- Email: [email protected]
Brief report: Combination effects of ciprofloxacin, clindamycin, and metronidazole intravenously in volunteers
Brief Report: Combination Effects of Ciprofloxacin, Clindamjcin, and .Metronidazole Intravenously in Volunteers DEPPERMANN, M.D., MICHAEL BOECKH, M.D., SABINE GRINEISEN, M.D., FUATSHOKRY,M.D., KLAUSBORNER,M.D., PETERKOEPPE!Ph.D.,CHRISTINA KRASEMANN, M.D., JUTTAWAGNER,M.D., HARMUTLODE,M.D. KARL-MAITHIAS
Berlin, Federal Republic of Germahy
Despite the broad antibacterial spectrum of ciprofloxacin, most anaerobic organisms are resistant to the .drug, whereas several gram-pdsitive organisms are only modetately susceptible. Thus, .in. some clinical situations, combined treatment with ciprofloxacin and metronidazole or clindapycin could be useful, “rherefore, the pharmacokinetics and serum bactericidal a&i&ties of ciprofloxacin in combintition with cljndamycin or metronidaziile %+re investiiated using-a randomized crossover study design in 10 healthy volunteers. Ciprofloxacin (200 rpg) was administered alqne and in-combination with clindamycin (600 mg) or’mi$ronidazole (500 mg); all diugs were given intravenously over 30 minutes, serum and urine concentrations of th& siibstances were measured using standard methods (high-performance li@id chromatography or gas chromatography). Blood s$mples for determhiation of serum bacteiicidal activity against five different aerobic and two anaerobic bacterial species (afotal of ‘58 strains) were obtained one hour and six-hours after drug infusion. All values were stqtistically analyzed by use of the Student t test. ..~
he development of the fluoroquinolones has reT sulted in antimicrobials with enhanced gramnkgative activity, including moderate activity against Pseudmnonas aeruginosa [l-3]. Ciprofloxaein appears to be the most active quinolone [4]. Gram-positive strains like streptococci or staphylococci and anaerobes are less susceptible [1,5]. Althqugh ciprofloxacin is often used as a single drug, there are clinical situations in which combination with other antibacterials is needed to expand its antibacterial spectrbm. Examples are mixed aerobic-anaerobic infections such as aspiration pneumonia or intra-abdominal infections, fey which initial therapy has to be empiric [6]. Another group is febrile neutropenic patients [7]. Clindamycin and nietronidazole have an antibacterial spectrum that includes mainly gram-positives and anaerobes [6]. Therefore, using ciprofloxacin in combintition with one bf these substances could be useful in some clinictil situations. However, before using antibiotic combjnations in treatment of infected patients, it is riecessary to analyze the pharmacokinetic profiles and possible interactions as well as the antibacterial efficacy of these drug combinations in volunteers [S]. The determination of the serum bactericidal activity usually @ves better information as to a@ibacterial activity of specific antibiotics in comparison with in vitro methods. Such analysis is especially indicated if previous in vitro studies have shown any indifferent or antagonistie results [4,9-111.
MATERIALS AND METHODS Study Design
I
I From the MedIcal Department, Klinikum Steglitz, Freie Universitdt Berlin, Berlin, Federal Republic of Germany. Requests for reprints should be addressed to Dr. KarlMatthlas Deppecmann, Medical Department, Kllnikum Steglitz, Freie Universitat Berlin, Hindenburgdamm 30, D-1000 Berlin 45, Federal Republic of Germany.
