Lomefloxacin Concentrations Single Oral Dose
in Bone After a
ANGELA ON, Pharm.D.,CHARLES H. NIGHTINGALE,Ph.D., RICHARDQUINTILIANI,M.D., KEVIN R. SWEENEY, Ph.D., HERBERTS. PASTERNAK,M.D., EUFRONIOG. MADERAZO, M.D., Hatiord, Connecticut
We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 PglmL at 2 hours post-dose and 3.0 pg/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still >l.O pg/mL. Two hours after dosing the average bone-to-plasma ratio was >0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.
L
omefloxacin is a difluorinated quinolone with a broad spectrum of activity against clinically important gram-positive and gram-negative bacteria. The minimum inhibitory concentration (MIC) values of lomefloxacin for 90% (MI&) of most gram-negative bacilli vary from 0.5 to 1.0 pg/mL, except for Pseudomonas aeruginosa, for which the MI&, is 4.0-8.0 pg/mL. The MI&, against Staphylococcus spp. (including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis) is 1.0-2.0 pg/mL [l-3]. Lomefloxacin is well absorbed when administered orally and has a relatively long half-life of 7-8 hours [4,5]. With the enhanced microbiologic activity and a promising pharmacokinetic profile, lomefloxacin may have a potential role to replace traditional long-term intravenous antibiotic therapy in treating certain infections, including osteomyelitis, caused by susceptible organisms. The effectiveness of an antimicrobial agent in treating bone infections is determined by drug disposition, the MIC values, and the actual drug concentrations achieved in serum and in bone tissue. The purpose of this study was to examine the adequacy of penetration of lomefloxacin into bone tissue after a single oral dose of 400 mg.
MATERIALSAND METHODS Patients A total of 32 patients (18 male and 14 female) with osteoarthritis undergoing total hip replacement were enrolled after obtaining written informed consent. They were 44-81 (mean, 67) years of age with a mean weight of 80 kg (range, 51-116 kg). Lomefloxacin 400 mg (2 x 200 mg capsules) was administered orally to each patient 1-12 hours prior to surgery. Patients also received a standard perioperative prophylactic antibiotic regimen.
Fromthe HartfordHospital,Hartford,Connecticut. Requestsfor reprintsshouldbe addressedto CharlesH. Nightingale,Ph.D., HartfordHospital,80 SeymourStreet,Hartford,Connecticut06115.
Sample Preparation Subchondral bone chips were obtained from the femoral heads of the patients during surgery. A 10 mL venous blood sample was obtained at the time of bone collection. Plasma was obtained after centrifugation and stored frozen until assayed. Bone chips were rinsed in sterile saline, dried, then
April 6, 1992 The AmericanJournalof Medicine Volume92 (suppl4A)
4A-15s
SYMPOSIUM
ON ONCE-A-DAY QUINOLONE
I ON ET AL
stored at -70°C until the time of assay. Prior to assay,the bonechipswere pulverizedusing a Spex freezer mill. The bone sampleswere weighed and diluted with phosphatebuffer. The mixture was vigorously stirred in a cold room by initially using a magnetic stirrer followed by mixing on a rotary mixer. The supernatant was removed for analysis of drug concentrationand for drug content associated with blood retained in bone.After centrifugation, lomefloxacin concentrations in plasma and bonewere assayedby high-pressureliquid chromatography with a fluorescencedetector. High-Pressure Liquid Chromatography
(RBC) :plasma partition coefficient, and the drug concentration as determined from the plasma assay. The following equation was used to determine the correction term (Xblood): Xblood = amount of drug in plasma + amount of drug in RBC = Xplasma + XRBC = Vblood * (1 - Hct) * Cplasma+ Vblood * Hct * Cplasma* 1.74 where Hct = hematocrit and the value 1.74 is the averageRBUplasma partition coefficientobtained in a previous study by Searle [6].
