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Brief report: Intravenous and sequential intravenous and oral ciprofloxacin in the treatment of severe infections
Brief Report: Intravenous and Sequential Intravenous and Oral Ciprofloxacin in the Treatment of Severe Infections JENNIFER S. DALY, M.D., MICHAEL Boston, Massachusetts
G. WORTHINGTON, M.D., SYED A. Rm, M.D., REN~EROBILLARD, M.A.
he fluoroquinolone ciprofloxacin is well absorbed T by the gastrointestinal tract [l]. Thus, when given orally, sufficient serum concentrations of this antimicrobial are achieved for the treatment of infections caused by either gram-positive or gram-negative bacteria [2,3]. Frequently, however, hospitalized patients with severe infections are too ill to take oral agents, or they have abnormalities of the gastrointestinal tract that may affect drug absorption. Other patients with severe infections, such as bacteremia, receive intravenous therapy to meet accepted standards of care. Treatment of such patients initially requires a parenteral agent so that optimal serum levels of drug can be achieved. Ciprofloxacin, which is one of the most active quinolones in vitro [4], is now under study in an intravenous formulation [5,6], making sequential therapy with its intravenous and then its oral form a potentially useful clinical regimen for seriously ill patients who require continued therapy after the signs and symptoms of acute infection have improved. We prospectively studied the clinical and bacteriologic results of therapy with sequential intravenous and oral ciprofloxacin in hospitalized patients with severe infections, many of whom had not been cured by antibacterial therapy with standard agents. We also examined serum concentrations of ciprofloxacin to assess the adequacy of the intravenous dosages used.
PATIENTSAND METHODS Men and women with culture-proven severe infections caused by ciprofloxacin-susceptible organisms were eligible for enrollment in the study. The patients had been determined by their attending physicians to require hospitalization and parenteral therapy. Patients treated unsuccessfully with other antimicrobial agents were preferentially considered for enrollment, as long as a positive culture was obtained from an actively infected site immediately before the ciprofloxatin therapy was begun. Patients were excluded from the study if they were pregnant or nursing, allergic to quinolone agents, not expected to live for more than 30 days, or needed concomitant antimicrobial therapy other than clindamycin or metronidazole. Informed consent was obtained from all patients or their legal guardians. Patients’ clinical diagnoses were confirmed by radiographic examination., radionuclear scanning, cultures, and laboratory testing appropriate to the infection. Ciprofloxacin was given intravenously at a dosage of 200 to 400 mg every eight to 12 hours. The maximal amount administered was 10 mg/kg of body weight, or From the Departments of Medicine and Surgery, Saint Elizabeth’s Hospital, and Tufts University School of Medicine, Boston, Massachusetts, This study was supported by a grant from Miles Inc., Pharmaceutical Division. Requests for reprints should be addressed to Dr. Jennifer S. Daly, Saint Elizabeth’s Hospital, 736 Cambridge Street, Boston, Massachusetts 02135.
5A-232s
November 30, 1989
The American Journal of Medicine
1,200 mg in a 24-hour period. Dosage was adjusted on the basis of assessments of renal function and (in some cases) serum levels. Oral ciprofloxacin was given at a dosage of 500 to 1,000 mg every 12 hours. The minimal duration of the complete regimen was four days. Patients were switched from intravenous to oral therapy if they had clinical improvement and could take orally administered medication. Specimens for culture were taken from the infected sites in all patients within 48 hours of entry, at the end of the intravenous treatment, at the end of the sequential intravenous and oral treatment, and at a follow-up visit within a month after therapy was completed. However, subsequent culture specimens were not obtained if no infected tissue remained at the site of infection. The clinical response was graded at the end of the intravenous therapy, at the end of all therapy, and at the follow-up visit, as “cure” if there was complete resolution of signs and symptoms of the infection without relapse or re-infection during the follow-up period, “improvement” if there was amelioration of signs and symptoms without complete resolution of the evidence of infection, “no response” if there was no change or deterioration in the patient’s clinical condition, and “indeterminate” if the patient died of underlying disease during treatment. The bacteriologic response was graded as “cure” if all pathogens were eradicated from the site of infection, “improvement” if one or more pathogens were eradicated from a mixed infection, and “no response” if all infecting organisms persisted in cultures from the infected site. Susceptibility to ciprofloxacin was determined by standard disk-diffusion techniques using a 5-pg disk and Mueller-Hinton agar [7]. Minimal inhibitory concentrations (MICs) were determined by a microbroth dilution technique using the Sensititre System (Radiometer, Copenhagen). Quality control was performed according to guidelines established by the National Committee for Clinical Laboratory Standards [8]. While receiving intravenous therapy, patients were observed closely for signs of toxicity and response to therapy with the use of daily history-taking and physical examinations. Serum chemistry, complete blood cell count, and urinalysis results were assessed every three to five days during intravenous therapy and every seven to 14 days during oral therapy. Serum concentrations of ciprofloxacin were monitored in 23 patients by a bioassay using Klebsiella pneumoniae (ATCC 10031) [21 or by high-pressure liquid chromatography [9]. Blood was drawn for the assays 30 minutes and eight hours after an intravenous dose was given.
