Vol. 34, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1990, p. 849-852
0066-4804/90/050849-04$02.00/0 Copyright © 1990, American Society for Microbiology
Oral Ciprofloxacin Treatment of Pseudomonas aeruginosa Osteomyelitis MICHAEL DAN,'* YARDENA SIEGMAN-IGRA,2 SILVIO PITLIK,3 AND RAUL RAZ4 The E. Wolfson Hospital, Holon 58100,1 Tel Aviv Medical Center, Tel Aviv,2 Beilinson Medical Center, Petah Tikva,3 and HaEmek Hospital, Afula,4 Israel Received 26 May 1989/Accepted 16 February 1990
Twenty-two adult patients with osteomyelitis due to Pseudomonas aeruginosa were enrolled in an open, prospective cooperative study to determine the efficacy of oral ciprofloxacin therapy in a dosage of 750 mg twice a day. Twenty patients received a complete course of treatment and could be assessed for efficacy. There were 12 men and 8 women, with a mean age of 55 years. Six patients had undergone previous, unsuccessful attempts at therapy. Eight patients had clinically important underlying conditions. The most common sites of infection were the sternum (six patients), hip (four patients), vertebrae (four patients), and tibia (two patients). Initial surgical debridement was performed in 18 of the 20 assessable patients. The mean duration of treatment was 2.85 months (range, 1 to 4 months), and that of the follow-up was 27 months (range, 6 to 52 months). Cure was achieved in 19 of the 20 (95%) patients. The only significant adverse effect (which prompted discontinuation of therapy) was severe nausea in one case. Oral ciprofloxacin coupled with adequate debridement is an effective, convenient, and safe therapy in patients with acute and subacute P. aeruginosa osteomyelitis.
Tel Aviv; E. Wolfson Hospital, Holon; Beilinson Medical Center, Petah Tikva; and HaEmek Hospital, Afula), were eligible for inclusion in the protocol. We excluded patients under 12 years of age, pregnant women, patients allergic to carboxyquinolones, and patients with advanced renal or liver impairment (serum creatinine, >2.0 mg/dl; serum glutamic pyruvic transaminase, >200 IU/liter). Initially only patients for whom standard therapy for P. aeruginosa infection failed were enrolled (six patients). The diagnosis of osteomyelitis was made by clinical presentation, radiographic or radionucleic scan evidence, and bacteriological confirmation. Pretherapy specimens for culture were obtained by bone aspiration or biopsy at the time of orthopedic surgery. Blood specimens for culture were drawn from all febrile patients. P. aeruginosa was identified by standard methods (11). The in vitro susceptibilities of the isolates to ciprofloxacin were determined by the KirbyBauer disk diffusion technique (2) or by MIC determination by the macrodilution tube method. Patients were treated orally with 750 mg of ciprofloxacin every 12 h. No other antibiotics were given concomitantly. The duration of ciprofloxacin administration in assessable patients ranged from 1 to 4 months. Adjunctive surgical drainage and debridement were performed in most patients. Patients were monitored throughout the course of treatment for drug safety. This included periodic physical examinations and blood tests for evidence of hematologic, renal, or hepatic abnormalities. The efficacy of ciprofloxacin therapy was assessed during and following treatment. Patients were monitored for at least 6 months after the termination of drug administration. Cure was defined as the disappearance of all signs and symptoms related to the infection, normalization of the erythrocyte sedimentation rate, and eradication of the infecting organism with no relapse during the period of follow-up. Clinical improvement was noted when signs of infection regressed but complete resolution was not achieved; failure was defined as the absence of any substantial improvement of symptoms and signs.