Measurement
,
I
5A-46s
November
Ten healthy volunteers, five women and five men, participated in a randomizgd, crossover study. The mean body weight was 67.6 t 10.1 kg and ages rapged between 21 and 35 years. The mean creatinine clearance was 506 + 11 ml/minute. Subjects had normal kidney and liver functions as well as normal’biochemical and hetiatologic laboratory profiles. Theyreceived the following by intravenous infusion dver 30 minutes: 500 mg metrohidazole; 200 mg ciprofloxacin; 600 mg clindamycin;. 200 mg clproflqxacin plus 600 mg clindamycin; or 200 mg diprofloxacin plus 500 mg metronidazole. Fol; the combination regimens, each drug was infused simultaneously but into a separate vein. Blood samples were obtained before and immediately after infusiori(zero), 0.25; 0.5, 1.0, 1.5,2.0,4.0,6.0! 8.0, 12, and 24 hours followmg the discontinuation of infusion. Urine was collected at hterv& of zero to six hours, six to 12 hours, 12 to 24 hours, and 24 to 48 hours post-infusion. Serum and urine concentr@,ions of ciprofloxacin and metronidazole were measured by high-performance
30, 1989 The AmericanJournalof Medicine Volume87 (suppl 5A)
SYMPOSIUM
Mean Concentration
ON CIPROFLOXACIN
i DEPPERMANN
ET AL
1
(w/l) 0.1 Figure 1. Mean serum concentrations of 10 patients. Circle = 200 mg ciprofloxacin; triangle = 200 mg ciprofloxacin plus 500 mg metronidazole; square = 200 mg ciprofloxacin plus 600 mg clindamycin.
720 Time (minutes)
1 10 Mean Concentration (mg4
1
Fkure 2. Mean strum concentrations of 10 paiients. Circle = 500 mg metronidazole; triahgle = 500 mg metronidazole in combinatlon with 200 mg ciprofloxacin; square = 600 mg clindamycin in combination with 200 mg ciprofloxacin.
I
I
I
I
360
720
1080
1440
Time
liquid chromatography as described elsewhere [12,13]. Serum concentrations of clindamycin were determined by a gas-chromatographic method involving organic extraction, liquid-liquid partitioning, derivatization with heptafluorobutyric anhydride, and capillary gas chromatography using electron capture detection (unpublished method of Analytical BioChemistry Laboratories, Upjohn Company, 1988). Bactericidal Activities
Serum bactericidal activity was performed according to the method of Reller and Stratton [14] on blood samples obtained one hour and six hours after infusion. The serum bactericidal activity against the following five aerobic and two anaerobic bacterial species was determined as: Staphylococcus aureus (IO strains), Escherichia coli (10 strains), Pseudomonas aeruginosa (10 strains), Streptococcus pneumoniae (10 strains), Klebsiella pneumoniae (10 strains), Bacteroides fragilis (six strains), Bacteroides thetaiotaomicron (two strains). All strains were fresh clinical isolates obtained by the Department of Microbiol%Y* Pharmacokinetics
All serum concentrations were normalized to an average body weight of 70 kg before being analyzed. Pharmacokinetic parameters were calculated according to open three-compartment models. The Student t test was used to distinguish the differences with a p value of less than 0.05 considered significant. RESULTS Mean serum concentrations of ciprofloxacin, clindaNovember
(minutes)
my&,
and metronidazole are depicted in Figure 1. the combined administration of ciprofloxacin with either clindamycin or metronidazole. Table I summarizes the important pharmacokinetic parameters. We did not observe any differences in the important pharmacokinetic parameters of ciprofloxacin alone or when administered in combination with clindamycin or metronidazole, with the exception of a decrease in the volume of distribution of ciprofloxacin when coadministered with metronidazole. The total area under the curve of ciprofloxacin administered in combination with clindamycin was slightly increased as compared with ciprofloxacin alone. Figure 2 demonstrates
Serum Bactericidal Activity
The mean serum bactericidal activity after one hour and six hours is depicted in Table II. The combination of ciprofloxacin and clindamycin resulted in higher bactericidal activities against gram-positive strains, particularly against S. aureus and S. pneumoniae: one hour ciprofloxacin alone-155 S. aureus; 1:2 S. pneumoniae; one hour ciprofloxacin plus clindamytin-1:19.9 S. aureus; 153 S. pneumoniae. The high activity of ciprofloxacin against gram-negative strains was not influenced when the drug was given with either clindamycin or metronidazole. The combination of ciprofloxacin with metronidazole or clindamycin, however, did not result in higher efficacy against the tested anaerobes. COMMENTS The fluoroquinolones are characterized as antimicrobials with a broad antibacterial spectrum [l-3]. 30, 1989
The American Journal of Medune
Volume 87 (suppl 5A)
!iA-47s
SYMPOSIUM
ON CIPROFLOXACIN
/ DEPPERMANN
ET AL
-
clindamycin against 30 strains of synergistic efficacy was observed with the combina1 plus tion of ciprofloxacin plus metronidazole. Werk and B. fragilis.