RESULTS Of 3’7 patients entered into the study, 32 had at least 48 hours of intravenous therapy and met all criteria for inclusion. The patients ranged in age from 21 years
Volume 87 (suppl 5A)
SYMPOSIUM
TABLE I Bacteriologic
ON CIPROFLOXACIN / DALY ET AL
Response Eradication
Pathogen
Number
End of Intravenous Therapy
End of All Therapy
Persistence
Gram.positive Enterococcussp. S. aureus (oxacillln.susceptible) S. aufeus (oxacillin~resistant) Streptococcussp. Gram.negative Escherichiaco/i Enterobacter sp. Klebsiellaoxytoca Proteus mirabilis F!aeruginosa 14 Xanfhomonas maitoph//ia 2 Other 7 30 Total 65 *Numbers in parentheses indicate the number of strains that developed resistance to ciprofloxacin.
to 91 years (mean, 61 years). The patients had skin or skin-structure infections (13 patients)., osteomyelitis (10 patients), pneumonia (five patients), sternal wound infections with bacteremia (two patients), peritonitis (one patient), or a complicated urinary tract infection (one patient). Twenty-four of the patients had not responded to previous antimicrobial therapy. Intravenous ciprofloxacin therapy was given for a median of five days (range, two to 19 days) followed by oral ciprofloxacin therapy for a median of 17.5 days (range, zero to 93 days). At the end of intravenous therapy, one patient had a complete clinical and bacteriologic cure, one had no response, and 30 had either clinical or bacteriologic improvement. After the intravenous therapy alone, the sequential intravenous and oral regimen, and a one-month follow-up period, 14 patients (44 percent) had complete clinical and bacteriologic cure, and 15 (50 percent) had clinical or bacteriologic improvement, for an overall response rate of 94 percent. One patient (3 percent) had no response, one (3 percent) did not complete follow-up, and one patient died before completing therapy. The patient who had no response to therapy was a 72-year-old man who had recently had a pneumonectomy for lung cancer. During therapy, he had adequate serum concentrations of ciprofloxacm; however, progressive pneumonia developed, along with breakdown of the suture line in the bronchial stump. He was removed from the study and switched to standard antimicrobial therapy. The bacteriologic response is shown in Table I. Of the 39 gram-negative bacteria isolated, 31 were eradicated by the end of therapy, and eight developed an increase in the ciprofloxacin MIC. Five of these eight were strains of Pseudomonas aeruginosa, and in several cases there were stepwise increases in MIC or progressive decreases in the diameter of the zone of inhibition in serial culture specimens obtained during several weeks of treatment (Table II). Of 15 strains of Staphylococcus aureus, only one (initially oxacillin resistant) developed resistance. This occurred in a stepwise fashion in a patient whose serum concentrations of ciprofloxacin eight hours after administration of the intravenous dose were very close to the MIC of the infecting organism (Table II). In addition, on Day 17 of therapy a strain of S. aureus emerged that had a MIC of more than 4.0 Fgiml and total lack of a measurable zone of inhibition on testing by the disk method. Oxacillin-susceptible S. aureus infection persisted in