Gram-negative bacillary osteomyelitis represents a real therapeutic challenge. Its management consists of a combined medical and surgical approach, including adequate surgical debridement of necrotic bone, removal of metal appliances, and prolonged parenteral administration of an antibacterial agent active against the causative organism (14). Osteomyelitis due to Pseudomonas aeruginosa is particularly difficult to treat because of the restricted arsenal of potent antibiotics and the ease with which the organism may develop drug resistance during therapy. The current therapeutic standard is intravenous administration of a combination of an aminoglycoside and an antipseudomonal penicillin for 4 to 6 weeks (16). Since aminoglycosides are associated with nephro- and ototoxicity and therapeutic concentrations are difficult to predict, the drug levels in the sera of patients receiving the agents should be monitored. It is not surprising, therefore, that there has been marked interest in the development of effective agents that can be given safely on an ambulatory basis. Ciprofloxacin was effective in the treatment of P. aeruginosa infection in animal models of pneumonia and osteomyelitis (15, 20). On the basis of these data, we elected to study the efficacy and safety of orally administered ciprofloxacin in the treatment of P. aeruginosa osteomyelitis. We used an open, noncomparative trial because of the lack of alternative oral antipseudomonal agents and because the drug was given initially on a compassionate basis after failure of standard therapy. (A part of this work was presented at the International Congress of Infectious Diseases, Rio de Janeiro, Brazil, April 1988.) MATERIALS AND METHODS Patients with bacteriological proof of osteomyelitis caused by ciprofloxacin-susceptible P. aeruginosa, seen at one of four medical institutions in Israel (Tel Aviv Medical Center, *
Corresponding author. 849
850
DAN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Characteristics of 22 patients with P. aeruginosa osteomyelitis receiving oral ciprofloxacin therapy
Patient
Symptom duration before
no.
Age (yr)Isexa
1 2 3 4
72/F 53/M 59/M 64/M
Spine Spine Spine Sternum
9 wk 1 yr 8 wk 12 wk
+/+ +/+ +/+ ND
5
58/M
Sternum
16 wk
ND
Hip Ribs Hip (prosthesis) Hip (prosthesis), spine Calcaneus Hip (prosthesis) Sternum Sternum, clavicle Tibia Sternum Femur Tibia Sternum
10 mo 5 wk 2 wk 9 wk 6 wk 4 wk 2 wk 10 wk 12 mo 10 wk
ND ND
6 36/M 7 64/F 8 65/F 9 76/F 10 18/M 11 81/F 12 72/M 13 62/F 14 36/F 15 67/M 16 63/M 17 22/M 18 59/M 19 53/M 20 15/M 21 47/M 22 84/M a M, Male; F, female. b
Affected bone(s)
Sternum Calcaneus Metatarsus Tibia
themapy
NRC 4 wk 6 wk 2 wk 2 wk 3 wk 4 wk
Bone ray/scan
+/ND ND/+ +/ND +/ND +/ND ND +/ND ND +/+ +/ND +/ND +/ND +/ND +/ND -/+
. Surscal
Duration of ciprofloxacin
proedure(s)
therapy (wk)
Duration follow-upof (mo)/outcome
None Debridement None Debridement, muscle flap Debridement, muscle flap Removal of prosthesis Debridement Removal of prosthesis None Debridement Removal of prosthesis Debridement Debridement Removal of plate Debridement None Debridement None None Debridement Debridement Bone biopsy
8 16 12 12
46/cure 52/cure 26/cure 37/cure
10
18/cure
16 12 16 12 4 12 12 12 14 12 12 8 12 16 4
32/cure 26/cure 26/cure 29/cure 23/cure 23/cure 26/cure 26/cure 22/failure 27/cure 17/cure NR/cure 25/cure 25/cure 6/cure Loss Deathe
2d 4
+, Positive finding; -, negative finding; ND, not done.
c NR, Not reported. d Treatment discontinued after 2 e Death due to unrelated cause.
days (see text).