TABLE I Pharmacokinetic
Parameters of Ciprofloxacin* Ciprofloxacin
5.8?r2.5
Cpo (mgiliter) tliti (minute] tl,@ (minute] t,.,_., ,?- (minute1
11.5 * 9.4
139.9+ 36.6 416.9 * 176.1
A%,
5.0i 0.9 403.4t 167.3
(mghouriliter)
Vd alea (liters)
Cl,,,,, (ml/minute) Cl,,,, (ml/minute\ Urinary recovery’ 1%of dose\ O-24hours O-48 hours
410.8 IL 1053 659.9 ? 136.8
. “ ~ “ I
Ciprofloxacin t Mefrohidazole
Ciprofloxacin t Clindamycin
10.5 t 5.1
12.0 * 7.4
9.1t 1.8 108.9* 21.1 370.1t 161.7
5.9+ 2.0 121.1i. 33.7 424.8* 202.5
5.6A 0.9 324.8+ 162.4t 346.3t 72.5 577.2A 105.8
5.8rt 1.4 357.9A 136.9 331.6k 78.8 570.3It 130.4
,
5Ei.6? 1.2 6ti.5+ 7.0
61.8 k 8.3
62.7+ 8.3
58.42 7.7 59.3i 8.0
ro = virtual concentration for t = 0; tl,aa = half-life at alpha phase; tiil = half-life at ta phase; tr,ar = half-life at tau phase; AU&r = total area under the curve; Vd a,ea= aa volume of distribution; Cl,,,,, = renal clearance; Cl,,,,, = total clearance. )ata are mean t SD. All data were normalized to 70 kg body weight.
TABLE II Serum Bactericidal Activity of Ciprofloxacin (mean) Obtained One Hour and Six Hours after Infusion Ciprofloxacin t Metronidazole
Ciprofloxacin 1 Hour
1 Hour
6 Hours
1:4.9 b2.0 ;;;“j3
1:2.1 1:2.0 1:il.a
1:19.9 1:53.0 1:38.6
1:2.9
1:5.5
S aureus S. pneumomae
1:5.5
1:2.3
1:2.0
1:2.0
E:co/i
1:30.9
1:ll.l
F! aeruginosa K pneumoniae 6. fragik B. fhetaiofaomicron
1:4.4
1:2.6
1:14.6 1:2.1 1:2.1
1:5.5 1:2.1 1:2.1
1:15.6 1:6.4 1:2.4 1:2.1 1:2.8 1:2.0
1 Hour
1:18.4 1:2.9 1:2.5
6 Hours
1:54 1:13.6 1:11.9 1:3.1
117.4 1:2.4 1:2.2
Their moderate antibacterial activity against grampositive strains and anaerobes could be supplemented when administered in combination with clindamycin or metronidazole. However, the antagonistic effects of these combinations must be prevented. A primary effect of the quinolones is inhibition,of bacterial deoxyribonucleic acid synthesis in the presence of competent ribonucleic acid and protein synthesis [15,16]. On the other hand, some other antimicrobials are also potent protein synthesis inhibitors. Antagonistic effects of chloramphenicol and rifampin with quinolones have been reported (Smith, unpublished observations, 1984). Cirjrofloxacin plus tetracycline, ciprofloxacin plus erythromycin! and ciprofloxacin plus clindamycin led to a prolongation of the 99.9 ljercent killing time curves [4]. However, the combination of ciprofloxacin with aminoglycosides reduced the 99.9 percent killing time [4,1’7,18], and Lewin and Smith [17], could demonstrate enhanced bacterial“ ‘activity of the fluoroquinolone in combination with aminoglycosides. In contrast, Kemmerich et al [19] found no difference between ciprofloxacin and the combination of ciprofloxacin plus tobramycjn in killing P. aeruginosa in guinea pigs with acute pneumonia. In vitro studies by Whiting et aE [20] suggested synergistic effects of ciprofloxacin in combination with clindamycin against the six genera of anaerobes except Peptostreptococcus intermedius. Similar results were obtained by Esposito et al [21] with ciprofloxacin 5A-48s
November
30,
1989
The American Journal of Medicine
