435
DIAGN MICROBIOL INFECT DIS 1991;14:435-441
ANTIMICROBIAL CLINICAL STUDIES
Oral Ofloxacin Therapy of Infections Due to Multiply-Resistant Bacteria Brian E. Scully, Neville Clynes, and Harold C. Neu
We determined the efficacy and safety of orally administered ofloxacin, 400 mg twice daily, in the treatment of infections due to multiply-resistant bacteria. Patients (n = 99) were treated for 84 infections in 82 patients evaluable for efficacy with a bacteriologic response of 71%. Organisms treated included Pseudomonas aeruginosa (39), Staphylococcus aureus (11), Serratia marcescens (9), Enterobacter species (7), five each of Escherichia coli, Citrobacter, Salmonella, Klebsiella, and other organisms. The overall clinical responses
was 89%: 28 (90%) of 16 osteomyelitis, 10 (83%) of 12 urinary tract infections, and three of three bacteremias. Insomnia occurred in 27% and responded to dose reduction. Resistance of P. aeruginosa to ofloxacin developed in 15% of isolates. No hepatic, renal, or hematologic toxicity developed in spite of long therapy, 283 days. Ofloxacin was an effective therapy for lower respiratory, urinary, bone, and soft tissue infections due to multiply-resistant Gram-negative bacteria and is effective for selected Staphylococcus aureus infections.
INTRODUCTION
treat infections. Accordingly, we decided to study the efficacy and safety of ofloxacin in a variety of clinical situations where infection with multiply antibiotic-resistant bacteria was proven or suspected.
Ofloxacin is a monofluorinated quinolone that possesses a number of favorable antibacterial and pharmacokinetic properties. Most staphylococci are inhibited by ~< 0.5 ixg/ml of ofloxacin, most of the Enterobacteriaceae by 0.1-0.25 Ixg/ml, and Pseudomonas aeruginosa by 2 ixg/ml (Barry et al., 1986; King et al., 1985). Pharmacokinetic properties of note include (a) excellent oral absorption, such that levels in serum of 3.5-5 ~g/ml are achieved following a 400-mg dose; (b) a large apparent volume of distribution reflecting high levels in tissue; and (c) a relatively long half-life in serum of 5-7 hrs, allowing for once or twice daily dosing (Flor, 1989; Kalager et al., 1986; Lode et al., 1987). These properties of good antibacterial activity, high tissue penetration, and long half-life should combine to make ofloxacin useful for the management of selected difficult-toFrom the Departments of Medicine (B.E.S., N.C., H.C.N.) and Pharmacology (H.C.N.), College of Physicians and Surgeons, Columbia University, New York, New York, USA. Address reprint requests to Dr. B.E. Scully, Department of Medicine, 630 West 168 Street, New York, NY 10032, USA. Received 9 November 1990; revised and accepted 29 January 1991. © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/91/$3.50
MATERIALS A N D M E T H O D S All patients were seen at the Presbyterian Hospital in N e w York City. For inclusion, a patient had to be 18 years of age and have an infection proven or suspected to be due to a bacterium resistant to one or more of the standard oral or parenteral antimicrobials used to treat the infection but susceptible to ofloxacin. Reasons for exclusion were treatment with an effective antimicrobial agent within the previous 72 hr, pregnancy, serious liver or renal (creatinine >2 mg/dl) disease, or a history of seizures, serious arthritis, or adverse reaction to nalidixic acid or other quinolones prior to therapy. All patients or an immediate family member gave informed, written consent in accordance with the guidelines of the institutional committee on human investigation. The clinical diagnosis was confirmed in each case by appropriate cultures, radiographic examination, and diagnostic tests appropriate to the infection. Patients had symptoms and signs appropriate to the illness such as fever, respiratory symptoms or pain
436
in an infected site. Patients with osteomyelitis had positive x-rays or bone scans and cultures of bone tissue biopsy samples. Patients with soft tissue infections had positive cultures of pus or aspirates of the appropriate body fluid. Patients with urinary tract infections had ~ 105 colony-forming units (CFU) per milliliter of urine, pyuria, or two positive urine cultures. Response to therapy was evaluated from clinical, radiologic, and bacteriologic aspects by the investigators and the primary physicians. Patients were considered to have responded clinically if satisfactory improvement in signs and symptoms of infection occurred; for example, complete resolution of fever, pronounced reduction in respiratory symptoms in pulmonary infections, clearing of both pus and signs of infection in soft tissue and bone infections, and complete clearing of urinary symptoms in urinary tract infections. Bacteriologic cure required elimination of the infecting pathogen from culture sites during treatment and at follow-up at 59 days for urinary tract infections and >24 hr after therapy for infections outside the urinary tract. Patients with osteomyelitis were followed for 2-52 months. Initial susceptibility to ofloxacin was determined for clinical isolates by the Kirby-Bauer disk method with 5-p,g ofloxacin disks. Minimum inhibitory concentrations (MICs) were determined by applying 104 CFU to Mueller-Hinton agar or by inoculating 5 x 10s CFU into Mueller-Hinton broth containing twofold increasing concentrations of antibiotic. Susceptibility to other antibiotics was determined by the microtube dilution method with the Microscan system (Mahway, NJ). Concentrations of ofloxacin in serum and body fluids were measured by the agar-well diffusion method with a susceptible strain of Klebsiella pneumoniae as the test organism. Peak serum samples were drawn 1-4 hr after a dose. Trough samples were drawn during the 30 min before a dose. Patients were questioned regarding any adverse symptoms during and after treatment. Serum chemistries, blood counts, and urinalysis were performed during and after therapy.