Conditions
The internal standardwas a structural analogof lomefloxacin, KK-123, supplied by Searle. The mobile phasewas 22% acetonitrile and 1% ammonium acetate(1.0M) in citric acid (0.05M), at a flow rate of 1.5 ml/minute. A 4.6 mm x 25 cm Nagel (Alltech) column with 10pm particle sizewas used. The retention time of lomefloxacin was approximately 3.6 minutes andthat of KK-123 was 6.6 minutes. The detector was a Kratos fluorescencespectrophotometerwith an excitation wavelengthof 280 nm and emission monitored at 455 nm. The mean interday assay variability was 2.7% at 1.5 pg/mL and 4.2%at 0.1 pg/mL; the meanintraday variability was 4.4% at 1.5 pg/mL and 1.8%at 0.1 PglmL. The minimum detectable concentration was 0.05 PglmL. Calculations
Lomefloxacin concentrationsin bonewere calculated by subtracting the amount of drug arising from blood contaminationin the bonesample from the measuredbone concentrations.The amount of drug arising from blood contaminationof the bone samplewas calculatedfrom the blood volume in the bone, the hematocrit, the red blood cell
RESULTS Two patients were dropped from the study because of cancellation of surgery. There were no adverseeffects attributable to lomefloxaeinduring this study. Lomefloxacin concentrationsproduced by the 400 mg dose were normalized to a 70 kg “standard individual” by the following equation: Cnormalized= Cobserved*7O/bodyweight. Figure 1 shows the composite curve of the results of lomefloxacinbone concentrationsand their simultaneouslyobtainedplasma concentrationsfor each patient at different times post-dose. The curveswere simulated using a least-squaresfitting program. The peak concentrationsreachedapproximately 4 pg/mL at 2 hourspost-dosein plasmaand approximately 3 pg/mL in boneat 3-5 hours postdose. At 12 hours post-doseboth plasma and bone lomefloxacin concentrations were maintained > 1 pg/mL. The bone-to-plasma concentration ratio versus time profile after dosing is shown in Figure 2. The mean bone-to-plasma concentration ratio was 0.7, with a standarddeviation of 0.3 in these30 patients examined at various time points 1-12
@g’m’) 1: . 3. . . 04 0:::::::::::’
conconw6Uon’
2
gure 1. Lomefloxacin
4A-16s
plasma and bone concentrations.
April 6, 1992
The American Journal of Medicine
lgure 2 Done/plasma
Volume 92 (suppl 4A)
concentration
4
6 Tim* (houn)
ratio versus time.
6
10
12
SYMPOSIUM
hours after dosing. An average ratio of ~0.6 was established within 2 hours after dosing.
COMMENT The antibiotic concentrations achieved at the site of infections are critical in determining the effectiveness of an agent. It is very important to demonstrate that the antibiotics used in treating osteomyelitis achieve therapeutic concentrations in bone tissue. Gram-negative or mixed bacterial osteomyelitis is usually difficult to treat and requires prolonged parenteral therapy, which is not only inconvenient but very expensive. Orally administered antibiotics, such as cloxacillin, dicloxacillin, and clindamycin, have been shown to be efficacious clinically in treating osteomyelitis caused by Stu$ylococcus spp. [‘7-g]. There are some reports of successful open studies using oral fluoroquinolones in treating osteomyelitis, most often caused by gramnegative bacilli [lo-141. One prospective, randomized study by Gentry et al indicated that oral ciprofloxacin monotherapy is as safe and effective as conventional parenteral therapy in osteomyelitis [ 151. In this study we found that significant lomefloxatin levels were achieved in bone tissue after a single 400 mg oral dose. With MIC values of cl.0 pg/mL for most of the Enterobacteriaceae U-31, therapeutic lomefloxacin bone concentrations should be expected after 400 mg oral dosing. Although lomefloxacin levels achieved in bone were above the MIC values (2.0 pg/mL) for S. czureus [l-3], the 400 mg oral dose may not provide adequate levels for this organism; however, clinical trials are needed to confirm this supposition. Lomefloxacin, with its broad-spectrum antimicrobial activity and good bioavailability and bone penetration ratio, could be a therapeutic alternative to traditional parenteral therapy in managing osteomyelitis caused by susceptible gram-negative Enterobacteriaceae. Further clinical trials in patients with osteomyelitis will be able to elucidate lomefloxacin’s role in such treatment. Due to the limitations of the study design, it was not possible to provide a complete pharmacokinetic analysis, but one based on the composite concentration-versus-time profile. However, the lomefloxatin elimination half-life was calculated from the fitted least-squares regression line of the composite plasma concentration-versus-time profile. The calculated elimination half-life of lomefloxacin was 6.9 hours (excluding one outlier at the 2-hour point), which is consistent with the published literature
ON ONCE-A-DAY QUINOLONE
I ON ET AL
value of 7-8 hours in healthy volunteers [4,5]. Although the penetration ratios are somewhat variable, with a coefficient of variation of 39% considering all time points, examination of Figure 2 (ratios vs time profile) reveals a trend toward an increasing ratio with time that is also demonstrated by the fitted curve in Figure 1. This suggests either a slow equilibrium process between plasma and bone or a slower rate of drug removal from bone. It cannot be determined which mechanism best describes the process in this study since the terminal phase of drug elimination was not reached by the end of the sampling period (12 hours). In conclusion, orally administered lomefloxacin penetrates well into bone. Clinical trials are needed to confirm whether lomefloxacin may have use in the therapy of osteomyelitis.
