Many cases of cutaneous vasculitis are druginduced with histology revealing leukocytoclastic vasculitis (LCV). We present a case of levofloxacin- associated LCV successfully treated with prednisone and cessation of the offending drug. Although case reports describe a link between LCV and older fluoroquinolones, such as ciprofloxacin and ofloxacin, recent reports have implicated the newer fluoroquinolone levofloxacin. Recognition of fluoroquinoloneinduced cutaneous vasculitis is important as continuation or re-exposure of the offending agent may have life-threatening consequences

Dana Blyth

Elizabeth Markelz

Jason Okulicz

Infectious Disease Reports

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[Infectious Disease Reports 2012; 4:e11] [page 35]Cutaneous leukocytoclasticvasculitis associated withlevofloxacin therapyDana M. Blyth,1 Elizabeth Markelz,2Jason F. Okulicz21Department of Internal Medicine and2Infectious Disease Service, San AntonioMilitary Medical Center, San Antonio, TX,USAAbstractMany cases of cutaneous vasculitis are drug-induced with histology revealing leukocytoclas-tic vasculitis (LCV). We present a case of lev-ofloxacin-associated LCV successfully treatedwith prednisone and cessation of the offendingdrug. Although case reports describe a linkbetween LCV and older fluoroquinolones, suchas ciprofloxacin and ofloxacin, recent reportshave implicated the newer fluoroquinolone lev-ofloxacin. Recognition of fluoroquinolone-induced cutaneous vasculitis is important ascontinuation or re-exposure of the offendingagent may have life-threatening consequences.IntroductionThe presentation of vasculitis is highly vari-able, with more severe cases resulting in hem-orrhage, ischemia, or other complicationsdepending on the degree of inflammation andto what extent the vascular architecture iscompromised.1 For cutaneous vasculitis, up to20% of cases are drug-induced with histologydemonstrating leukocytoclastic vasculitis(LCV).2 The classic presentation of cutaneousvasculitis is palpable purpura, but ranges fromerythematous lesions to deep ulcers or digitalgangrene.3 A high index of suspicion is neces-sary for diagnosis and successful treatment.The identification of drug-induced LCV is crit-ical since withdrawal of the offending agentcan be life-saving.4 We describe a case of lev-ofloxacin-associated LCV and review the perti-nent literature involving the association of flu-oroquinolones with cutaneous vasculitis. Case ReportA 64-year old man presented for evaluationof a painful, erythematous, and violaceousrash on his left leg that had developed over theprevious 24 h. The day before presentation, thepatient had completed a 5-day-course of lev-ofloxacin 500 mg twice daily for a presumedrespiratory infection. The patient had a historyof severe varicose veins in his lower extremi-ties which had led to chronic lower extremityedema after undergoing elective vein removalprocedures. Other past medical history includ-ed benign prostatic hypertrophy, erectile dys-function, and a distant history of left great toeosteomyelitis. Medications included felodipine5 mg daily, hydrochlorothiazide 25 mg daily,terazosin 1 mg daily, vardenafil 5 mg as need-ed, and the recently prescribed levofloxacin.He denied any use of over the counter orherbal medications.Patient’s vital signs on presentation werebody temperature 96.8°F, pulse 63/min, respi-ratory rate 18/min, blood pressure 155/95mmHg, and pulse oximetry 98% on room air.Examination of his left lower extremityrevealed 3-4+ pitting edema. Numerous pur-puric papules coalescing into large plaqueswere present on the medial and anterior distalleft leg with dark purple coloration centrallyand non-blanching erythema around theperiphery of the lesions. There was an approx-imately 2 cm in diameter coalesced plaque ofpalpable purpura on the proximal left lateralleg with a few small bullae centrally