RESULTS
There were 99 patients w h o were entered into the study. Among them there were 84 infections occurring in 82 patients, which could be evaluated for efficacy of ofloxacin therapy. All patients were evaluated for safety. Several patients were excluded from efficacy evaluation because of inadequate or negative pretherapy cultures. An additional patient was withdrawn after three days of therapy because of intolerable side effects (see below). The majority of
B.E. Scully et al.
TABLE 1
Ofloxacin Therapy of Infections due to Multiply-Resistant Bacteria Number
Treatment courses Evaluable for efficacy Men Women Age, range Duration of therapy, range Underlying illness (of 82 patients) Cardiovascular Respiratory Central nervous system Renal/genitourinary Gastrointestinal Diabetes mellitus Immunosuppression AIDS/ARC Steroid therapy Cancer Alcohol/drug addiction Recent trauma/surgery Prosthesis
99 84 courses; 82 patients 48 34 18-82 yr (Mean: 51 yr) 5-283 d (Mean: 40 d) 14 18 7 6 3 15 12 5 7 3 3 7 3
patients, 69, received 400 mg of ofloxacin every 12 hr. A number of the patients received 200 mg every 12 hr by virtue of their small size or advanced age. Also, in five patients, the dosage of ofloxacin was reduced because of side effects, usually insomnia. The patient characteristics are listed in Table 1. The mean age was 51 years (range, 18-82 years). The mean duration of therapy was 40 days (range, 5-283 days). All but seven of the patients had significant underlying disease, including 12 who were significantly immunosuppressed by virtue of AIDS, steroid therapy, or congenital immune deficiency. Table 2 lists the infecting bacteria and their ofloxacin MICs. There were 107 organisms cultured, 86 of which were Gram-negative bacilli. Pseudomonas aeruginosa was the most common pathogen (38 strains), and it was the sole pathogen in 34 infections. The mean ofloxacin MIC for Pseudomonas was 1.4 ~g/ml. Nearly all of the remaining Gram-negative pathogens were inhibited by
DIAGN MICROBIOL INFECT DIS 1991;14:435-441
ANTIMICROBIAL CLINICAL STUDIES
Oral Ofloxacin Therapy of Infections Due to Multiply-Resistant Bacteria Brian E. Scully, Neville Clynes, and Harold C. Neu
We determined the efficacy and safety of orally administered ofloxacin, 400 mg twice daily, in the treatment of infections due to multiply-resistant bacteria. Patients (n = 99) were treated for 84 infections in 82 patients evaluable for efficacy with a bacteriologic response of 71%. Organisms treated included Pseudomonas aeruginosa (39), Staphylococcus aureus (11), Serratia marcescens (9), Enterobacter species (7), five each of Escherichia coli, Citrobacter, Salmonella, Klebsiella, and other organisms. The overall clinical responses
was 89%: 28 (90%) of 16 osteomyelitis, 10 (83%) of 12 urinary tract infections, and three of three bacteremias. Insomnia occurred in 27% and responded to dose reduction. Resistance of P. aeruginosa to ofloxacin developed in 15% of isolates. No hepatic, renal, or hematologic toxicity developed in spite of long therapy, 283 days. Ofloxacin was an effective therapy for lower respiratory, urinary, bone, and soft tissue infections due to multiply-resistant Gram-negative bacteria and is effective for selected Staphylococcus aureus infections.
INTRODUCTION
treat infections. Accordingly, we decided to study the efficacy and safety of ofloxacin in a variety of clinical situations where infection with multiply antibiotic-resistant bacteria was proven or suspected.
