537
Successful Treatment of Malignant External Otitis with Oral Ciprofloxacin: Report of Experience with 23 Patients R. Lang, S. Goshen, R. Kitzes-Cohen, and J. Sade
From the Infectious Diseases Unit and the Department of Otolaryngology, Meir Hospital, Kfar-Saba, the Department of Clinical Pharmacology, Hacarmel Hospital, Haifa, and the Sackler School of Medicine, Tel-Aviv University, Israel
Twenty-three consecutive patients with malignant external otitis (MEO) were treated with oral ciprofloxacin, 1.5-2.25 g/day for 6 weeks. Treatment was combined with local surgical debridement. Patients were discharged early for ambulatory follow-up. Fewminor side effects were reported, and full compliance with the study drug was observed. In 21 patients cure was achieved; in 2 the response wasnot adequate. Oral ciprofloxacin is an effective, convenient, nontoxic, economically justified alternative to the combination intravenous therapy previously advocated.
Received 18 May 1989; revised 7 September 1989. Presented in part: 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, October 1988. Informed consent was obtained from all patients. Guidelines of the Helsinki Committee of the hospital and of the Israel Department of Health were followed. Grant support: Bayer, Leverkusen, FRG. Reprints and correspondence: Dr. R. Lang, Infectious Diseases Unit, Meir Hospital, Kfar-Saba, 44281, Israel. The Journal of Infectious Diseases 1990;161:537-540 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6103-0026$01.00
oral route, prompted the present prospective open study in which patients were treated with oral ciproftoxacin for 6 weeks in combination with surgical debridement of infected tissues.
Patients and Methods Patients. The patients were evaluated and treated by the senior otolaryngology staff. Patients were included only after fulfilling the four following criteria: (1) a severe infection of the external ear canal not responsive to routine conservative local treatment of external otitis for at least 10 days; (2) signs of severe local inflammation with typical granulation tissue in the ear canal; (3) agonizing pain exacerbated at night; and (4) repeated isolation of a gram-negative pathogen, predominantly P. aeruginosa. A positive bone scan was not a necessary criterion for inclusion in the study, but if present lent support to the diagnosis. Between June 1987 and December 1988, 23 patients diagnosed with MEO were enrolled. Seven women and 16 men aged 54-92 years (mean, 72.7) fulfilled the clinical and bacteriologic criteria for MEO. Duration of disease before the present hospitalization was 7-42 days (mean, 23.8) In 12 patients, previous attempts to cure the external ear infection included removal of granulation tissue in the outpatient clinic. Fifteen patients (65.2%) had diabetes mellitus, 1 was diagnosed as preleukemia, and in 1 a foreign body was removed from the external ear. Diabetes was controlled by diet alone in 4 patients, by oral hypoglycemics in 7, and by insulin in 4. No patient with diabetes required alteration of previous treatment. Study design and laboratory methods. After documentation of local and general physical findings and laboratory data, treatment with ciproftoxacin(Ciproxin; Bayer,Leverkusen, FRO), 750 mg twice daily, was initiated. Surgery (local debridement) was performed after at least 72 h of therapy. The operation completely removed infected granulation tissue down to the bony structure. Debridement of necrotic bone and cartilage was performed when necessary. The mastoid was not routinely explored, but the middle ear or the posterior parotid region was exposed and cleaned surgically if found to be involved. Tissue specimens were taken for histologic studies and drug level determination [4]. Patients completed their initial recovery in the hospital. During their stay, serum peak and trough inhibitory and bactericidal activ-
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
Malignant external otitis (MEO) or necrotizing external otitis is a severe infection of the external ear canal usually caused by Pseudomonas aeruginosa, typically in elderly diabetic patients. The disease is most prevalent in hot, humid climates. By definition the disease progresses to affect the bony structure of the base of the skull. Eventually, if untreated, MEO involves cranial nerves and may even cause death. Until 30 years ago, MEO was almost unknown, and during the first few years after it was identified the disease was indeed malignant and patients were doomed to die in great agony. Early diagnosis, adequate surgical debridement of infected tissues, and the advent of effective intravenous anti-Pseudomonas medications [1] improved significantly the previous severe prognosis of this disease, and today cure is the rule rather than the exception. Between 1972 and 1987, the Department of Otolaryngology in Meir Hospital has gained substantial experience in the management of >75 patients affected by the disease [2]. This enabled the treating physicians to study the clinical behavior of the disease and its unique histopathologic features in detail [3]. The first successful antibiotic treatment involved 6-8 weeks of in-hospital intravenous therapy with a combination of high dose (j-lactam antibiotics and aminoglycosides, with all the cost and side effects inherent to such a regimen. The availability of the quinolones, with their excellent anti-Pseudomonas activity and effective penetration into tissues via the
538
Lang et aI.