Schneider [22] found the combination of ciprofloxacin plus metronidazole to be slightly more active for Clostridium perfringens and Clostridium difficile than ciprofloxacin or metronidazole alone. Data about synergistic effects with various antibacterials in combination with ciprofloxacin are rather conflicting [4]. Our results indicate enhanced antibacterial activity for the ciprofloxacin plus, clindamycin combination against streptococci and staphylococci. The high activity of ciprofloxacin against gram-negative bacteria was unaffected, although there was no improvement concerning anaerobes; however, there are some doubts as to whether the serum bactericidal activity technique is adequate for evaluating antimicrobial activity of drugs against anaerobic bacteria [6]. The ciprofloxacin-plus-metronidazole and ciprofloxacin-plus-clindamycin combinations had no beneficial effect concerning the bactericidal activity against anaerobes, although the pharmacokinetics ‘of each drug were not altered. Further clinical studies are needed to clarify the value ,of combination therapy.
REFERENCES
Ciprofloxacin t Clindaniycin
6 Hours
No
1. Wolfson JS, Hoop& DC: The fluroquinolones: structures, mechanism of acbon and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 1985; 28: 5.81586. 2. Bauernfeind A: Antimicrobial activity of crprofloxacin: an overview. In: Neu HC, Weuta H, eds: Proceedrngs of the 1st International Ciprofloxacin Workshop, Vol. 8. Amsterdam: Excerpta Medica, 1986; 1-21. 3. Sanders CC, Sanders WE, Goering RV: Overview of preclinical studies with ciprofloxacin. Am J Med 1987; 82 (suppl 4A): 2-11. 4. Norris A, Mandell GL: In: Andriole VT ed: The qurnolones. History and overview. London: Academic Press Limited, 1988; l-22. 5. Chin NX, Neu HC: Ciprofloxacrn, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 1984; 25: 319-326. 6. Finegold SM, Wexler HM: Therapeutic implications of bacteriologic findings in mixed aerobic-anaerobic infections. Antimicrob Agents Chemother 1988; 5: 611-616. 7. Smith JT: Awakening the slumbering potential of the 4-quinolone’antibacterials. Pharm J 1984; 233: 299-305. 8. Lode H, Hoffken G, Olschewski P, et a/r Pharmacokinetics of of!pxacin after parenteral and oral administration. Antimicrob Agents Chemother 1987; 31: 1338-1342. 9. Moody JA, Gerding DN, Peterson LR: Evaluation of crprofloxacin’s synergism with other agents by multiple in viva methods. Am J Med 1987; 82 (suppl 2A): 44-54. 10. Neu HC, Labthavrkul P: In vitro activity of norfloxacin, a quinoline-carboxylic acid, compared with that of p-lactams, aminoglycosides and trimethoprim. Antimicrob Agents Chemother 1982; 22: 23-27. 11. Chin NX, Neu HC: In vifro activity of enoxacin, a quinolone carboxylic acid, compared with those of norfioxacin, new p-lactams, aminoglycosides and trimethoprim. Antimicrob Agents Chemother 1980; 4: 754-763. 12. Borner K, Lode H, Hoffken G, Priming C, Wiley R: Liquid chromatographic determination of ciprofloxacin and some metabolites in human body fluids. J Clin Chem Clin Biothem 1986; 24: 325-331. 13. Nilsson-Ehle I, Ursing B, Nilsson-Ehle P: Liquid chromatography assay for metronidazole and’tinidazole: pharmacokinetic and metabolrc studies in human subjects. Antimicrob Agents Chemother 1981; 19: 754-760. 14. Reller LB, Stratton CW: Serum dilution test for bactericidal activity. Il. Standardization and correlation with antimicrobial assays and susceptibility tests. J Infect Dis 19n; 136: 196-204. 15. Crumplin GC, Smith JT: Nalidixrc acid: antibacterial paradox. Antimicrob Agents Chemother 1975; 8: 251-261. 16. Wang JC: DNA topoisomerases. Annu Rev Biochem 1985; 54: 665-697. 17. Lewin CS, Smith JT: The bactericidal action of nalidrxic acrd can be potentiated by . aminoglycosides. J Pharm Pharmacol 1985; 37: 94-97. 18. Lewin CS, Smith JT: Should 4.quinotones be used in combination therapy? (abstr 345). In: Proceedings of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1986; 159. 