Ofloxacin is a monofluorinated quinolone that possesses a number of favorable antibacterial and pharmacokinetic properties. Most staphylococci are inhibited by ~< 0.5 ixg/ml of ofloxacin, most of the Enterobacteriaceae by 0.1-0.25 Ixg/ml, and Pseudomonas aeruginosa by 2 ixg/ml (Barry et al., 1986; King et al., 1985). Pharmacokinetic properties of note include (a) excellent oral absorption, such that levels in serum of 3.5-5 ~g/ml are achieved following a 400-mg dose; (b) a large apparent volume of distribution reflecting high levels in tissue; and (c) a relatively long half-life in serum of 5-7 hrs, allowing for once or twice daily dosing (Flor, 1989; Kalager et al., 1986; Lode et al., 1987). These properties of good antibacterial activity, high tissue penetration, and long half-life should combine to make ofloxacin useful for the management of selected difficult-toFrom the Departments of Medicine (B.E.S., N.C., H.C.N.) and Pharmacology (H.C.N.), College of Physicians and Surgeons, Columbia University, New York, New York, USA. Address reprint requests to Dr. B.E. Scully, Department of Medicine, 630 West 168 Street, New York, NY 10032, USA. Received 9 November 1990; revised and accepted 29 January 1991. © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/91/$3.50
MATERIALS A N D M E T H O D S All patients were seen at the Presbyterian Hospital in N e w York City. For inclusion, a patient had to be 18 years of age and have an infection proven or suspected to be due to a bacterium resistant to one or more of the standard oral or parenteral antimicrobials used to treat the infection but susceptible to ofloxacin. Reasons for exclusion were treatment with an effective antimicrobial agent within the previous 72 hr, pregnancy, serious liver or renal (creatinine >2 mg/dl) disease, or a history of seizures, serious arthritis, or adverse reaction to nalidixic acid or other quinolones prior to therapy. All patients or an immediate family member gave informed, written consent in accordance with the guidelines of the institutional committee on human investigation. The clinical diagnosis was confirmed in each case by appropriate cultures, radiographic examination, and diagnostic tests appropriate to the infection. Patients had symptoms and signs appropriate to the illness such as fever, respiratory symptoms or pain
436
in an infected site. Patients with osteomyelitis had positive x-rays or bone scans and cultures of bone tissue biopsy samples. Patients with soft tissue infections had positive cultures of pus or aspirates of the appropriate body fluid. Patients with urinary tract infections had ~ 105 colony-forming units (CFU) per milliliter of urine, pyuria, or two positive urine cultures. Response to therapy was evaluated from clinical, radiologic, and bacteriologic aspects by the investigators and the primary physicians. Patients were considered to have responded clinically if satisfactory improvement in signs and symptoms of infection occurred; for example, complete resolution of fever, pronounced reduction in respiratory symptoms in pulmonary infections, clearing of both pus and signs of infection in soft tissue and bone infections, and complete clearing of urinary symptoms in urinary tract infections. Bacteriologic cure required elimination of the infecting pathogen from culture sites during treatment and at follow-up at 59 days for urinary tract infections and >24 hr after therapy for infections outside the urinary tract. Patients with osteomyelitis were followed for 2-52 months. Initial susceptibility to ofloxacin was determined for clinical isolates by the Kirby-Bauer disk method with 5-p,g ofloxacin disks. Minimum inhibitory concentrations (MICs) were determined by applying 104 CFU to Mueller-Hinton agar or by inoculating 5 x 10s CFU into Mueller-Hinton broth containing twofold increasing concentrations of antibiotic. Susceptibility to other antibiotics was determined by the microtube dilution method with the Microscan system (Mahway, NJ). Concentrations of ofloxacin in serum and body fluids were measured by the agar-well diffusion method with a susceptible strain of Klebsiella pneumoniae as the test organism. Peak serum samples were drawn 1-4 hr after a dose. Trough samples were drawn during the 30 min before a dose. Patients were questioned regarding any adverse symptoms during and after treatment. Serum chemistries, blood counts, and urinalysis were performed during and after therapy.
RESULTS
There were 99 patients w h o were entered into the study. Among them there were 84 infections occurring in 82 patients, which could be evaluated for efficacy of ofloxacin therapy. All patients were evaluated for safety. Several patients were excluded from efficacy evaluation because of inadequate or negative pretherapy cultures. An additional patient was withdrawn after three days of therapy because of intolerable side effects (see below). The majority of
B.E. Scully et al.
TABLE 1
Ofloxacin Therapy of Infections due to Multiply-Resistant Bacteria Number
Treatment courses Evaluable for efficacy Men Women Age, range Duration of therapy, range Underlying illness (of 82 patients) Cardiovascular Respiratory Central nervous system Renal/genitourinary Gastrointestinal Diabetes mellitus Immunosuppression AIDS/ARC Steroid therapy Cancer Alcohol/drug addiction Recent trauma/surgery Prosthesis
99 84 courses; 82 patients 48 34 18-82 yr (Mean: 51 yr) 5-283 d (Mean: 40 d) 14 18 7 6 3 15 12 5 7 3 3 7 3
patients, 69, received 400 mg of ofloxacin every 12 hr. A number of the patients received 200 mg every 12 hr by virtue of their small size or advanced age. Also, in five patients, the dosage of ofloxacin was reduced because of side effects, usually insomnia. The patient characteristics are listed in Table 1. The mean age was 51 years (range, 18-82 years). The mean duration of therapy was 40 days (range, 5-283 days). All but seven of the patients had significant underlying disease, including 12 who were significantly immunosuppressed by virtue of AIDS, steroid therapy, or congenital immune deficiency. Table 2 lists the infecting bacteria and their ofloxacin MICs. There were 107 organisms cultured, 86 of which were Gram-negative bacilli. Pseudomonas aeruginosa was the most common pathogen (38 strains), and it was the sole pathogen in 34 infections. The mean ofloxacin MIC for Pseudomonas was 1.4 ~g/ml. Nearly all of the remaining Gram-negative pathogens were inhibited by