Results Twenty-three patients were admitted for severe, uncontrolled external otitis (table 1). Diagnosis ofMEO was made before admission in 2 patients; in 21 patients the disease was defined as MEO after 1-9 days (mean, 3.4) of in-hospital observation. Most patients (22) stayed in the hospital 4-30 days (average, 16.2); 1 stayed 45 days. During hospitalization 18 patients were operated on once and 3 required repeated surgery; 2 patients required no surgery. The debridement was usually performed under general anesthesia, but in 3, debridement under local anesthesia was possible. In 3 patients, MEO in the same or contralateral ear had been diagnosed and treated previously by the same team. Technetium bone scan was positive in 16 patients (69.5 %) and negative in 7. Plain radiographs were less sensitive than bone scans. Computed tomography was performed only in the first patient who failed ciprofloxacin therapy and was normal despite a repeated positive bone scan. P. aeruginosa was repeatedly isolated from the external ear canal, alone in 20 patients and in combination with Proteus vulgaris in 1. In 1 patient only Klebsiella repeatedly grew, and in another Enterobacter and Klebsiella were isolated. The latter patient had suffered from MEO previously and had been treated with piperacillin and gentamicin, but relapsed and was enrolled in the present study. Minimum inhibitory and bactericidal concentrations of ciprofloxacin with all isolated pathogens were routinely performed, and no resistance was detected (range, 0.07-0.85 #-,glml for all strains of P. aeruginosa). The first negative culture from the external ear canal was achieved in 22 patients at 2-14 days (average, 7.04). In one patient (case 18), intensive local treatment alone resulted in eradication of P. aeruginosa: however, as all other parameters of MEO were present, he was enrolled in the study. In all patients, clinical relief of pain lagged significantly behind eradication of the pathogen and occurred at 7~42 days (average, 17.8). In 16 (69.6 %) of 23 patients, dosage and duration of ther-
apy remained unaltered until completion of 6 weeks. In 6 patients in whom disease was thought to be especially severe and initial response slow, dosage was increase to 750 mg three times daily or 1000 mg twice daily, either temporarily or until completion of treatment. In 3 patients, deliberate prolongation of therapy (2 for 52 and 1 for 57 days) was chosen in view ofa suboptimal response toward completion ofprotocol. Two patients had both increase in dosage and prolongation of therapy. Mild adverse reactions to the drug were observed (table 1). None of the side effects necessitated discontinuation of the drug. All patients complied with the drug protocol as confirmed by drug levels obtained during the weekly visit to the infectious diseases clinic [4]. Treatment failed in two patients. One patient (case 8) did not respond optimally at the completion of a full course of 42 days. Intravenous mezlocillin and gentamicin were instituted, but he developed drug fever, leukopenia, and liver damage. The treatment was changed to ceftazidime, resulting in complete disappearance of drug reactions and gradual improvement and cure of the external otitis. In an 88-year-old debilitated diabetic man, agonizing ear pain did not subside at the end of29 days oforal ciprofloxacin (759 mg three times daily) despite repeated negative cultures and improvement of inflammation of the external ear. His treatment was changed to piperacillin and gentamicin intravenously. Although pain gradually improved, the patient developed fever, severe thrombocytopenia, and renal and cardiac failure, all possibly related to drug toxicity. His subsequent death 3 weeks later from heart and renal failure was unrelated to the ear infection or the study drug. Twenty-one patients successfully completed the ambulatory protocol and obtained bacteriologic and clinical cure. Followup periods after cure for patients enrolled in 1987 are 16-25 months (mean, 21.5) and for patients enrolled in 1988 are 9-13 months (mean, 10). At present, no relapses have occurred (table 1). Discussion The introduction of effective anti-Pseudomonas drug combinations, such as extended-spectrum penicillins and aminoglycosides, caused a revolution in the management of MEO. However, high cost, prolonged hospitalization, and iatrogenic complications were inherent problems with these regimens, especially in an elderly, chronically ill population. The idea of an oral drug for the management of MEO seemed attractive. It involved, however, a fourfold change in the traditional approach to the management of MEO. First, an intravenous regimen was replaced by an oral, compliancedependent protocol. Second, MEO, an osteomyelitis of the base of the skull, was treated via the oral rather than the traditional intravenous route. Third, two-drug therapy was replaced by monotherapy with the increased risk of development of
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
ity against the last isolated pathogen was determined. Laboratory tests including sedimentation rate and complete blood count, and renal and liver function tests were routinely performed. Minimum inhibitory concentrations of ciproftoxacin were tested with all pathogens isolated from the ear. Patients were discharged to ambulatory follow-up on healing of the local ear lesion and lessening of pain. The ambulatory protocol included twice-weekly visits to the outpatient otolaryngology clinic for evaluation of the external ear and once-weekly visits to the infectious diseases clinic, in which the patients were interviewed for adverse drug reactions and a complete laboratory work-up was performed. Patients reported their last intake of drug, and serum specimens were sent for drug level analysis as a strict measure of compliance control [4]. At all stages of the study, the progress of the patient, changes in drug dosage or duration of therapy, and cross-over to traditional intravenous regimens were discussed between the otolaryngology senior staff and the infectious diseases consultant.