19. Kemmerich B, Small GJ, Pennington JE: Comparative evaluation of ciprofloxacin, enoxacin and ofloxacin in experimental Pseudomonas aeruginosa pneumonra. Antimrcrob Agents Chemother 1986; 29: 395-399. 20. Whiting JL, Cheng N, Chow AW: lnteracbons of ciprofloxacin with dindamycin, metronidazole, cefoxitin,, cefotaxime and mezlozillin against gram-posibve and gram-negative anaerobic bacteria. Antimicrob Agents Chemother 1987; 31: 1379-1382. 21. Espositi S, Gupta A, Thadepalli H. In vitro synergy of ciprofloxacin and three other antibiotics against Bacteroides fragi/is. Drugs Exp Clin Res.1987; 13: 489-492. 22. Werk R, Schneider L: Ciprofloxacin in combination with metronrdazole. Infection 1988; 16: 237-260.
Volume 87 (suppl 5A)
Berlin, Federal Republic of Germahy
Despite the broad antibacterial spectrum of ciprofloxacin, most anaerobic organisms are resistant to the .drug, whereas several gram-pdsitive organisms are only modetately susceptible. Thus, .in. some clinical situations, combined treatment with ciprofloxacin and metronidazole or clindapycin could be useful, “rherefore, the pharmacokinetics and serum bactericidal a&i&ties of ciprofloxacin in combintition with cljndamycin or metronidaziile %+re investiiated using-a randomized crossover study design in 10 healthy volunteers. Ciprofloxacin (200 rpg) was administered alqne and in-combination with clindamycin (600 mg) or’mi$ronidazole (500 mg); all diugs were given intravenously over 30 minutes, serum and urine concentrations of th& siibstances were measured using standard methods (high-performance li@id chromatography or gas chromatography). Blood s$mples for determhiation of serum bacteiicidal activity against five different aerobic and two anaerobic bacterial species (afotal of ‘58 strains) were obtained one hour and six-hours after drug infusion. All values were stqtistically analyzed by use of the Student t test. ..~
he development of the fluoroquinolones has reT sulted in antimicrobials with enhanced gramnkgative activity, including moderate activity against Pseudmnonas aeruginosa [l-3]. Ciprofloxaein appears to be the most active quinolone [4]. Gram-positive strains like streptococci or staphylococci and anaerobes are less susceptible [1,5]. Althqugh ciprofloxacin is often used as a single drug, there are clinical situations in which combination with other antibacterials is needed to expand its antibacterial spectrbm. Examples are mixed aerobic-anaerobic infections such as aspiration pneumonia or intra-abdominal infections, fey which initial therapy has to be empiric [6]. Another group is febrile neutropenic patients [7]. Clindamycin and nietronidazole have an antibacterial spectrum that includes mainly gram-positives and anaerobes [6]. Therefore, using ciprofloxacin in combintition with one bf these substances could be useful in some clinictil situations. However, before using antibiotic combjnations in treatment of infected patients, it is riecessary to analyze the pharmacokinetic profiles and possible interactions as well as the antibacterial efficacy of these drug combinations in volunteers [S]. The determination of the serum bactericidal activity usually @ves better information as to a@ibacterial activity of specific antibiotics in comparison with in vitro methods. Such analysis is especially indicated if previous in vitro studies have shown any indifferent or antagonistie results [4,9-111.