as well asscattered purpuric papules on the left thigh.On the dorsum of the left foot there werenumerous petechiae that were becoming con-fluent. He had significant tenderness to palpa-tion on the medial and anterior distal left leg.Several scattered purpuric papules were alsopresent on the right lower extremity. The restof his physical examination was normal. Laboratory analysis revealed white blood cellcount (WBC) 8.16¥109/L (normal range 3.4-9.8¥109/L) with 71% neutrophils (normalrange 41-73%), 20% lymphocytes (18-46%),and 1% eosinophils (0-3.2%). Hemoglobin andhematocrit were 14.1 g/dL (14-18 g/dL) and42.2% (41-52%), respectively, while plateletcount was 296¥109/L (142-362¥109/L). Hisrenal function and serum electrolytes werewithin normal limits. Since cutaneous vasculi-tis was suspected, based on clinical appear-ance of palpable purpura, diagnostic testingwas carried out to determine the etiology.Complement levels were normal and othertests for potential causes of vasculitis werealso negative, including ANA, rheumatoid fac-tor, anti-streptolysin-O, C-ANCA, P-ANCA, andtesting for hepatitis B and C. Serum proteinelectrophoresis demonstrated a normal elec-trophoresis pattern. A punch biopsy was performed (Figure 1)and was consistent with leukocytoclastic vas-culitis. Upon review of the patient’s recentmedications, levofloxacin-induced vasculitiswas suspected. After the patient confirmed thathe was no longer taking levofloxacin, he wasprescribed a 7-day course of prednisone 60 mgdaily followed by a 14-day taper. A 2-weekcourse of clindamycin was also given for possi-ble cellulitis due to bacterial super-infection ofthe area involving LCV. Fluoroquinolones wereavoided due to suspicion of levofloxacin-induced vasculitis and a concern for a potentialcross-reaction among other agents in the samedrug class. At follow up one month after his ini-tial presentation, the patient had significantimprovement in his lower extremity lesions. Inthe area of his left lower extremity with thegreatest skin involvement, a large but shallowulceration remained and was treated with localwound care. The rest of the patient’s dermato-logical manifestations had completely resolved.DiscussionAfter evaluation of the patient’s clinical his-tory and physical examination findings, adrug-induced cutaneous vasculitis was sus-pected and later confirmed by biopsy. Theinterval between the first exposure to the drugand the initial onset of symptoms can rangebetween hours and years, with onset occurringfollowing an increased dose or re-challenge. Incases of drug-induced hypersensitivity vasculi-tis, discontinuation of the offending agent isInfectious Disease Reports 2012; volume 4:e11Correspondence: Dana M. Blyth, MD, BrookeArmy Medical Center, 3851 Roger Brooke Drive,Fort Sam Houston, TX 78234-6200, USA.Tel: +1.210.916.4355 - Fax. +1.210.916-5900.E-mail: dana.m.blyth@us.af.milKey words: levofloxacin, drug induced cutaneousvasculitis, leukocytoclastic vasculitis, fluoro-quinolone.Contributions: DMB, manuscript preparation, lit-erature research; EM, images providing, case dis-cussion, manuscript review; JFO, manuscriptconception, preparation, supervision.Conflict of interest: the authors do not declareany potential conflicts of interest with this publi-cation.The views expressed in this article are those ofthe authors and do not reflect the official policy ofthe Department of the Army, the Department ofDefense, or the U. S. Government.Received for publication: 23 August 2011.Revision received: 6 November 2011.Accepted for publication: 14 November 2011.This work is licensed under a Creative CommonsAttribution NonCommercial 3.0 License (CC BY-NC 3.0).