JID 1990;161 (March)
JlD 1990;161 (March)
Table 1.
539
Ciprofloxacin in Malignant Otitis
Admission data and response to ciprofloxacin therapy in patients with malignant external otitis.
Risk factors, therapy for diabetes
1 (73, F) 2 (67, M) 3 (64, F) 4 (60, F) 5 (78, F) 6 (59, M) 7 (90, F) 8 (54, M)
None Diabetes, diet Preleukemia Diabetes, insulin Diabetes, oral drugs Diabetes, insulin None Diabetes, oral drugs
9 (80, F) 10 (75, M) 11 (92, M) 12 (67, M) 13 (74, F) 14 (69, M) 15 (73, M) 16 (66, M)
None Diabetes, None Diabetes, None Diabetes, Diabetes, Diabetes,
17 (61, M) 18 (68, M) 19 (88, M) 20 (68, M) 21 (83, M) 22 (86, M) 23 (76, M)
Foreign body Diabetes, oral drugs Diabetes, diet Diabetes, insulin Diabetes, oral drugs Diabetes, insulin Diabetes, oral drugs
oral drugs
21 7 20 40
21 21 21 40
30 30 7
diet
30 21
diet oral drugs diet
10
20 30 12 30 30 42 40 10
14
+ + + + + + + + + + + + + + + +
Pathogen
4 4
PA PA PA PA KO PA PA PA
11
14 10 2 8 6
13 14 7 23 20
19 30 4 6 21
10
10 13
9 42
PA PA, PV PA PA PA EC,KO PA PA
2 1 0 1 1 2 1 1
14 12 6 4 5 3 4 6
19 20 10 26t lOt 42t 16 18t
PA PA PA PA PA PA PA
1 0 2 1 1 1 1
4 -4 8 12 5 8 5
10
8 29t 20
14 20 17 30 19 14
42 44
42 42 42 42 42 42 42 57* 42 42 40
10
52*
14 26
44
12 14 45 20
13
13
12 30t
12 18
42 42 42 29 42 42 42 52*
Adverse drug effects None None None None None None None Restlessness, headache None Constipation None None None None None Nausea, vertigo None None None None None None None
Outcome
Follow-up (mo)
Cure Cure Cure Cure Cure Cure Cure Failure
25 24 22 22 22 22 22 20
Cure Cure Cure Cure Cure Cure Cure Cure
22 22 21 20 16
Cure Cure Failure Cure Cure Cure Cure
12
13 13
12
11 Died 10 10 10
9
NOTE. PA = Pseudomonas aeruginosa, KO = Klebsiella oxytoca, PV = Proteus vulgaris, EC = Enterobacter cloacae. * Prolongation of therapy. t Dosage increase.