MATERIALS AND METHODS Study Design
I
I From the MedIcal Department, Klinikum Steglitz, Freie Universitdt Berlin, Berlin, Federal Republic of Germany. Requests for reprints should be addressed to Dr. KarlMatthlas Deppecmann, Medical Department, Kllnikum Steglitz, Freie Universitat Berlin, Hindenburgdamm 30, D-1000 Berlin 45, Federal Republic of Germany.
Measurement
,
I
5A-46s
November
Ten healthy volunteers, five women and five men, participated in a randomizgd, crossover study. The mean body weight was 67.6 t 10.1 kg and ages rapged between 21 and 35 years. The mean creatinine clearance was 506 + 11 ml/minute. Subjects had normal kidney and liver functions as well as normal’biochemical and hetiatologic laboratory profiles. Theyreceived the following by intravenous infusion dver 30 minutes: 500 mg metrohidazole; 200 mg ciprofloxacin; 600 mg clindamycin;. 200 mg clproflqxacin plus 600 mg clindamycin; or 200 mg diprofloxacin plus 500 mg metronidazole. Fol; the combination regimens, each drug was infused simultaneously but into a separate vein. Blood samples were obtained before and immediately after infusiori(zero), 0.25; 0.5, 1.0, 1.5,2.0,4.0,6.0! 8.0, 12, and 24 hours followmg the discontinuation of infusion. Urine was collected at hterv& of zero to six hours, six to 12 hours, 12 to 24 hours, and 24 to 48 hours post-infusion. Serum and urine concentr@,ions of ciprofloxacin and metronidazole were measured by high-performance
30, 1989 The AmericanJournalof Medicine Volume87 (suppl 5A)
SYMPOSIUM
Mean Concentration
ON CIPROFLOXACIN
i DEPPERMANN
ET AL
1
(w/l) 0.1 Figure 1. Mean serum concentrations of 10 patients. Circle = 200 mg ciprofloxacin; triangle = 200 mg ciprofloxacin plus 500 mg metronidazole; square = 200 mg ciprofloxacin plus 600 mg clindamycin.
720 Time (minutes)
1 10 Mean Concentration (mg4
1
Fkure 2. Mean strum concentrations of 10 paiients. Circle = 500 mg metronidazole; triahgle = 500 mg metronidazole in combinatlon with 200 mg ciprofloxacin; square = 600 mg clindamycin in combination with 200 mg ciprofloxacin.