two other patients, but resistance did not develop. All the Enterococcus and Streptococcus species were found in infections due to multiple pathogens., at least one of which was S. aureus or a gram-negative bacillus, Two of the six strains of enterococci initially appeared to be susceptible to ciprofloxacin, but reculture during therapy showed them to be moderately susceptible. The serum concentrations obtained with intravenous ciprofloxacin are shown in Table III; these were consistent with previously reported results [lo]. Peak concentrations (those obtained 30 minutes after infusion of the dose) below 1.0 pg/ml occurred in several patients, all of whom were under 50 years of age and had normal renal function. One patient who received 400 mg every eight hours weighed 120 kg and had a postoperative sternal wound infection and bacteremia due to S. aureus. With this dosage, ciprofloxacin serum concentrations above the MIC for her infecting organism were maintained throughout the interval between doses. Adverse reactions to ciprofloxacin included rash necessitating discontinuation of therapy (one patient), crystalluria (two), irritation at the site of the intravenous injection (six), and nausea or anorexia (three). The crystalluria occurred during oral therapy given after hospital discharge, and it resolved when oral intake of fluids was increased. COMMENTS Intravenous or sequential intravenous and oral ciprofloxacin produced a complete clinical and bacteriologic cure in 14 of 32 patients (44 percent) with serious infections, many of whom had not been cured by standard therapy. Overall response rate (cure plus improvement) was 94 percent. Adverse effects were minor, except in one patient with a rash necessitating discontinuation of therapy. During therapy with ciprofloxacin, 50 of 65 pathogens were eradicated from the primary sites of infections. Twelve bacterial pathogens developed resistance to ciprofloxacin, including five of 14 P. aeruginosa organisms and one of three oxacillin-resistant S. aureus isolates. Similar findings in patients with bone, joint, and soft-tissue infections have been reported by other investigators [ll]. Such results are not surprising, since it is relatively easy in vitro to select resistant colonies of P. aeruginosa with MICs
November 30, 1989
The American Journal of Medicine
Volume 87 (suppl 5A)
5A-233s
SYMPOSIUM
ON CIPROFLOXACIN
I DALY ET AL
TABLE II MlCs and Serum Concentrations of Ciprofloxacin in Five Patients with Resistant Strains Serum Drug Concentration kg/ml) Patient Number
Pathogen
1:
Fi aerughma F! aerughsa
18
FI aeruginosa
Day of Therapy
MIC kg/ml)
1
0.25 0.75
18
::i 0.25 4.0 2.0
; 25 1
i? aeruginosa
19
a
:,i >4:0 0.5
S. aureus (oxacillin-resistant)
f8
8t
410 >4.0
S. aureus (oxacillin-resistant)
Dosage
30 Minutes*
200 mg q12h mg - q12h
8 Hours* 0.19 1.20 -
0.92 -
300mi q8h 300mg q8h
-
0.36
1% -
0.93 -
300m;ql2h
1.25 2.03
029
mg q8h q8h 300 mg -
-
300 m
-
0.24
0.64 0.66 -
-
3h = every eight hours; q12h = every 12 hours. rime after administration of intravenous dose. Values were obtained within the same three.day period as corresponding MIC. Tln Patient 8, a second strain of S. aureus emerged as indicated by a loss of the beta-hemolytic reaction on blood agar and a lack of a measurable the Bauer-Kirby method, as compared with the original beta-hemolytic strain that had a zone of 15 mm on Day 17 of therapy.
zone of inhibition
when tested by
TABLE Ill Serum Concentrations Achieved with Intravenous Ciprofloxacin Mean Concentration Dosage
Number of Patients
200 mg q12h
30 Minutes after Dose
1:
300 mgql2h 300mg q8h 400mg q12h 400mg q8h
1.87 (0.92-3.96)*
2.28(0.98-4.21) 1.96 (1.89-2.03)
2 1 1
1.36 (1.31-1.41)
2.97(2.06-3.55)
&/ml) 8 Hours after Dose
0.74 (0.13-1.84) 0.75 (0.20-1.86) 0.75 (0.48-1.23) 0.38 (0.20-0.56) 1.30(1.20-1.40)
3h = every eight hours; q12h = every 12 hours. slumbers in parentheses, range.