resistance to the drug. Fourth, the disease became mainly ambulatory, thus omitting from the management the important component of continuous in-hospital supervision. Twenty-three patients were eligible for the study. In two, the local inflammatory findings did not mandate surgery under general anesthesia. In both cases, all inclusion criteria were satisfied and bone scans were positive. Of the 23 patients, 21 responded well to ciprofloxacin therapy without important side effects or laboratory abnormalities and had not relapsed by 9-25 months of follow-up. One patient failed and benefitted from cross-over to the traditional regimen despite drug side effects. In this patient, a relatively young (54 years) diabetic man, low trough levels of ciprofloxacin (0.06-0.07 pg/ml) were measured on an inhospital pharmacokinetic study performed on treatment day 7. This may have accounted for the poor response. Dosage increase was introduced into the study in view of the experience with this patient. Another patient with severe atherosclerotic heart disease
and peripheral vascular disease responded suboptimally to the study drug. In this man, drug levels measured twice intraoperatively were: serum, 1.6 and 1.8 J-tg/ml; granulation tissue, 8.4 and 5.8 J-tg/ml; cartilage, 9.0 and 4.4 J-tg/ml; and bone, 1.3 J-tg/ml. All ciprofloxacin levels measured in all specimens were >1.2 J-tg/ml; while minimum inhibitory concentrations of ciprofloxacin with all isolates of P. aeruginosa were 0.05 J-tg/ml. Failure in this patient cannot be explained by these data alone. The patient died with renal and cardiac failure and bone marrow suppression as a complication of intravenous combination therapy. Our data clearly demonstrate that oral ciprofloxacin is an effective therapy for the treatment of MEa. A full therapeutic course can be completed with minimal hospitalization and, therefore, significantly lower cost. The present protocol is associated with significantly fewer iatrogenic complications than two-drug therapy with an extended-spectrum penicillin and an aminoglycoside and is much more convenient for the patients. These advantages especially should be emphasized in
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
Case no. (age, gender)
Duration of disease before treatment Bone (d) scan
Days between start of therapy and Duration Surgery eradica- Clinical Hospital of (no. of tion of response stay therapy (d) times) pathogen (d) (d)
540
Lang et al.
References 1. Chandler IR. Pathogenesisand treatment of facial paralysis die to malignant external otitis. Ann Otol Rhinol Laryngol 1972;81:648-658
2. Babiatzki A, Sade 1. Malignant external otitis. 1 Laryngol Otol 1987; 101:205-210 3. Bernheim 1, Sade 1. Histopathology of the soft parts in 50 patients with malignant external otitis. 1 Laryngol Otol 1989;103:366-368 4. Kitzes-Cohen R, Lang R, Frumennan I, Goshen S, Sade 1. Pharmacokinetics of oral ciproftoxacinein patients with malignant external otitis (abstract 1372). In: Program and abstracts of the 16th International Congress of Chemotherapy, Jerusalem, 1989 5. Kraus DH, Rehm 81, Kinney SE. The evolvingtreatment of necrotizing external otitis. Laryngoscope 1988;98:934-939 6. Murphy RL, Phair IP, Daikos GL. Oral ciproftoxacin in patients with malignant external otitis (MEO) (abstract 131). In: Program and abstracts of the 2nd InternationalCongress on New Quinolones, Geneva, 1988 7. Giamarellu M, Galanakis N, Christidis K, Dokianakis G. Malignant external otitis and newer quinolones (abstract 133). In: Program and abstracts of the 2nd InternationalCongress on New Quinolones, Geneva, 1988 8. Sabater F, Mensa J, Domenech J, Lonca M, Carulla M. Necrotizing external otitis treated with ciproftoxacin. J Laryngol Otol 1988;102: 606-607 9. Rubin 1, YuVL. Malignantexternalotitis: insightsintopathogenesis,clinical manifestations, diagnosisandtherapy. Am 1 Moo 1988;85:391-398
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
view of a report published in 1988 that still strongly advocated the traditional intravenous regimen as the only mode of therapy and included a suggestion for home intravenous therapy for some patients in order to shorten hospitalization and minimize nosocomial complications [5]. In viewof our results and thosein other preliminary reports [6-9], weconcludethat MEO shouldbe treatedwith ciprofloxacin under close medical supervision. Most patients will benefit from 6 weeks of oral ciprofloxacin, 1.5 g/day. However, both dosage and duration of therapy must be individually tailored to the clinical course, bearing in mind that the alleviationof symptomslags considerablybehind the bacteriologiceradicationof the infecting organismfrom the external ear canal. When more experience is gained with ciprofloxacin and MEO, we hope to achievea further reduction in hospitalization and treat the disease mainly as an ambulatory condition.
