absorption leading to a temporary vitamin K-deficient state and explaining the raised INR and APTT. We postulate that selective deficiencies of vitamin K-dependent clotting factors were a possible causative link for the coagulopathy and that factor VII in particular is implicated due to the relatively quick
Fig. 1. Trends in creatinine and INR in case 2.
G.C. Moore et al. / Journal of Cystic Fibrosis 6 (2007) 209–211
return of INR to baseline in both cases after stopping ciprofloxacin. In both patients, there were no adverse clinical consequences from the temporary prolongation of the INR. However, massive haemoptysis is a recognised complication of CF with an average annual incidence of just under 1% and a lifetime incidence of 4.1% [13]. In patients with haemoptysis, an unexpected coagulopathy could have significant clinical consequences. Unfortunately, in neither case, clotting factor assays were undertaken. If a similar effect is seen in the future, measurement of clotting factor levels would be helpful. In conclusion, we present two cases of a prolonged INR and APTT in patients with CF on ciprofloxacin therapy. In one case, the patient was on enoxaparin in view of a previous prothrombotic history and in the other case the patient also developed an interstitial nephritis. These co-morbid factors may have predisposed the patients to developing the coagulopathy that we have reported. However, in the first case, the significant rise in INR cannot be explained by longterm enoxaparin therapy and in the second case the nephritis would not explain the marked prolongation of APTT and INR. In addition, the coagulopathy reversed promptly in both cases when the ciprofloxacin was stopped. The aetiology of this mechanism is unclear and would benefit from further investigation. Due to the frequency of ciprofloxacin prescription, it is important to be aware of this potential adverse drug reaction in clinical practice in caring for patients with CF. We would encourage reporting further similarly observed reactions through MRHA in addition to measurement of clotting factor levels to enable further details regarding the aetiology of this effect to be obtained. References [1] Taccetti G, Campana S, Fastini F, Mascherini M, Doring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J Sep 2005;26(3):458–61.
211
[2] Canton R, Cobos N, de Gracia J, Baquero F, Honorato J, Gartner S, et al. Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect Sep 2005;11(9):690–703. [3] Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin–warfarin coagulopathy: a case series. Am J Hematol Jan 2000;63(1):28–31. [4] Bianco TM, Bussey HI, Farnett LE, Linn WD, Roush MK, Yong YW. Potential warfarin–ciprofloxacin interaction in patients receiving longterm anticoagulation. Pharmacotherapy 1992;12(6):435–9. [5] Fuhr U, Anders EM, Mahr G, Sorgel F, Staib AH. Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrob Agents Chemother May 1992;36 (5):942–8. [6] http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_ PAGE&nodeId=742 Accessed 05/02/06. [7] Miesbach W. Rituximab in the treatment of factor VIII inhibitor possibly caused by Ciprofloxacin. Thromb Haemost May 2005;93 (5):1001–3. [8] Castaman G, Lattuada A, Mannucci PM, Rodeghiero F. Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor. Am J Hematol May 1995;49(1):83–6. [9] Pilmore HL, Walker RJ. Prolonged bleeding time during ciprofloxacin therapy. J Clin Pharm Ther 1995;20:45–6. [10] Miesbach W, Voigt J, Peetz D, Scharrer I. Massive bleeding symptoms in two patients with factor V inhibitor and antiphospholipid antibodies after treatment with ciprofloxacin. Med Klin (Munich) Jun 15 2003;98 (6):339–43. [11] Rey E, Treluyer GM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet Oct 1998;35(4):313–29. [12] Wilson DC, Rashid M, Durie PR, Tsang A, Kalnins D, Andrew M, et al. Treatment of vitamin K deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr Jun 2001;138(6):851–5. [13] Flume PA, Yankaskas JR, Ebeling M, Hulsey T, Clark LL. Massive hemoptysis in cystic fibrosis. Chest Aug 2005;128(2):729–38.