©Copyright D.M. Blyth et al., 2012Licensee PAGEPress, ItalyInfectious Disease Reports 2012; 4:e11doi:10.4081/idr.2012.e11Non-commercial use only[page 36] [Infectious Disease Reports 2012; 4:e11]usually followed by a rapid improvement insymptoms. Re-challenge is not recommendeddue to the potential of recurrence withincreased severity.2Evaluation of a patient with suspected cuta-neous vasculitis should include history, physicalexamination, and laboratory and histologicalevaluations.5 The first step in classifying thelesion is based on caliber of the vessels involved(small, medium, or large) by performing a skinbiopsy. LCV involves small vessels and punchbiopsy is the diagnostic method of choice.2Since neutrophils are replaced by lymphocytesand macrophages within 48 h after the appear-ance of a lesion, early biopsy is of highest diag-nostic yield.3 Tissue eosinophilia is also sugges-tive of a drug etiology but is not always present.Direct immunoflourescence confirms and fur-ther classifies the presence of vasculitis byidentifying specific immunoglobulins.6In drug-induced vasculitis, the offendingdrug can be hard to identify, and further labora-tory tests can be helpful. An ANCA testing ispositive in some cases of drug induced vasculi-tis, including propylthiouracil, hydralazine,allopurinol, minocycline, penicillamine, andphenytoin which may induce systemic vasculi-tis syndromes with a life-threatening visceralinvolvement.1 Our patient was not prescribedany of the above agents and ANCA testing wasnegative. According to the Naranjo adversedrug reaction probability scale with a score of6, levofloxacin was a probable cause of LCV inour case as the adverse event occurred afterthe suspected drug was administered,improved after discontinuation with additionof steroids, was proven by biopsy to be LCV, andCase ReportTable 1. Prior case reports of fluoroquinolone-associated vasculitis.Fluoroquinolone Dose Time to Other Clinical diagnosis Final diagnosis Treatment Year(FQ) symptom medications or biopsy proven PublishedonsetCiprofloxacin17 500 mg po BID 3 days None Skin biopsy Perivascular Withdrawal of FQ 1989mononuclear-cell infiltrateCiprofloxacin18 500 po mg/day 4 days Cephradine Skin biopsy LCV Withdrawal of FQ 1992Ciprofloxacin18 Unknown 10 days Diuretic Clinical diagnosis Haemorrhagic vasculitis None 1992Ciprofloxacin19 500 mg po BID 4 days Fluoxetine Clinical diagnosis Cutaneous vasculitis Withdrawal of FQ; 1997fluoxetine continuedCiprofloxacin20 Unknown 10 days None Clinical diagnosis; Cutaneous vasculitis Withdrawal of FQ; 2007subsequent renal prednisonebiopsyCiprofloxacin4 Unknown 7 days Rifampin Clinical diagnosis Drug-induced vasculitis Withdrawal of FQ; 2009rifampin given withoutrecurrenceCiprofloxacin4 Unknown 8 days Flucloxacillin Clinical diagnosis Drug hypersensitivity Withdrawal of FQ; 2009flucloxacillin continuedOfloxacin21 200 mg po BID 1 day None Skin biopsy and mast Leukocytoclastic angiitis Withdrawal of FQ; 1989cell degranulation test prednisonefor ofloxacinOfloxacin22 200 mg po BID 5 days Bumetanide, Skin biopsy Vasculitis Unknown 1989spirinolactone2 weeks priorOfloxacin23 200 mg po BID 3 days Aspirin, Skin biopsy Leukocytoclastic Withdrawal of FQ; 1995digoxin vasculitis prednisoloneOfloxacin24 200 mg po BID 3 days None Skin biopsy Leukocytoclastic angiitis Withdrawal of FQ 1996Levofloxacin25 500 mg po daily 3 days None Clinical diagnosis Nephrotoxicity and Withdrawal of FQ; 2002purpura prednisoneLevofloxacin26 500 mg po daily 5 days Azithromycine, Clinical diagnosis LCV Withdrawal of FQ; 2006piperacilline- prednisonetazobactamLevofloxacin4 Unknown 3 days Rifampin Skin biopsy LCV Withdrawal of FQ and 2009rifampin changed torifampicinLevofloxacin 500 mg po BID 5 days None Skin biopsy LCV Withdrawal of FQ; Currentprednisone caseFigure 1. Skin biopsy of left lower extremity with hematoxylin and eosin staining underA) low and B) high power demonstrating a predominant neutrophilic infiltration, pres-ence of eosinophils, and the formation of subepidermal bullae consistent with leukocyto-clastic vasculitis.  