greater than or equal to 64 pg/ml by serial passage on media containing incremental concentrations of ciprofloxacin [l&13]. The mechanism of resistance in viva may correlate with the two types of resistance described in vitro, involving alterations in the A subunit of the target enzyme deoxyribonucleic acid gyrase and changes in the bacterial outer membrane [131. Both the clinical and laboratory data indicate that during therapy with ciprofloxacin, patients with infections outside the urinary tract caused by Pseudomonas sp. or oxacillin-resistant S. aureua should be monitored for the emergence of resistant strains with the use of frequent cultures. Because these organisms developed resistance to ciprofloxacin during our study and have also been found to develop resistance to other classes of antimicrobial agents [14], a combined regimen of intravenous ciprofloxacin and an antipseudomonal penicillin for P. aeruginosa, or of ciprofloxacin and rifampin for S. aureus, may be the most useful therapy for infections due to such pathogens [15]. A dosage regimen of 300 mg of intravenous ciprofloxacin every 12 hours was not uniformly effective in achieving sustained serum concentrations above the MICs for organisms observed. These subinhibitory levels may have contributed to the emergence of bacterial resistance during therapy. However., we found that intravenous ciprofloxacin and sequential intravenous and oral ciprofloxacin constituted promising therapy for severe infections, even in patients in whom therapy with standard agents had failed. 5A-234S
November 30, 1989
The American
Journal
of Medicine
Volume
REFERENCES 1. Hoffken G, Lode H, Prinzing C, Borner K, Koeppe P: Pharmacokinetics of ciprofloxacin after oral and parenteral administration, Antimicrob Agents Chemother 1985; 27: 375379. 2. Gonzalez MA, Uribe F, Moisen SD, et al: Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1984; 26: 741-744. 3. Arcieri G, Griffith E, Gruenwaldt G, et at Ciprofloxacin: an update on clinical experience. Am J Med 1987; 82 (suppl 4A): 381-386. 4. Auckenthaler R, Michea-Hamzehpour M, Pechere JC: In-vitro activity of the newer quinolones against aerobic bacteria. J Antimicrob Chemother 1985; 17 (suppl B): 2939. 5. Scully BE, Neu HC: Treatment of serious infections with intravenous ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 369-375. 6. Giamarellou H, Galanakis N: Use of intravenous ciprofloxacin in difficult-to-treat infections. Am J Med 1987; 82 (suppl 4A): 346-351. 7. Grimm H: In vitro study with ciprofloxacin: interpretive criteria of agar diffusion test according to standards of the NCCLS and DIN. Am J Med 1987; 82 (suppl4A): 376-380. 8. National Committee for Clinical Laboratory Standards, Approved Standard: M2-A3. Performance standards for antimicrobial disk susceptibility tests. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1984. 9. Joos B, Ledergerber B, Flepp M, Bettex J-D, Luthy R, Siegenthaler W: Comparison of high-pressure liquid chromatography and bioassay for determination of ciprofloxacin in serum and urine. Antimicrob Agents Chemother 1985; 27: 353-356. 10. Drusano GL: An overview of the pharmacology of intravenously administered ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 339-345. 11. Greenberg RN, Kennedy DJ, Reilly PM, et al: Treatment of bone, (oint, and soft-tissue infections with oral ciprofloxacin. Antimicrob Agents Chemother 1987; 31: 151-155. 12. Eliopoulos GM, Gardella A, Moeilering RC Jr: In vitro activity of ciprofloxacin, a new carboxyquinolone antimicrobial agent. Antimicrob Agents Chemother 1984: 25: 331-335. 13. Hooper DC, Wolfson JS, Ng EY, Swartz MN: Mechanisms of action of and resistance to ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 12-20. 14. Simberkoff MS, Rahal JJ Jr: Bactericidal activity of ciprofloxacin against amikacin and cefotaxime+esistant gram-negative bacilli and methicillin-resistant staphylococci. An. timicrob Agents Chemother 1986; 29: 1098-1100. 16. Desplaces N, Gutmann L, Carlet J, Gurbert J, Acar JF: The new quinolones and their combinations with other agents for therapy of severe infections. J Antimicrob Chemother 1986; 17 (suppl A): 25-39. 87 (suppl
5A)