RESULTS Of the 22 patients initially enrolled, 20 could be assessed for response to therapy (Table 1). The two who could not be evaluated included a 47-year-old patient with a metatarsal infection who developed severe nausea after ciprofloxacin treatment was initiated and refused to continue the treatment and an 84-year-old man with advanced ischemic heart disease who died suddenly 4 weeks after treatment had been initiated for tibial osteomyelitis and marked clinical improvement had been noted. Twenty patients met all criteria for evaluation; 12 were men and 8 were women. Their ages ranged from 14 to 84 years, with a mean of 55 years. The mean duration of symptoms before ciprofloxacin therapy was initiated was 4 months, with a range of 0.5 to 13 months (
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1990, p. 849-852
0066-4804/90/050849-04$02.00/0 Copyright © 1990, American Society for Microbiology
Oral Ciprofloxacin Treatment of Pseudomonas aeruginosa Osteomyelitis MICHAEL DAN,'* YARDENA SIEGMAN-IGRA,2 SILVIO PITLIK,3 AND RAUL RAZ4 The E. Wolfson Hospital, Holon 58100,1 Tel Aviv Medical Center, Tel Aviv,2 Beilinson Medical Center, Petah Tikva,3 and HaEmek Hospital, Afula,4 Israel Received 26 May 1989/Accepted 16 February 1990
Twenty-two adult patients with osteomyelitis due to Pseudomonas aeruginosa were enrolled in an open, prospective cooperative study to determine the efficacy of oral ciprofloxacin therapy in a dosage of 750 mg twice a day. Twenty patients received a complete course of treatment and could be assessed for efficacy. There were 12 men and 8 women, with a mean age of 55 years. Six patients had undergone previous, unsuccessful attempts at therapy. Eight patients had clinically important underlying conditions. The most common sites of infection were the sternum (six patients), hip (four patients), vertebrae (four patients), and tibia (two patients). Initial surgical debridement was performed in 18 of the 20 assessable patients. The mean duration of treatment was 2.85 months (range, 1 to 4 months), and that of the follow-up was 27 months (range, 6 to 52 months). Cure was achieved in 19 of the 20 (95%) patients. The only significant adverse effect (which prompted discontinuation of therapy) was severe nausea in one case. Oral ciprofloxacin coupled with adequate debridement is an effective, convenient, and safe therapy in patients with acute and subacute P. aeruginosa osteomyelitis.
Tel Aviv; E. Wolfson Hospital, Holon; Beilinson Medical Center, Petah Tikva; and HaEmek Hospital, Afula), were eligible for inclusion in the protocol. We excluded patients under 12 years of age, pregnant women, patients allergic to carboxyquinolones, and patients with advanced renal or liver impairment (serum creatinine, >2.0 mg/dl; serum glutamic pyruvic transaminase, >200 IU/liter). Initially only patients for whom standard therapy for P. aeruginosa infection failed were enrolled (six patients). The diagnosis of osteomyelitis was made by clinical presentation, radiographic or radionucleic scan evidence, and bacteriological confirmation. Pretherapy specimens for culture were obtained by bone aspiration or biopsy at the time of orthopedic surgery. Blood specimens for culture were drawn from all febrile patients. P. aeruginosa was identified by standard methods (11). The in vitro susceptibilities of the isolates to ciprofloxacin were determined by the KirbyBauer disk diffusion technique (2) or by MIC determination by the macrodilution tube method. Patients were treated orally with 750 mg of ciprofloxacin every 12 h. No other antibiotics were given concomitantly. The duration of ciprofloxacin administration in assessable patients ranged from 1 to 4 months. Adjunctive surgical drainage and debridement were performed in most patients. Patients were monitored throughout the course of treatment for drug safety. This included periodic physical examinations and blood tests for evidence of hematologic, renal, or hepatic abnormalities. The efficacy of ciprofloxacin therapy was assessed during and following treatment. Patients were monitored for at least 6 months after the termination of drug administration. Cure was defined as the disappearance of all signs and symptoms related to the infection, normalization of the erythrocyte sedimentation rate, and eradication of the infecting organism with no relapse during the period of follow-up. Clinical improvement was noted when signs of infection regressed but complete resolution was not achieved; failure was defined as the absence of any substantial improvement of symptoms and signs.