I
I
I
I
360
720
1080
1440
Time
liquid chromatography as described elsewhere [12,13]. Serum concentrations of clindamycin were determined by a gas-chromatographic method involving organic extraction, liquid-liquid partitioning, derivatization with heptafluorobutyric anhydride, and capillary gas chromatography using electron capture detection (unpublished method of Analytical BioChemistry Laboratories, Upjohn Company, 1988). Bactericidal Activities
Serum bactericidal activity was performed according to the method of Reller and Stratton [14] on blood samples obtained one hour and six hours after infusion. The serum bactericidal activity against the following five aerobic and two anaerobic bacterial species was determined as: Staphylococcus aureus (IO strains), Escherichia coli (10 strains), Pseudomonas aeruginosa (10 strains), Streptococcus pneumoniae (10 strains), Klebsiella pneumoniae (10 strains), Bacteroides fragilis (six strains), Bacteroides thetaiotaomicron (two strains). All strains were fresh clinical isolates obtained by the Department of Microbiol%Y* Pharmacokinetics
All serum concentrations were normalized to an average body weight of 70 kg before being analyzed. Pharmacokinetic parameters were calculated according to open three-compartment models. The Student t test was used to distinguish the differences with a p value of less than 0.05 considered significant. RESULTS Mean serum concentrations of ciprofloxacin, clindaNovember
(minutes)
my&,
and metronidazole are depicted in Figure 1. the combined administration of ciprofloxacin with either clindamycin or metronidazole. Table I summarizes the important pharmacokinetic parameters. We did not observe any differences in the important pharmacokinetic parameters of ciprofloxacin alone or when administered in combination with clindamycin or metronidazole, with the exception of a decrease in the volume of distribution of ciprofloxacin when coadministered with metronidazole. The total area under the curve of ciprofloxacin administered in combination with clindamycin was slightly increased as compared with ciprofloxacin alone. Figure 2 demonstrates
Serum Bactericidal Activity
The mean serum bactericidal activity after one hour and six hours is depicted in Table II. The combination of ciprofloxacin and clindamycin resulted in higher bactericidal activities against gram-positive strains, particularly against S. aureus and S. pneumoniae: one hour ciprofloxacin alone-155 S. aureus; 1:2 S. pneumoniae; one hour ciprofloxacin plus clindamytin-1:19.9 S. aureus; 153 S. pneumoniae. The high activity of ciprofloxacin against gram-negative strains was not influenced when the drug was given with either clindamycin or metronidazole. The combination of ciprofloxacin with metronidazole or clindamycin, however, did not result in higher efficacy against the tested anaerobes. COMMENTS The fluoroquinolones are characterized as antimicrobials with a broad antibacterial spectrum [l-3]. 30, 1989
The American Journal of Medune
Volume 87 (suppl 5A)
!iA-47s
SYMPOSIUM
ON CIPROFLOXACIN
/ DEPPERMANN
ET AL
-
clindamycin against 30 strains of synergistic efficacy was observed with the combina1 plus tion of ciprofloxacin plus metronidazole. Werk and B. fragilis.
TABLE I Pharmacokinetic
Parameters of Ciprofloxacin* Ciprofloxacin
5.8?r2.5
Cpo (mgiliter) tliti (minute] tl,@ (minute] t,.,_., ,?- (minute1
11.5 * 9.4
139.9+ 36.6 416.9 * 176.1
A%,
5.0i 0.9 403.4t 167.3
(mghouriliter)
Vd alea (liters)
Cl,,,,, (ml/minute) Cl,,,, (ml/minute\ Urinary recovery’ 1%of dose\ O-24hours O-48 hours
410.8 IL 1053 659.9 ? 136.8
. “ ~ “ I
Ciprofloxacin t Mefrohidazole
Ciprofloxacin t Clindamycin
10.5 t 5.1
12.0 * 7.4
9.1t 1.8 108.9* 21.1 370.1t 161.7
5.9+ 2.0 121.1i. 33.7 424.8* 202.5
5.6A 0.9 324.8+ 162.4t 346.3t 72.5 577.2A 105.8
5.8rt 1.4 357.9A 136.9 331.6k 78.8 570.3It 130.4
,
5Ei.6? 1.2 6ti.5+ 7.0
61.8 k 8.3
62.7+ 8.3
58.42 7.7 59.3i 8.0
ro = virtual concentration for t = 0; tl,aa = half-life at alpha phase; tiil = half-life at ta phase; tr,ar = half-life at tau phase; AU&r = total area under the curve; Vd a,ea= aa volume of distribution; Cl,,,,, = renal clearance; Cl,,,,, = total clearance. )ata are mean t SD. All data were normalized to 70 kg body weight.