REFERENCES 1. Chin N-X, Novelli A, Neu HC. In vitro activity of lomefloxacin (SC-47111: NY-198), a difluoroquinolone 3carboxylic acid, compared with those of other quinolones. Antimicrob Agents Chemother 1988; 32: 656-62. 2. Hirose T, Okezaki E, Kato H, Ito Y, moue M. Mitsuhashi S. In vitro and in vivo activity of NY-198, a new difluorinated quinolone. Antimicrob Agents Chemother 1987; 31: 854-9. 3. Wise R, Andrews JM. Ashby JP, Matthews RS. In vitro activity of lomefloxacin, a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988; 32: 617-22. 4. Morrison PJ, Mant TGK, Norman GT, Robinson J, Kunka RL. Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses. Antimicrob Agents Chemother 1988; 32: 1503-7. 5. Stone JW, Andrews JM, Ashby JP, Griggs D, Wise R. Pharmacokinetics and tissue penetration of orally administered lomefloxacin. Antimicrob Agents Chemother 1988; 32: 1508-10. 6. Kurkemyer J. Lima J, Adams M, Hunt T. Lomefloxacin pharmacokinetics: binding to plasma proteins and effect of food on absorption [Abstract No. 12751. Abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, Texas, September 20, 1989. 7. Bell S. Further observations on the value of oral penicillins in chronic staphylococcal osteomyelitis. Med J Aust 1976; 2: 591-3. 8. Blockey NJ, McAllister TA. Antibiotics in acute osteomyelitis in children. J Bone Joint Surg 1972; 54: 299-309. 9. Feigin RD, Pickering LK, Anderson D, Keeney RE, Shackleford PG. Clindamycin treatment of osteomyelitis and septic arthritis in children. Pediatrics 1975; 55: 21323. 10. Gilbert DN, Tree AD, Marsh PK, Craven PC, Preheim LC. Oral ciprofloxacin therapy for chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli. Am J Med 1987; 82 (Suppl 4A): 254-8. 11. Greenberg RN, Kennedy DJ, Reilly PM, et al. Treatment of bone, joint, and soft-tissue infecbons with oral ciprofloxacin. Antimicrob Agents Chemother 1987; 31: 151-5. 12. Hessen MT, lngerman MJ, Kaufman DH, et al. Clinical efficacy of ciprofloxacin therapy for gram-negative bacillary osteomyelitis. Am J Med 1987; 82 (Suppl 4A): 262-5. 13. Slama TG, Misinskr J, Sklar S. Oral ciprofloxacin therapy for osteomyelitis caused by aerobic gram-negative bacilli. Am J Med 1987; 82 (Suppl 4A): 259-61. 14. Ketterl R, Beckurts T, Stubingr B, Claudi 8. Use of ofloxacin in open fractures and in treatment of post-traumatic osteomyelitis. J Antimicrob Chemother 1988; 22 (Suppl C): 159-66. 15. Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother 1990; 34: 40-3.