G. WORTHINGTON, M.D., SYED A. Rm, M.D., REN~EROBILLARD, M.A.
he fluoroquinolone ciprofloxacin is well absorbed T by the gastrointestinal tract [l]. Thus, when given orally, sufficient serum concentrations of this antimicrobial are achieved for the treatment of infections caused by either gram-positive or gram-negative bacteria [2,3]. Frequently, however, hospitalized patients with severe infections are too ill to take oral agents, or they have abnormalities of the gastrointestinal tract that may affect drug absorption. Other patients with severe infections, such as bacteremia, receive intravenous therapy to meet accepted standards of care. Treatment of such patients initially requires a parenteral agent so that optimal serum levels of drug can be achieved. Ciprofloxacin, which is one of the most active quinolones in vitro [4], is now under study in an intravenous formulation [5,6], making sequential therapy with its intravenous and then its oral form a potentially useful clinical regimen for seriously ill patients who require continued therapy after the signs and symptoms of acute infection have improved. We prospectively studied the clinical and bacteriologic results of therapy with sequential intravenous and oral ciprofloxacin in hospitalized patients with severe infections, many of whom had not been cured by antibacterial therapy with standard agents. We also examined serum concentrations of ciprofloxacin to assess the adequacy of the intravenous dosages used.
PATIENTSAND METHODS Men and women with culture-proven severe infections caused by ciprofloxacin-susceptible organisms were eligible for enrollment in the study. The patients had been determined by their attending physicians to require hospitalization and parenteral therapy. Patients treated unsuccessfully with other antimicrobial agents were preferentially considered for enrollment, as long as a positive culture was obtained from an actively infected site immediately before the ciprofloxatin therapy was begun. Patients were excluded from the study if they were pregnant or nursing, allergic to quinolone agents, not expected to live for more than 30 days, or needed concomitant antimicrobial therapy other than clindamycin or metronidazole. Informed consent was obtained from all patients or their legal guardians. Patients’ clinical diagnoses were confirmed by radiographic examination., radionuclear scanning, cultures, and laboratory testing appropriate to the infection. Ciprofloxacin was given intravenously at a dosage of 200 to 400 mg every eight to 12 hours. The maximal amount administered was 10 mg/kg of body weight, or From the Departments of Medicine and Surgery, Saint Elizabeth’s Hospital, and Tufts University School of Medicine, Boston, Massachusetts, This study was supported by a grant from Miles Inc., Pharmaceutical Division. Requests for reprints should be addressed to Dr. Jennifer S. Daly, Saint Elizabeth’s Hospital, 736 Cambridge Street, Boston, Massachusetts 02135.
5A-232s
November 30, 1989
The American Journal of Medicine
1,200 mg in a 24-hour period. Dosage was adjusted on the basis of assessments of renal function and (in some cases) serum levels. Oral ciprofloxacin was given at a dosage of 500 to 1,000 mg every 12 hours. The minimal duration of the complete regimen was four days. Patients were switched from intravenous to oral therapy if they had clinical improvement and could take orally administered medication. Specimens for culture were taken from the infected sites in all patients within 48 hours of entry, at the end of the intravenous treatment, at the end of the sequential intravenous and oral treatment, and at a follow-up visit within a month after therapy was completed. However, subsequent culture specimens were not obtained if no infected tissue remained at the site of infection. The clinical response was graded at the end of the intravenous therapy, at the end of all therapy, and at the follow-up visit, as “cure” if there was complete resolution of signs and symptoms of the infection without relapse or re-infection during the follow-up period, “improvement” if there was amelioration of signs and symptoms without complete resolution of the evidence of infection, “no response” if there was no change or deterioration in the patient’s clinical condition, and “indeterminate” if the patient died of underlying disease during treatment. The bacteriologic response was graded as “cure” if all pathogens were eradicated from the site of infection, “improvement” if one or more pathogens were eradicated from a mixed infection, and “no response” if all infecting organisms persisted in cultures from the infected site. Susceptibility to ciprofloxacin was determined by standard disk-diffusion techniques using a 5-pg disk and Mueller-Hinton agar [7]. Minimal inhibitory concentrations (MICs) were determined by a microbroth dilution technique using the Sensititre System (Radiometer, Copenhagen). Quality control was performed according to guidelines established by the National Committee for Clinical Laboratory Standards [8]. While receiving intravenous therapy, patients were observed closely for signs of toxicity and response to therapy with the use of daily history-taking and physical examinations. Serum chemistry, complete blood cell count, and urinalysis results were assessed every three to five days during intravenous therapy and every seven to 14 days during oral therapy. Serum concentrations of ciprofloxacin were monitored in 23 patients by a bioassay using Klebsiella pneumoniae (ATCC 10031) [21 or by high-pressure liquid chromatography [9]. Blood was drawn for the assays 30 minutes and eight hours after an intravenous dose was given.