Non-commercial use only[Infectious Disease Reports 2012; 4:e11] [page 37]no other alternative causes for the reactionwere identified.7 Levofloxacin is a commonlyprescribed antibiotic and is indicated for anumber of infections, including communityacquired and nosocomial pneumonia, uncom-plicated or complicated urinary tract infectionsand pyelonephritis, acute bacterial sinusitis,acute or chronic bronchitis, as well as skin andskin structure infections.8-10Adverse events commonly associated withfluoroquinolones as a class include: gastroin-testinal and CNS toxicity, EKG abnormalitiesincluding QT prolongation, dysglycemia, pho-totoxicity, tendon and joint disorders, hyper-sensitivity reactions, and hepatotoxicity.11-13While some structural components are clearlyassociated with adverse reactions, such asphototoxicity with the addition of chlorine orfluorine at the 8-position, and CNS effectswhich are seen more commonly with theunsubstituted 7-piperazine derivatives, othersdo not appear to have any obvious structuralassociations including QT prolongation14 andtendon rupture.12 In previous studies,ciprofloxacin, ofloxacin, levofloxacin, moxi-floxacin and gatifloxacin have been associatedwith torsades de pointes.15 However, the devel-opment of torsades de pointes is likely influ-enced by multiple risk factors in a patientalready at risk.16 In other reports, ciprofloxacinhas been the predominant fluoroquinoloneassociated with cutaneous vasculitis. All reported cases of fluoroquinolone-associ-ated LCV in the literature involve ciprofloxacin,ofloxacin, and levofloxacin (Table 1). This asso-ciation may be due to structural similaritiesbetween these agents. For example, lev-ofloxacin is the L-enantiomer of ofloxacin.27Ciprofloxacin is distinguished by a cyclopropylgroup at position 1 of the molecule and hasother structural differences compared toofloxacin and levofloxacin. While ciprofloxacinhas an unsubstituted piperazine ring and lev-ofloxacin and ofloxacin have a 4-methyl piper-azine at position 7, there is great variability atposition 7 in other fluoroquinolones.28,29 Despitesome similarities in structure, the associationof LCV with ciprofloxacin, ofloxacin and lev-ofloxacin may also be attributed to their pre-dominant use in clinical practice. For all reported cases in the literature, theduration of fluoroquinolone therapy was 4-10days. Many were clinically diagnosed withouthistological confirmation, but they reveal atheme of recovery following withdrawal of theagent as seen in our case. Cutaneous vasculitismay be limited to skin which offers a betterprognosis, but can involve other organs withsmall-vessels including the kidney,30 as hasbeen reported in one case report involvingciprofloxacin20 and another involving lev-ofloxacin.26 In comparison to previous reports oflevofloxacin-induced vasculitis, our case hadseveral additional elements that may have con-tributed to the patient’s risk of developing LCV.Following review of medical records, the patienthad previously been prescribed 2 courses ofciprofloxacin, eight months and five years priorto his course of levofloxacin, with no reportedadverse effects. It is not known whether previ-ous courses of ciprofloxacin could have beensensitizing events for later development of LCVupon challenge with levofloxacin. Levofloxacinwas noted as an allergy in the patient’s medicalrecord and the patient was counseled to avoidfluoroquinolones in the future.ConclusionConsistent with previous case reports involv-ing ciprofloxacin and ofloxacin, levofloxacinwas a probable cause of LCV in our patientaccording to the Naranjo adverse drug reactionprobability scale.7 As in previous case reports,our patient had a full recovery with prednisonetreatment and withdrawal of levofloxacin.Recognition of drug-induced vasculitis is criti-cal as LCV can be life-threatening without dis-continuation of the offending agent. Review