April 6, 1992
The American Journal of Medicine
Volume 92 (suppl 4A)
4A-17s
in Bone After a
ANGELA ON, Pharm.D.,CHARLES H. NIGHTINGALE,Ph.D., RICHARDQUINTILIANI,M.D., KEVIN R. SWEENEY, Ph.D., HERBERTS. PASTERNAK,M.D., EUFRONIOG. MADERAZO, M.D., Hatiord, Connecticut
We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 PglmL at 2 hours post-dose and 3.0 pg/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still >l.O pg/mL. Two hours after dosing the average bone-to-plasma ratio was >0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.
L
omefloxacin is a difluorinated quinolone with a broad spectrum of activity against clinically important gram-positive and gram-negative bacteria. The minimum inhibitory concentration (MIC) values of lomefloxacin for 90% (MI&) of most gram-negative bacilli vary from 0.5 to 1.0 pg/mL, except for Pseudomonas aeruginosa, for which the MI&, is 4.0-8.0 pg/mL. The MI&, against Staphylococcus spp. (including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis) is 1.0-2.0 pg/mL [l-3]. Lomefloxacin is well absorbed when administered orally and has a relatively long half-life of 7-8 hours [4,5]. With the enhanced microbiologic activity and a promising pharmacokinetic profile, lomefloxacin may have a potential role to replace traditional long-term intravenous antibiotic therapy in treating certain infections, including osteomyelitis, caused by susceptible organisms. The effectiveness of an antimicrobial agent in treating bone infections is determined by drug disposition, the MIC values, and the actual drug concentrations achieved in serum and in bone tissue. The purpose of this study was to examine the adequacy of penetration of lomefloxacin into bone tissue after a single oral dose of 400 mg.
MATERIALSAND METHODS Patients A total of 32 patients (18 male and 14 female) with osteoarthritis undergoing total hip replacement were enrolled after obtaining written informed consent. They were 44-81 (mean, 67) years of age with a mean weight of 80 kg (range, 51-116 kg). Lomefloxacin 400 mg (2 x 200 mg capsules) was administered orally to each patient 1-12 hours prior to surgery. Patients also received a standard perioperative prophylactic antibiotic regimen.
Fromthe HartfordHospital,Hartford,Connecticut. Requestsfor reprintsshouldbe addressedto CharlesH. Nightingale,Ph.D., HartfordHospital,80 SeymourStreet,Hartford,Connecticut06115.
Sample Preparation Subchondral bone chips were obtained from the femoral heads of the patients during surgery. A 10 mL venous blood sample was obtained at the time of bone collection. Plasma was obtained after centrifugation and stored frozen until assayed. Bone chips were rinsed in sterile saline, dried, then
April 6, 1992 The AmericanJournalof Medicine Volume92 (suppl4A)
4A-15s
SYMPOSIUM
ON ONCE-A-DAY QUINOLONE
I ON ET AL
stored at -70°C until the time of assay. Prior to assay,the bonechipswere pulverizedusing a Spex freezer mill. The bone sampleswere weighed and diluted with phosphatebuffer. The mixture was vigorously stirred in a cold room by initially using a magnetic stirrer followed by mixing on a rotary mixer. The supernatant was removed for analysis of drug concentrationand for drug content associated with blood retained in bone.After centrifugation, lomefloxacin concentrations in plasma and bonewere assayedby high-pressureliquid chromatography with a fluorescencedetector. High-Pressure Liquid Chromatography
(RBC) :plasma partition coefficient, and the drug concentration as determined from the plasma assay. The following equation was used to determine the correction term (Xblood): Xblood = amount of drug in plasma + amount of drug in RBC = Xplasma + XRBC = Vblood * (1 - Hct) * Cplasma+ Vblood * Hct * Cplasma* 1.74 where Hct = hematocrit and the value 1.74 is the averageRBUplasma partition coefficientobtained in a previous study by Searle [6].