110 1990;161 (March)
Successful Treatment of Malignant External Otitis with Oral Ciprofloxacin: Report of Experience with 23 Patients R. Lang, S. Goshen, R. Kitzes-Cohen, and J. Sade
From the Infectious Diseases Unit and the Department of Otolaryngology, Meir Hospital, Kfar-Saba, the Department of Clinical Pharmacology, Hacarmel Hospital, Haifa, and the Sackler School of Medicine, Tel-Aviv University, Israel
Twenty-three consecutive patients with malignant external otitis (MEO) were treated with oral ciprofloxacin, 1.5-2.25 g/day for 6 weeks. Treatment was combined with local surgical debridement. Patients were discharged early for ambulatory follow-up. Fewminor side effects were reported, and full compliance with the study drug was observed. In 21 patients cure was achieved; in 2 the response wasnot adequate. Oral ciprofloxacin is an effective, convenient, nontoxic, economically justified alternative to the combination intravenous therapy previously advocated.
Received 18 May 1989; revised 7 September 1989. Presented in part: 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, October 1988. Informed consent was obtained from all patients. Guidelines of the Helsinki Committee of the hospital and of the Israel Department of Health were followed. Grant support: Bayer, Leverkusen, FRG. Reprints and correspondence: Dr. R. Lang, Infectious Diseases Unit, Meir Hospital, Kfar-Saba, 44281, Israel. The Journal of Infectious Diseases 1990;161:537-540 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6103-0026$01.00
oral route, prompted the present prospective open study in which patients were treated with oral ciproftoxacin for 6 weeks in combination with surgical debridement of infected tissues.
Patients and Methods Patients. The patients were evaluated and treated by the senior otolaryngology staff. Patients were included only after fulfilling the four following criteria: (1) a severe infection of the external ear canal not responsive to routine conservative local treatment of external otitis for at least 10 days; (2) signs of severe local inflammation with typical granulation tissue in the ear canal; (3) agonizing pain exacerbated at night; and (4) repeated isolation of a gram-negative pathogen, predominantly P. aeruginosa. A positive bone scan was not a necessary criterion for inclusion in the study, but if present lent support to the diagnosis. Between June 1987 and December 1988, 23 patients diagnosed with MEO were enrolled. Seven women and 16 men aged 54-92 years (mean, 72.7) fulfilled the clinical and bacteriologic criteria for MEO. Duration of disease before the present hospitalization was 7-42 days (mean, 23.8) In 12 patients, previous attempts to cure the external ear infection included removal of granulation tissue in the outpatient clinic. Fifteen patients (65.2%) had diabetes mellitus, 1 was diagnosed as preleukemia, and in 1 a foreign body was removed from the external ear. Diabetes was controlled by diet alone in 4 patients, by oral hypoglycemics in 7, and by insulin in 4. No patient with diabetes required alteration of previous treatment. Study design and laboratory methods. After documentation of local and general physical findings and laboratory data, treatment with ciproftoxacin(Ciproxin; Bayer,Leverkusen, FRO), 750 mg twice daily, was initiated. Surgery (local debridement) was performed after at least 72 h of therapy. The operation completely removed infected granulation tissue down to the bony structure. Debridement of necrotic bone and cartilage was performed when necessary. The mastoid was not routinely explored, but the middle ear or the posterior parotid region was exposed and cleaned surgically if found to be involved. Tissue specimens were taken for histologic studies and drug level determination [4]. Patients completed their initial recovery in the hospital. During their stay, serum peak and trough inhibitory and bactericidal activ-
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
Malignant external otitis (MEO) or necrotizing external otitis is a severe infection of the external ear canal usually caused by Pseudomonas aeruginosa, typically in elderly diabetic patients. The disease is most prevalent in hot, humid climates. By definition the disease progresses to affect the bony structure of the base of the skull. Eventually, if untreated, MEO involves cranial nerves and may even cause death. Until 30 years ago, MEO was almost unknown, and during the first few years after it was identified the disease was indeed malignant and patients were doomed to die in great agony. Early diagnosis, adequate surgical debridement of infected tissues, and the advent of effective intravenous anti-Pseudomonas medications [1] improved significantly the previous severe prognosis of this disease, and today cure is the rule rather than the exception. Between 1972 and 1987, the Department of Otolaryngology in Meir Hospital has gained substantial experience in the management of >75 patients affected by the disease [2]. This enabled the treating physicians to study the clinical behavior of the disease and its unique histopathologic features in detail [3]. The first successful antibiotic treatment involved 6-8 weeks of in-hospital intravenous therapy with a combination of high dose (j-lactam antibiotics and aminoglycosides, with all the cost and side effects inherent to such a regimen. The availability of the quinolones, with their excellent anti-Pseudomonas activity and effective penetration into tissues via the
538
Lang et aI.
