Systemic Antimicrobial Therapy in Skin and Skin Structure Infections: Comparison of Temafloxacin and Ciprofloxacin LAWRENCE
CHARLES
PARISH,
M.D.,
DONALD
L.
JUNGKIND,
Ph.D., fhi/ade/phia, Pennsyhania
Temafloxacin is an investigational fluoroquinolone with in vitro activity against common skin pathogens and a favorable pharmacokinetic profile. A randomized, double-blind, multicenter study was conducted in 492 patients to compare the safety and efficacy of temafloxacin 600 mg with ciprofloxacin 750 mg for the treatment of bacterial infections of the skin or skin structure. Both drugs were given twice daily for 7-28 days. The most common diagnoses were abscess and superficial skin infection, which were usually caused by staphylococci. In evaluable patients, clinical success (cure plus improvement) rates were 96% in the temafloxacin group and 99% in the ciprofloxacin group. Bacteriologic eradication rates were 95% and 93% in the temafloxacin and ciprofloxacin groups, respectively. Both regimens were well tolerated. Temafloxacin appears to be safe and effective for the management of bacterial infections of the skin and skin structure.
S
kin and skin structure infections are most commonly caused by gram-positive bacteria such as
Streptococcus
pyogenes,
Staphylococcus
aureus,
and coagulase-negative staphylococci. Gram-negative pathogens are sometimes implicated, causing serious and more difficult to treat infections [1,2]. Temafloxacin is an investigational fluoroquinolone, which, like other members of its class, has improved microbiologic and pharmacokinetic features in comparison with the prototype quinolone, nalidixic acid. Temafloxacin has broad-spectrum antimicrobial activity against clinically important gram-positive and gram-negative pathogens. The majority of skin pathogens including S. aureus (90% minimum inhibitory concentration [MI&J = 0.25 pg/mL), S. pyogenes (MICgO = 0.5 PgimL), and most Enterobacteriaceae (MICSO 51 pg/mL) are inhibited by clinically achievable concentrations of temafloxacin [3,4]. Temafloxacin follows a linear pharmacokinetic profile and has excellent tissue penetration characteristics. At steady state, maximum and minimum plasma concentrations, per 100 mg of temafloxacin, are approximately 1 and 0.5 pg/mL, respectively [5]. Thus, following administration of 600 mg b.i.d., the plasma steady-state maximum and minimum concentrations are approximately 6 and 3 PgimL, respectively, well above the MIC& values for common skin pathogens. Concentrations of temafloxacin in blister fluid follow similar pharmacokinetics
F-51. The objective of this study was to evaluate the safety and efficacy of temafloxacin 600 mg b.i.d. in the treatment of bacterial infections of the skin or skin structure. Ciprofloxacin was selected as the reference fluoroquinolone, having previously demonstrated efficacy for the management of these infections U-141.
PATIENTSAND METHODS From the Department of Dermatology and Clinical Microbiology Laboratory, Jefferson Medical College, Thomas Jefferson Unlverslty, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Lawrence Charles Parish, M.D., 1819 John F. Kennedy Boulevard, Philadelphia, Pennsylvania 19103.