Conditions
The internal standardwas a structural analogof lomefloxacin, KK-123, supplied by Searle. The mobile phasewas 22% acetonitrile and 1% ammonium acetate(1.0M) in citric acid (0.05M), at a flow rate of 1.5 ml/minute. A 4.6 mm x 25 cm Nagel (Alltech) column with 10pm particle sizewas used. The retention time of lomefloxacin was approximately 3.6 minutes andthat of KK-123 was 6.6 minutes. The detector was a Kratos fluorescencespectrophotometerwith an excitation wavelengthof 280 nm and emission monitored at 455 nm. The mean interday assay variability was 2.7% at 1.5 pg/mL and 4.2%at 0.1 pg/mL; the meanintraday variability was 4.4% at 1.5 pg/mL and 1.8%at 0.1 PglmL. The minimum detectable concentration was 0.05 PglmL. Calculations
Lomefloxacin concentrationsin bonewere calculated by subtracting the amount of drug arising from blood contaminationin the bonesample from the measuredbone concentrations.The amount of drug arising from blood contaminationof the bone samplewas calculatedfrom the blood volume in the bone, the hematocrit, the red blood cell
RESULTS Two patients were dropped from the study because of cancellation of surgery. There were no adverseeffects attributable to lomefloxaeinduring this study. Lomefloxacin concentrationsproduced by the 400 mg dose were normalized to a 70 kg “standard individual” by the following equation: Cnormalized= Cobserved*7O/bodyweight. Figure 1 shows the composite curve of the results of lomefloxacinbone concentrationsand their simultaneouslyobtainedplasma concentrationsfor each patient at different times post-dose. The curveswere simulated using a least-squaresfitting program. The peak concentrationsreachedapproximately 4 pg/mL at 2 hourspost-dosein plasmaand approximately 3 pg/mL in boneat 3-5 hours postdose. At 12 hours post-doseboth plasma and bone lomefloxacin concentrations were maintained > 1 pg/mL. The bone-to-plasma concentration ratio versus time profile after dosing is shown in Figure 2. The mean bone-to-plasma concentration ratio was 0.7, with a standarddeviation of 0.3 in these30 patients examined at various time points 1-12
@g’m’) 1: . 3. . . 04 0:::::::::::’
conconw6Uon’
2
gure 1. Lomefloxacin
4A-16s
plasma and bone concentrations.
April 6, 1992
The American Journal of Medicine
lgure 2 Done/plasma
Volume 92 (suppl 4A)
concentration
4
6 Tim* (houn)
ratio versus time.
6
10
12
SYMPOSIUM
hours after dosing. An average ratio of ~0.6 was established within 2 hours after dosing.
COMMENT The antibiotic concentrations achieved at the site of infections are critical in determining the effectiveness of an agent. It is very important to demonstrate that the antibiotics used in treating osteomyelitis achieve therapeutic concentrations in bone tissue. Gram-negative or mixed bacterial osteomyelitis is usually difficult to treat and requires prolonged parenteral therapy, which is not only inconvenient but very expensive. Orally administered antibiotics, such as cloxacillin, dicloxacillin, and clindamycin, have been shown to be efficacious clinically in treating osteomyelitis caused by Stu$ylococcus spp. [‘7-g]. There are some reports of successful open studies using oral fluoroquinolones in treating osteomyelitis, most often caused by gramnegative bacilli [lo-141. One prospective, randomized study by Gentry et al indicated that oral ciprofloxacin monotherapy is as safe and effective as conventional parenteral therapy in osteomyelitis [ 151. In this study we found that significant lomefloxatin levels were achieved in bone tissue after a single 400 mg oral dose. With MIC values of cl.0 pg/mL for most of the Enterobacteriaceae U-31, therapeutic lomefloxacin bone concentrations should be expected after 400 mg oral dosing. Although lomefloxacin levels achieved in bone were above the MIC values (2.0 pg/mL) for S. czureus [l-3], the 400 mg oral dose may not provide adequate levels for this organism; however, clinical trials are needed to confirm this supposition. Lomefloxacin, with its broad-spectrum antimicrobial activity and good bioavailability and bone penetration ratio, could be a therapeutic alternative to traditional parenteral therapy in managing osteomyelitis caused by susceptible gram-negative Enterobacteriaceae. Further clinical trials in patients with osteomyelitis will be able to elucidate lomefloxacin’s role in such treatment. Due to the limitations of the study design, it was not possible to provide a complete pharmacokinetic analysis, but one based on the composite concentration-versus-time profile. However, the lomefloxatin elimination half-life was calculated from the fitted least-squares regression line of the composite plasma concentration-versus-time profile. The calculated elimination half-life of lomefloxacin was 6.9 hours (excluding one outlier at the 2-hour point), which is consistent with the published literature
ON ONCE-A-DAY QUINOLONE
I ON ET AL
value of 7-8 hours in healthy volunteers [4,5]. Although the penetration ratios are somewhat variable, with a coefficient of variation of 39% considering all time points, examination of Figure 2 (ratios vs time profile) reveals a trend toward an increasing ratio with time that is also demonstrated by the fitted curve in Figure 1. This suggests either a slow equilibrium process between plasma and bone or a slower rate of drug removal from bone. It cannot be determined which mechanism best describes the process in this study since the terminal phase of drug elimination was not reached by the end of the sampling period (12 hours). In conclusion, orally administered lomefloxacin penetrates well into bone. Clinical trials are needed to confirm whether lomefloxacin may have use in the therapy of osteomyelitis.