Results Twenty-three patients were admitted for severe, uncontrolled external otitis (table 1). Diagnosis ofMEO was made before admission in 2 patients; in 21 patients the disease was defined as MEO after 1-9 days (mean, 3.4) of in-hospital observation. Most patients (22) stayed in the hospital 4-30 days (average, 16.2); 1 stayed 45 days. During hospitalization 18 patients were operated on once and 3 required repeated surgery; 2 patients required no surgery. The debridement was usually performed under general anesthesia, but in 3, debridement under local anesthesia was possible. In 3 patients, MEO in the same or contralateral ear had been diagnosed and treated previously by the same team. Technetium bone scan was positive in 16 patients (69.5 %) and negative in 7. Plain radiographs were less sensitive than bone scans. Computed tomography was performed only in the first patient who failed ciprofloxacin therapy and was normal despite a repeated positive bone scan. P. aeruginosa was repeatedly isolated from the external ear canal, alone in 20 patients and in combination with Proteus vulgaris in 1. In 1 patient only Klebsiella repeatedly grew, and in another Enterobacter and Klebsiella were isolated. The latter patient had suffered from MEO previously and had been treated with piperacillin and gentamicin, but relapsed and was enrolled in the present study. Minimum inhibitory and bactericidal concentrations of ciprofloxacin with all isolated pathogens were routinely performed, and no resistance was detected (range, 0.07-0.85 #-,glml for all strains of P. aeruginosa). The first negative culture from the external ear canal was achieved in 22 patients at 2-14 days (average, 7.04). In one patient (case 18), intensive local treatment alone resulted in eradication of P. aeruginosa: however, as all other parameters of MEO were present, he was enrolled in the study. In all patients, clinical relief of pain lagged significantly behind eradication of the pathogen and occurred at 7~42 days (average, 17.8). In 16 (69.6 %) of 23 patients, dosage and duration of ther-
apy remained unaltered until completion of 6 weeks. In 6 patients in whom disease was thought to be especially severe and initial response slow, dosage was increase to 750 mg three times daily or 1000 mg twice daily, either temporarily or until completion of treatment. In 3 patients, deliberate prolongation of therapy (2 for 52 and 1 for 57 days) was chosen in view ofa suboptimal response toward completion ofprotocol. Two patients had both increase in dosage and prolongation of therapy. Mild adverse reactions to the drug were observed (table 1). None of the side effects necessitated discontinuation of the drug. All patients complied with the drug protocol as confirmed by drug levels obtained during the weekly visit to the infectious diseases clinic [4]. Treatment failed in two patients. One patient (case 8) did not respond optimally at the completion of a full course of 42 days. Intravenous mezlocillin and gentamicin were instituted, but he developed drug fever, leukopenia, and liver damage. The treatment was changed to ceftazidime, resulting in complete disappearance of drug reactions and gradual improvement and cure of the external otitis. In an 88-year-old debilitated diabetic man, agonizing ear pain did not subside at the end of29 days oforal ciprofloxacin (759 mg three times daily) despite repeated negative cultures and improvement of inflammation of the external ear. His treatment was changed to piperacillin and gentamicin intravenously. Although pain gradually improved, the patient developed fever, severe thrombocytopenia, and renal and cardiac failure, all possibly related to drug toxicity. His subsequent death 3 weeks later from heart and renal failure was unrelated to the ear infection or the study drug. Twenty-one patients successfully completed the ambulatory protocol and obtained bacteriologic and clinical cure. Followup periods after cure for patients enrolled in 1987 are 16-25 months (mean, 21.5) and for patients enrolled in 1988 are 9-13 months (mean, 10). At present, no relapses have occurred (table 1). Discussion The introduction of effective anti-Pseudomonas drug combinations, such as extended-spectrum penicillins and aminoglycosides, caused a revolution in the management of MEO. However, high cost, prolonged hospitalization, and iatrogenic complications were inherent problems with these regimens, especially in an elderly, chronically ill population. The idea of an oral drug for the management of MEO seemed attractive. It involved, however, a fourfold change in the traditional approach to the management of MEO. First, an intravenous regimen was replaced by an oral, compliancedependent protocol. Second, MEO, an osteomyelitis of the base of the skull, was treated via the oral rather than the traditional intravenous route. Third, two-drug therapy was replaced by monotherapy with the increased risk of development of
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
ity against the last isolated pathogen was determined. Laboratory tests including sedimentation rate and complete blood count, and renal and liver function tests were routinely performed. Minimum inhibitory concentrations of ciproftoxacin were tested with all pathogens isolated from the ear. Patients were discharged to ambulatory follow-up on healing of the local ear lesion and lessening of pain. The ambulatory protocol included twice-weekly visits to the outpatient otolaryngology clinic for evaluation of the external ear and once-weekly visits to the infectious diseases clinic, in which the patients were interviewed for adverse drug reactions and a complete laboratory work-up was performed. Patients reported their last intake of drug, and serum specimens were sent for drug level analysis as a strict measure of compliance control [4]. At all stages of the study, the progress of the patient, changes in drug dosage or duration of therapy, and cross-over to traditional intravenous regimens were discussed between the otolaryngology senior staff and the infectious diseases consultant.