RESULTS Of 3’7 patients entered into the study, 32 had at least 48 hours of intravenous therapy and met all criteria for inclusion. The patients ranged in age from 21 years
Volume 87 (suppl 5A)
SYMPOSIUM
TABLE I Bacteriologic
ON CIPROFLOXACIN / DALY ET AL
Response Eradication
Pathogen
Number
End of Intravenous Therapy
End of All Therapy
Persistence
Gram.positive Enterococcussp. S. aureus (oxacillln.susceptible) S. aufeus (oxacillin~resistant) Streptococcussp. Gram.negative Escherichiaco/i Enterobacter sp. Klebsiellaoxytoca Proteus mirabilis F!aeruginosa 14 Xanfhomonas maitoph//ia 2 Other 7 30 Total 65 *Numbers in parentheses indicate the number of strains that developed resistance to ciprofloxacin.
to 91 years (mean, 61 years). The patients had skin or skin-structure infections (13 patients)., osteomyelitis (10 patients), pneumonia (five patients), sternal wound infections with bacteremia (two patients), peritonitis (one patient), or a complicated urinary tract infection (one patient). Twenty-four of the patients had not responded to previous antimicrobial therapy. Intravenous ciprofloxacin therapy was given for a median of five days (range, two to 19 days) followed by oral ciprofloxacin therapy for a median of 17.5 days (range, zero to 93 days). At the end of intravenous therapy, one patient had a complete clinical and bacteriologic cure, one had no response, and 30 had either clinical or bacteriologic improvement. After the intravenous therapy alone, the sequential intravenous and oral regimen, and a one-month follow-up period, 14 patients (44 percent) had complete clinical and bacteriologic cure, and 15 (50 percent) had clinical or bacteriologic improvement, for an overall response rate of 94 percent. One patient (3 percent) had no response, one (3 percent) did not complete follow-up, and one patient died before completing therapy. The patient who had no response to therapy was a 72-year-old man who had recently had a pneumonectomy for lung cancer. During therapy, he had adequate serum concentrations of ciprofloxacm; however, progressive pneumonia developed, along with breakdown of the suture line in the bronchial stump. He was removed from the study and switched to standard antimicrobial therapy. The bacteriologic response is shown in Table I. Of the 39 gram-negative bacteria isolated, 31 were eradicated by the end of therapy, and eight developed an increase in the ciprofloxacin MIC. Five of these eight were strains of Pseudomonas aeruginosa, and in several cases there were stepwise increases in MIC or progressive decreases in the diameter of the zone of inhibition in serial culture specimens obtained during several weeks of treatment (Table II). Of 15 strains of Staphylococcus aureus, only one (initially oxacillin resistant) developed resistance. This occurred in a stepwise fashion in a patient whose serum concentrations of ciprofloxacin eight hours after administration of the intravenous dose were very close to the MIC of the infecting organism (Table II). In addition, on Day 17 of therapy a strain of S. aureus emerged that had a MIC of more than 4.0 Fgiml and total lack of a measurable zone of inhibition on testing by the disk method. Oxacillin-susceptible S. aureus infection persisted in