REFERENCES 1. Chin N-X, Novelli A, Neu HC. In vitro activity of lomefloxacin (SC-47111: NY-198), a difluoroquinolone 3carboxylic acid, compared with those of other quinolones. Antimicrob Agents Chemother 1988; 32: 656-62. 2. Hirose T, Okezaki E, Kato H, Ito Y, moue M. Mitsuhashi S. In vitro and in vivo activity of NY-198, a new difluorinated quinolone. Antimicrob Agents Chemother 1987; 31: 854-9. 3. Wise R, Andrews JM. Ashby JP, Matthews RS. In vitro activity of lomefloxacin, a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988; 32: 617-22. 4. Morrison PJ, Mant TGK, Norman GT, Robinson J, Kunka RL. Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses. Antimicrob Agents Chemother 1988; 32: 1503-7. 5. Stone JW, Andrews JM, Ashby JP, Griggs D, Wise R. Pharmacokinetics and tissue penetration of orally administered lomefloxacin. Antimicrob Agents Chemother 1988; 32: 1508-10. 6. Kurkemyer J. Lima J, Adams M, Hunt T. Lomefloxacin pharmacokinetics: binding to plasma proteins and effect of food on absorption [Abstract No. 12751. Abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, Texas, September 20, 1989. 7. Bell S. Further observations on the value of oral penicillins in chronic staphylococcal osteomyelitis. Med J Aust 1976; 2: 591-3. 8. Blockey NJ, McAllister TA. Antibiotics in acute osteomyelitis in children. J Bone Joint Surg 1972; 54: 299-309. 9. Feigin RD, Pickering LK, Anderson D, Keeney RE, Shackleford PG. Clindamycin treatment of osteomyelitis and septic arthritis in children. Pediatrics 1975; 55: 21323. 10. Gilbert DN, Tree AD, Marsh PK, Craven PC, Preheim LC. Oral ciprofloxacin therapy for chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli. Am J Med 1987; 82 (Suppl 4A): 254-8. 11. Greenberg RN, Kennedy DJ, Reilly PM, et al. Treatment of bone, joint, and soft-tissue infecbons with oral ciprofloxacin. Antimicrob Agents Chemother 1987; 31: 151-5. 12. Hessen MT, lngerman MJ, Kaufman DH, et al. Clinical efficacy of ciprofloxacin therapy for gram-negative bacillary osteomyelitis. Am J Med 1987; 82 (Suppl 4A): 262-5. 13. Slama TG, Misinskr J, Sklar S. Oral ciprofloxacin therapy for osteomyelitis caused by aerobic gram-negative bacilli. Am J Med 1987; 82 (Suppl 4A): 259-61. 14. Ketterl R, Beckurts T, Stubingr B, Claudi 8. Use of ofloxacin in open fractures and in treatment of post-traumatic osteomyelitis. J Antimicrob Chemother 1988; 22 (Suppl C): 159-66. 15. Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother 1990; 34: 40-3.
April 6, 1992
The American Journal of Medicine
Volume 92 (suppl 4A)
4A-17s