JID 1990;161 (March)
JlD 1990;161 (March)
Table 1.
539
Ciprofloxacin in Malignant Otitis
Admission data and response to ciprofloxacin therapy in patients with malignant external otitis.
Risk factors, therapy for diabetes
1 (73, F) 2 (67, M) 3 (64, F) 4 (60, F) 5 (78, F) 6 (59, M) 7 (90, F) 8 (54, M)
None Diabetes, diet Preleukemia Diabetes, insulin Diabetes, oral drugs Diabetes, insulin None Diabetes, oral drugs
9 (80, F) 10 (75, M) 11 (92, M) 12 (67, M) 13 (74, F) 14 (69, M) 15 (73, M) 16 (66, M)
None Diabetes, None Diabetes, None Diabetes, Diabetes, Diabetes,
17 (61, M) 18 (68, M) 19 (88, M) 20 (68, M) 21 (83, M) 22 (86, M) 23 (76, M)
Foreign body Diabetes, oral drugs Diabetes, diet Diabetes, insulin Diabetes, oral drugs Diabetes, insulin Diabetes, oral drugs
oral drugs
21 7 20 40
21 21 21 40
30 30 7
diet
30 21
diet oral drugs diet
10
20 30 12 30 30 42 40 10
14
+ + + + + + + + + + + + + + + +
Pathogen
4 4
PA PA PA PA KO PA PA PA
11
14 10 2 8 6
13 14 7 23 20
19 30 4 6 21
10
10 13
9 42
PA PA, PV PA PA PA EC,KO PA PA
2 1 0 1 1 2 1 1
14 12 6 4 5 3 4 6
19 20 10 26t lOt 42t 16 18t
PA PA PA PA PA PA PA
1 0 2 1 1 1 1
4 -4 8 12 5 8 5
10
8 29t 20
14 20 17 30 19 14
42 44
42 42 42 42 42 42 42 57* 42 42 40
10
52*
14 26
44
12 14 45 20
13
13
12 30t
12 18
42 42 42 29 42 42 42 52*
Adverse drug effects None None None None None None None Restlessness, headache None Constipation None None None None None Nausea, vertigo None None None None None None None
Outcome
Follow-up (mo)
Cure Cure Cure Cure Cure Cure Cure Failure
25 24 22 22 22 22 22 20
Cure Cure Cure Cure Cure Cure Cure Cure
22 22 21 20 16
Cure Cure Failure Cure Cure Cure Cure
12
13 13
12
11 Died 10 10 10
9
NOTE. PA = Pseudomonas aeruginosa, KO = Klebsiella oxytoca, PV = Proteus vulgaris, EC = Enterobacter cloacae. * Prolongation of therapy. t Dosage increase.