two other patients, but resistance did not develop. All the Enterococcus and Streptococcus species were found in infections due to multiple pathogens., at least one of which was S. aureus or a gram-negative bacillus, Two of the six strains of enterococci initially appeared to be susceptible to ciprofloxacin, but reculture during therapy showed them to be moderately susceptible. The serum concentrations obtained with intravenous ciprofloxacin are shown in Table III; these were consistent with previously reported results [lo]. Peak concentrations (those obtained 30 minutes after infusion of the dose) below 1.0 pg/ml occurred in several patients, all of whom were under 50 years of age and had normal renal function. One patient who received 400 mg every eight hours weighed 120 kg and had a postoperative sternal wound infection and bacteremia due to S. aureus. With this dosage, ciprofloxacin serum concentrations above the MIC for her infecting organism were maintained throughout the interval between doses. Adverse reactions to ciprofloxacin included rash necessitating discontinuation of therapy (one patient), crystalluria (two), irritation at the site of the intravenous injection (six), and nausea or anorexia (three). The crystalluria occurred during oral therapy given after hospital discharge, and it resolved when oral intake of fluids was increased. COMMENTS Intravenous or sequential intravenous and oral ciprofloxacin produced a complete clinical and bacteriologic cure in 14 of 32 patients (44 percent) with serious infections, many of whom had not been cured by standard therapy. Overall response rate (cure plus improvement) was 94 percent. Adverse effects were minor, except in one patient with a rash necessitating discontinuation of therapy. During therapy with ciprofloxacin, 50 of 65 pathogens were eradicated from the primary sites of infections. Twelve bacterial pathogens developed resistance to ciprofloxacin, including five of 14 P. aeruginosa organisms and one of three oxacillin-resistant S. aureus isolates. Similar findings in patients with bone, joint, and soft-tissue infections have been reported by other investigators [ll]. Such results are not surprising, since it is relatively easy in vitro to select resistant colonies of P. aeruginosa with MICs
November 30, 1989
The American Journal of Medicine
Volume 87 (suppl 5A)
5A-233s
SYMPOSIUM
ON CIPROFLOXACIN
I DALY ET AL
TABLE II MlCs and Serum Concentrations of Ciprofloxacin in Five Patients with Resistant Strains Serum Drug Concentration kg/ml) Patient Number
Pathogen
1:
Fi aerughma F! aerughsa
18
FI aeruginosa
Day of Therapy
MIC kg/ml)
1
0.25 0.75
18
::i 0.25 4.0 2.0
; 25 1
i? aeruginosa
19
a
:,i >4:0 0.5
S. aureus (oxacillin-resistant)
f8
8t
410 >4.0
S. aureus (oxacillin-resistant)
Dosage
30 Minutes*
200 mg q12h mg - q12h
8 Hours* 0.19 1.20 -
0.92 -
300mi q8h 300mg q8h
-
0.36
1% -
0.93 -
300m;ql2h
1.25 2.03
029
mg q8h q8h 300 mg -
-
300 m
-
0.24
0.64 0.66 -
-
3h = every eight hours; q12h = every 12 hours. rime after administration of intravenous dose. Values were obtained within the same three.day period as corresponding MIC. Tln Patient 8, a second strain of S. aureus emerged as indicated by a loss of the beta-hemolytic reaction on blood agar and a lack of a measurable the Bauer-Kirby method, as compared with the original beta-hemolytic strain that had a zone of 15 mm on Day 17 of therapy.
zone of inhibition
when tested by
TABLE Ill Serum Concentrations Achieved with Intravenous Ciprofloxacin Mean Concentration Dosage
Number of Patients
200 mg q12h
30 Minutes after Dose
1:
300 mgql2h 300mg q8h 400mg q12h 400mg q8h
1.87 (0.92-3.96)*
2.28(0.98-4.21) 1.96 (1.89-2.03)
2 1 1
1.36 (1.31-1.41)
2.97(2.06-3.55)
&/ml) 8 Hours after Dose
0.74 (0.13-1.84) 0.75 (0.20-1.86) 0.75 (0.48-1.23) 0.38 (0.20-0.56) 1.30(1.20-1.40)
3h = every eight hours; q12h = every 12 hours. slumbers in parentheses, range.