ofcurrent literature shows that LCV has beenassociated with fluoroquinolones includingciprofloxacin, ofloxacin, and levofloxacin, buthas yet to be reported in association with otheragents in the fluoroquinolone class. References1. Carlson JA, Cavaliere LF, Grant-Kels JM.Cutaneous vasculitis: diagnosis and man-agement. Clin Dermatol 2006;24:414-29.2. Chen KR, Carlson JA. Clinical approach tocutaneous vasculitis. Am J Clin Dermatol2008;9:71-92.3. Carlson JA. The histological assessment ofcutaneous vasculitis. Histopathology 2010;56:3-23.4. Maunz G, Conzett T, Zimmerli W. Cuta-neous vasculitis associated with fluoro-quinolones. Infection 2009;37:466-8.5. Gibson LE, Su WP. Cutaneous vasculitis.Rheum Dis Clin North Am 1995;21:1097-113.6. Gibson LE. Cutaneous vasculitis update.Clin Dermatol 2001;19:603-15.7. Naranjo CA, Busto U, Sellers EM. A methodfor estimating the probability of adversedrug reactions. Clin Pharmacol Ther 1981;30:239-45.8. Schaeffer AJ. The expanding role of fluoro-quinolones. Am J Med 2002;113:45S-54S.9. Garrison J, Hooton TM.  Fluoroquinolones inthe treatment of acute uncomplicated uri-nary tract infections in adult women. ExpertOpin Pharmacother 2001;2:1227-37.10. Noreddin AM, Elkhatib WF. Levofloxacin inthe treatment of community acquired pneu-monia. Expert Rev Anti Infect Ther2010;8:505-14.11. Bolon MK. The newer fluoroquinolones.Infect Dis Clin N Am 2009;23:1027–1051.12. Liu, Hans H. Safety profile of the fluoro-quinolones focus on levofloxacin. DrugSafety 2010;33:353-69.13. Owens RC, Ambrose PG. Antimicrobial safe-ty: focus on fluoroquinolones. Clin InfectDis 2005;41:S144-57.14. Ball P. Quinolone generations: natural histo-ry or natural selection? J AntimicrobChemother 2000;46:17-24.15. Frothingham R. Rates of torsades de pointesassociated with ciprofloxacin, ofloxacin, lev-ofloxacin, gatifloxacin, and moxifloxacin.Pharmacotherapy 2001;21: 1468-72.16. Owens RC, Ambrose PG. Torsades depointes associated with fluoroquinolones.Pharmacotherapy 2002; 22:663-72.17. Choe U, Rothschild BM, Laitman L.Ciprofloxacin-induced vasculitis (Letter). NEngl J Med 1989;320:257.18. Stubbings J, Sheehan-Dare R, Walton S.Cutaneous vasculitis due to ciprofloxacin.Br Med J volume 1992;305:29.19. Lieu PK, Tok SC, Ismail NH, Chng HH.Ciprofloxacin-induced cutaneous vasculitis.Allergy 1997;52:593-600.20. Storsley L, Gerldenhuys L. Ciprofloxacin-induced ANCA-negative cutaneous andrenal vasculitis-resolution with drug with-drawal. Nephrol Dial Transpl 2007;22:660-72.21. Huminer D, Cohen J, Majadla R, Dux S.Hypersensitivity vasculitis due to ofloxacin.Br Med J 1989;299:303.22. Pace JL, Gatt P. Fatal vasculitis associatedwith ofloxacin. Br Med J 1989;299:658.23. Berrin BC, Lawrence R, Sungur M, et al.Ofloxacin-induced vasculitis. InternalMedicine 1995;34:872-4.24. Pipek, Ruben, et al. Ofloxacin-induced hy-persensitivity vasculitis. Am J Med Sci 1996;311:82-3. 25. Famularo G, De Simone C. Nephrotoxicityand purpura associated with levofloxacin.Ann Pharmacother 2002;36:1380-2. 26. Zaigraykin N, Kovalev J, Elias N, Naschitz J.Levofloxacin-induced interstitial nephritisin an elderly woman. Isr Med Assoc J2006;8:726-7.27. Walker RC. The fluoroquinolones. Mayo ClinProc 1999;74:1030-7.28. Van Bambeke F, Michot JM, Tulkens PM.Quinolones in 2005: an update. ClinMicrobiol Infect. 2005;11:256-80.29. Appelbaum PC, Hunter PA. The fluoro-quinolone antibacterials: past, present, andfuture perspectives. Int J Antimicrob Agents2000;16:5-15.30. Gonzales-Gay MA, Garcia-Porrua C, PujolRM. Clinical approach to cutaneous vasculi-tis. Current Opin Rheumatol 2004;17: 56-61.Case ReportNon-commercial use oly

Cutaneous leukocytoclastic vasculitis associated with levofloxacin therapy

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Cutaneous leukocytoclastic vasculitis associated with levofloxacin therapy

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