resistance to the drug. Fourth, the disease became mainly ambulatory, thus omitting from the management the important component of continuous in-hospital supervision. Twenty-three patients were eligible for the study. In two, the local inflammatory findings did not mandate surgery under general anesthesia. In both cases, all inclusion criteria were satisfied and bone scans were positive. Of the 23 patients, 21 responded well to ciprofloxacin therapy without important side effects or laboratory abnormalities and had not relapsed by 9-25 months of follow-up. One patient failed and benefitted from cross-over to the traditional regimen despite drug side effects. In this patient, a relatively young (54 years) diabetic man, low trough levels of ciprofloxacin (0.06-0.07 pg/ml) were measured on an inhospital pharmacokinetic study performed on treatment day 7. This may have accounted for the poor response. Dosage increase was introduced into the study in view of the experience with this patient. Another patient with severe atherosclerotic heart disease
and peripheral vascular disease responded suboptimally to the study drug. In this man, drug levels measured twice intraoperatively were: serum, 1.6 and 1.8 J-tg/ml; granulation tissue, 8.4 and 5.8 J-tg/ml; cartilage, 9.0 and 4.4 J-tg/ml; and bone, 1.3 J-tg/ml. All ciprofloxacin levels measured in all specimens were >1.2 J-tg/ml; while minimum inhibitory concentrations of ciprofloxacin with all isolates of P. aeruginosa were 0.05 J-tg/ml. Failure in this patient cannot be explained by these data alone. The patient died with renal and cardiac failure and bone marrow suppression as a complication of intravenous combination therapy. Our data clearly demonstrate that oral ciprofloxacin is an effective therapy for the treatment of MEa. A full therapeutic course can be completed with minimal hospitalization and, therefore, significantly lower cost. The present protocol is associated with significantly fewer iatrogenic complications than two-drug therapy with an extended-spectrum penicillin and an aminoglycoside and is much more convenient for the patients. These advantages especially should be emphasized in
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 12, 2015
Case no. (age, gender)
Duration of disease before treatment Bone (d) scan
Days between start of therapy and Duration Surgery eradica- Clinical Hospital of (no. of tion of response stay therapy (d) times) pathogen (d) (d)
540
Lang et al.
References 1. Chandler IR. Pathogenesisand treatment of facial paralysis die to malignant external otitis. Ann Otol Rhinol Laryngol 1972;81:648-658
2. Babiatzki A, Sade 1. Malignant external otitis. 1 Laryngol Otol 1987; 101:205-210 3. Bernheim 1, Sade 1. Histopathology of the soft parts in 50 patients with malignant external otitis. 1 Laryngol Otol 1989;103:366-368 4. Kitzes-Cohen R, Lang R, Frumennan I, Goshen S, Sade 1. Pharmacokinetics of oral ciproftoxacinein patients with malignant external otitis (abstract 1372). In: Program and abstracts of the 16th International Congress of Chemotherapy, Jerusalem, 1989 5. Kraus DH, Rehm 81, Kinney SE. The evolvingtreatment of necrotizing external otitis. Laryngoscope 1988;98:934-939 6. Murphy RL, Phair IP, Daikos GL. Oral ciproftoxacin in patients with malignant external otitis (MEO) (abstract 131). In: Program and abstracts of the 2nd InternationalCongress on New Quinolones, Geneva, 1988 7. Giamarellu M, Galanakis N, Christidis K, Dokianakis G. Malignant external otitis and newer quinolones (abstract 133). In: Program and abstracts of the 2nd InternationalCongress on New Quinolones, Geneva, 1988 8. Sabater F, Mensa J, Domenech J, Lonca M, Carulla M. Necrotizing external otitis treated with ciproftoxacin. J Laryngol Otol 1988;102: 606-607 9. Rubin 1, YuVL. Malignantexternalotitis: insightsintopathogenesis,clinical manifestations, diagnosisandtherapy. Am 1 Moo 1988;85:391-398
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view of a report published in 1988 that still strongly advocated the traditional intravenous regimen as the only mode of therapy and included a suggestion for home intravenous therapy for some patients in order to shorten hospitalization and minimize nosocomial complications [5]. In viewof our results and thosein other preliminary reports [6-9], weconcludethat MEO shouldbe treatedwith ciprofloxacin under close medical supervision. Most patients will benefit from 6 weeks of oral ciprofloxacin, 1.5 g/day. However, both dosage and duration of therapy must be individually tailored to the clinical course, bearing in mind that the alleviationof symptomslags considerablybehind the bacteriologiceradicationof the infecting organismfrom the external ear canal. When more experience is gained with ciprofloxacin and MEO, we hope to achievea further reduction in hospitalization and treat the disease mainly as an ambulatory condition.
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