Gram-negative bacillary osteomyelitis represents a real therapeutic challenge. Its management consists of a combined medical and surgical approach, including adequate surgical debridement of necrotic bone, removal of metal appliances, and prolonged parenteral administration of an antibacterial agent active against the causative organism (14). Osteomyelitis due to Pseudomonas aeruginosa is particularly difficult to treat because of the restricted arsenal of potent antibiotics and the ease with which the organism may develop drug resistance during therapy. The current therapeutic standard is intravenous administration of a combination of an aminoglycoside and an antipseudomonal penicillin for 4 to 6 weeks (16). Since aminoglycosides are associated with nephro- and ototoxicity and therapeutic concentrations are difficult to predict, the drug levels in the sera of patients receiving the agents should be monitored. It is not surprising, therefore, that there has been marked interest in the development of effective agents that can be given safely on an ambulatory basis. Ciprofloxacin was effective in the treatment of P. aeruginosa infection in animal models of pneumonia and osteomyelitis (15, 20). On the basis of these data, we elected to study the efficacy and safety of orally administered ciprofloxacin in the treatment of P. aeruginosa osteomyelitis. We used an open, noncomparative trial because of the lack of alternative oral antipseudomonal agents and because the drug was given initially on a compassionate basis after failure of standard therapy. (A part of this work was presented at the International Congress of Infectious Diseases, Rio de Janeiro, Brazil, April 1988.) MATERIALS AND METHODS Patients with bacteriological proof of osteomyelitis caused by ciprofloxacin-susceptible P. aeruginosa, seen at one of four medical institutions in Israel (Tel Aviv Medical Center, *
Corresponding author. 849
850
DAN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Characteristics of 22 patients with P. aeruginosa osteomyelitis receiving oral ciprofloxacin therapy
Patient
Symptom duration before
no.
Age (yr)Isexa
1 2 3 4
72/F 53/M 59/M 64/M
Spine Spine Spine Sternum
9 wk 1 yr 8 wk 12 wk
+/+ +/+ +/+ ND
5
58/M
Sternum
16 wk
ND
Hip Ribs Hip (prosthesis) Hip (prosthesis), spine Calcaneus Hip (prosthesis) Sternum Sternum, clavicle Tibia Sternum Femur Tibia Sternum
10 mo 5 wk 2 wk 9 wk 6 wk 4 wk 2 wk 10 wk 12 mo 10 wk
ND ND
6 36/M 7 64/F 8 65/F 9 76/F 10 18/M 11 81/F 12 72/M 13 62/F 14 36/F 15 67/M 16 63/M 17 22/M 18 59/M 19 53/M 20 15/M 21 47/M 22 84/M a M, Male; F, female. b
Affected bone(s)
Sternum Calcaneus Metatarsus Tibia
themapy
NRC 4 wk 6 wk 2 wk 2 wk 3 wk 4 wk
Bone ray/scan
+/ND ND/+ +/ND +/ND +/ND ND +/ND ND +/+ +/ND +/ND +/ND +/ND +/ND -/+
. Surscal
Duration of ciprofloxacin
proedure(s)
therapy (wk)
Duration follow-upof (mo)/outcome
None Debridement None Debridement, muscle flap Debridement, muscle flap Removal of prosthesis Debridement Removal of prosthesis None Debridement Removal of prosthesis Debridement Debridement Removal of plate Debridement None Debridement None None Debridement Debridement Bone biopsy
8 16 12 12
46/cure 52/cure 26/cure 37/cure
10
18/cure
16 12 16 12 4 12 12 12 14 12 12 8 12 16 4
32/cure 26/cure 26/cure 29/cure 23/cure 23/cure 26/cure 26/cure 22/failure 27/cure 17/cure NR/cure 25/cure 25/cure 6/cure Loss Deathe
2d 4
+, Positive finding; -, negative finding; ND, not done.
c NR, Not reported. d Treatment discontinued after 2 e Death due to unrelated cause.
days (see text).
RESULTS Of the 22 patients initially enrolled, 20 could be assessed for response to therapy (Table 1). The two who could not be evaluated included a 47-year-old patient with a metatarsal infection who developed severe nausea after ciprofloxacin treatment was initiated and refused to continue the treatment and an 84-year-old man with advanced ischemic heart disease who died suddenly 4 weeks after treatment had been initiated for tibial osteomyelitis and marked clinical improvement had been noted. Twenty patients met all criteria for evaluation; 12 were men and 8 were women. Their ages ranged from 14 to 84 years, with a mean of 55 years. The mean duration of symptoms before ciprofloxacin therapy was initiated was 4 months, with a range of 0.5 to 13 months (