greater than or equal to 64 pg/ml by serial passage on media containing incremental concentrations of ciprofloxacin [l&13]. The mechanism of resistance in viva may correlate with the two types of resistance described in vitro, involving alterations in the A subunit of the target enzyme deoxyribonucleic acid gyrase and changes in the bacterial outer membrane [131. Both the clinical and laboratory data indicate that during therapy with ciprofloxacin, patients with infections outside the urinary tract caused by Pseudomonas sp. or oxacillin-resistant S. aureua should be monitored for the emergence of resistant strains with the use of frequent cultures. Because these organisms developed resistance to ciprofloxacin during our study and have also been found to develop resistance to other classes of antimicrobial agents [14], a combined regimen of intravenous ciprofloxacin and an antipseudomonal penicillin for P. aeruginosa, or of ciprofloxacin and rifampin for S. aureus, may be the most useful therapy for infections due to such pathogens [15]. A dosage regimen of 300 mg of intravenous ciprofloxacin every 12 hours was not uniformly effective in achieving sustained serum concentrations above the MICs for organisms observed. These subinhibitory levels may have contributed to the emergence of bacterial resistance during therapy. However., we found that intravenous ciprofloxacin and sequential intravenous and oral ciprofloxacin constituted promising therapy for severe infections, even in patients in whom therapy with standard agents had failed. 5A-234S
November 30, 1989
The American
Journal
of Medicine
Volume
REFERENCES 1. Hoffken G, Lode H, Prinzing C, Borner K, Koeppe P: Pharmacokinetics of ciprofloxacin after oral and parenteral administration, Antimicrob Agents Chemother 1985; 27: 375379. 2. Gonzalez MA, Uribe F, Moisen SD, et al: Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1984; 26: 741-744. 3. Arcieri G, Griffith E, Gruenwaldt G, et at Ciprofloxacin: an update on clinical experience. Am J Med 1987; 82 (suppl 4A): 381-386. 4. Auckenthaler R, Michea-Hamzehpour M, Pechere JC: In-vitro activity of the newer quinolones against aerobic bacteria. J Antimicrob Chemother 1985; 17 (suppl B): 2939. 5. Scully BE, Neu HC: Treatment of serious infections with intravenous ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 369-375. 6. Giamarellou H, Galanakis N: Use of intravenous ciprofloxacin in difficult-to-treat infections. Am J Med 1987; 82 (suppl 4A): 346-351. 7. Grimm H: In vitro study with ciprofloxacin: interpretive criteria of agar diffusion test according to standards of the NCCLS and DIN. Am J Med 1987; 82 (suppl4A): 376-380. 8. National Committee for Clinical Laboratory Standards, Approved Standard: M2-A3. Performance standards for antimicrobial disk susceptibility tests. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1984. 9. Joos B, Ledergerber B, Flepp M, Bettex J-D, Luthy R, Siegenthaler W: Comparison of high-pressure liquid chromatography and bioassay for determination of ciprofloxacin in serum and urine. Antimicrob Agents Chemother 1985; 27: 353-356. 10. Drusano GL: An overview of the pharmacology of intravenously administered ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 339-345. 11. Greenberg RN, Kennedy DJ, Reilly PM, et al: Treatment of bone, (oint, and soft-tissue infections with oral ciprofloxacin. Antimicrob Agents Chemother 1987; 31: 151-155. 12. Eliopoulos GM, Gardella A, Moeilering RC Jr: In vitro activity of ciprofloxacin, a new carboxyquinolone antimicrobial agent. Antimicrob Agents Chemother 1984: 25: 331-335. 13. Hooper DC, Wolfson JS, Ng EY, Swartz MN: Mechanisms of action of and resistance to ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 12-20. 14. Simberkoff MS, Rahal JJ Jr: Bactericidal activity of ciprofloxacin against amikacin and cefotaxime+esistant gram-negative bacilli and methicillin-resistant staphylococci. An. timicrob Agents Chemother 1986; 29: 1098-1100. 16. Desplaces N, Gutmann L, Carlet J, Gurbert J, Acar JF: The new quinolones and their combinations with other agents for therapy of severe infections. J Antimicrob Chemother 1986; 17 (suppl A): 25-39. 87 (suppl
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