TABLE II Serum Bactericidal Activity of Ciprofloxacin (mean) Obtained One Hour and Six Hours after Infusion Ciprofloxacin t Metronidazole
Ciprofloxacin 1 Hour
1 Hour
6 Hours
1:4.9 b2.0 ;;;“j3
1:2.1 1:2.0 1:il.a
1:19.9 1:53.0 1:38.6
1:2.9
1:5.5
S aureus S. pneumomae
1:5.5
1:2.3
1:2.0
1:2.0
E:co/i
1:30.9
1:ll.l
F! aeruginosa K pneumoniae 6. fragik B. fhetaiofaomicron
1:4.4
1:2.6
1:14.6 1:2.1 1:2.1
1:5.5 1:2.1 1:2.1
1:15.6 1:6.4 1:2.4 1:2.1 1:2.8 1:2.0
1 Hour
1:18.4 1:2.9 1:2.5
6 Hours
1:54 1:13.6 1:11.9 1:3.1
117.4 1:2.4 1:2.2
Their moderate antibacterial activity against grampositive strains and anaerobes could be supplemented when administered in combination with clindamycin or metronidazole. However, the antagonistic effects of these combinations must be prevented. A primary effect of the quinolones is inhibition,of bacterial deoxyribonucleic acid synthesis in the presence of competent ribonucleic acid and protein synthesis [15,16]. On the other hand, some other antimicrobials are also potent protein synthesis inhibitors. Antagonistic effects of chloramphenicol and rifampin with quinolones have been reported (Smith, unpublished observations, 1984). Cirjrofloxacin plus tetracycline, ciprofloxacin plus erythromycin! and ciprofloxacin plus clindamycin led to a prolongation of the 99.9 ljercent killing time curves [4]. However, the combination of ciprofloxacin with aminoglycosides reduced the 99.9 percent killing time [4,1’7,18], and Lewin and Smith [17], could demonstrate enhanced bacterial“ ‘activity of the fluoroquinolone in combination with aminoglycosides. In contrast, Kemmerich et al [19] found no difference between ciprofloxacin and the combination of ciprofloxacin plus tobramycjn in killing P. aeruginosa in guinea pigs with acute pneumonia. In vitro studies by Whiting et aE [20] suggested synergistic effects of ciprofloxacin in combination with clindamycin against the six genera of anaerobes except Peptostreptococcus intermedius. Similar results were obtained by Esposito et al [21] with ciprofloxacin 5A-48s
November
30,
1989
The American Journal of Medicine
Schneider [22] found the combination of ciprofloxacin plus metronidazole to be slightly more active for Clostridium perfringens and Clostridium difficile than ciprofloxacin or metronidazole alone. Data about synergistic effects with various antibacterials in combination with ciprofloxacin are rather conflicting [4]. Our results indicate enhanced antibacterial activity for the ciprofloxacin plus, clindamycin combination against streptococci and staphylococci. The high activity of ciprofloxacin against gram-negative bacteria was unaffected, although there was no improvement concerning anaerobes; however, there are some doubts as to whether the serum bactericidal activity technique is adequate for evaluating antimicrobial activity of drugs against anaerobic bacteria [6]. The ciprofloxacin-plus-metronidazole and ciprofloxacin-plus-clindamycin combinations had no beneficial effect concerning the bactericidal activity against anaerobes, although the pharmacokinetics ‘of each drug were not altered. Further clinical studies are needed to clarify the value ,of combination therapy.
REFERENCES
Ciprofloxacin t Clindaniycin
6 Hours
No
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