This was a randomized, double-blind, multicenter (16 centers) trial. Patients were randomly assigned to receive temafloxacin 600 mg b.i.d. or ciprofloxatin 750 mg b.i.d., both given orally for 7-28 days. Adults (218 years of age) with bacterial infections of the skin or skin structure were eligible for the
SYMPOSIUM
ON FLUOROQUINOLONES
/ PARISH and JUNGKIND
study. Women who were pregnant or nursing and patients with any of the following conditions were excluded from enrollment: skin infection caused by bacteria resistant to temafloxacin or ciprofloxacin; skin lesion requiring surgical drainage or debridement; quinolone hypersensitivity; concurrent antacids, theophylline, systemic or topical antibiotic, investigational drug therapy, steroids, or chemotherapy; or renal or hepatic impairment. Informed consent was obtained prior to study enrollment. Patients were discontinued from the study if any of the following occurred: no pathogen isolated in pretreatment culture, organism isolated from pretreatment culture resistant to temafloxacin or ciprofloxacin, or an adverse event necessitating discontinuation of the study drug. Patients were evaluated as follows: (a) within 48 hours prior to treatment (pretreatment); (b) during treatment (if receiving more than 11 days of therapy); (c) within 48 hours after the last dose (posttreatment); and (d) at 5-9 days after the last dose (follow-up). Medical and physical examinations, culture and susceptibility determination, and dermatologic assessments were performed at each evaluation period. Infections were classified as acute if they occurred within 3 weeks of initiation of drug therapy; otherwise, they were considered to be chronic. Standard clinical laboratory evaluations were done at the pre- and post-treatment examinations. Evaluation of the clinical response occurred at the 5-9 day follow-up visit. Clinical, Bacteriologic,
and Safety Evaluations
Specimens for culture were obtained according to standard procedures. The method for obtaining the sample (for example, swab, needle aspirate) depended on the condition of the infected skin. In vitro susceptibility was determined by disk-diffusion methods recommended by the National Committee for Clinical Laboratory Standards. Susceptibility to temafloxacin was defined as a diameter ~20 mm; resistance was defined as a diameter ~16 mm. Susceptibility to ciprofloxacin was defined as a diameter of ~21 mm; resistance was defined as a diameter ~15 mm. Clinical response was based on the signs and symptoms of skin infection at the time of the followup visit and was categorized as cure (complete resolution), improvement (improvement without complete resolution), failure (no improvement or worsening), or unevaluable (indeterminable because of concomitant antibiotic therapy or patient noncompliance). To be clinically evaluable, patients had to receive a minimum of 3 days’ therapy to be considered a treatment failure or 5 days to be considered a cure. 6A-116s
December 30, 1991
The American Journal of Medicine
Bacteriologic response was based on culture results at the post-treatment and follow-up visits and was categorized as eradication (absence of pretreatment pathogen or no specimen available to culture), persistence/failure (noneradication of original pathogen), or unevaluable (indeterminable because of missing cultures, concomitant antibiotic, or noncompliance). Adverse events observed by the investigators were recorded according to onset, duration, severity, etiology, relationship to study drug, and action taken. Each adverse event was rated by the investigator as mild (transient and easily tolerated), moderate (discomforting and causing interruption of patient’s usual activities), or severe (considerable interference with usual activities and potentially incapacitating or life-threatening). Data Analysis
All statistical tests were two-tailed with p ~0.05 as the breakpoint for statistical significance. Demographic variables were summarized with descriptive statistics. Comparability of patients assigned to treatment groups and among investigators was assessed by two-way analysis of variance (for example, age, height, and weight) or MantelHaenszel test (for example, gender and race). For overall comparison, efficacy variables were analyzed with Fisher’s exact test. For investigator interactions, efficacy variables were analyzed by the Breslow-Day test of homogeneity. For vital signs and laboratory data, a one-way analysis of variance was performed on the change from pre- to posttreatment. Within each treatment group, shifts of laboratory values with respect to normal ranges were assessed by Stuart-Maxwell or McNemar’s test.
RESULTS A total of 492 patients from 16 centers were enrolled into the study. There were no differences betw,een treatment groups on the basis of demographic variables or diagnoses (Table I). Overall, the male:female ratio was 1.5:1 in the temafloxacin group and l.l:l in the ciprofloxacin group. The mean ages were 45.3 and 45.9 years in the two groups, respectively. Within individual investigator sites, differences in mean age were detected; however, this was attributed to small sample size. Otherwise, there were no differences within individual investigator sites, so data were combined and analyzed according to treatment groups. The most common diagnoses were abscess and superficial skin infection (Table I). Most infections were mild to moderate in severity. The majority of patients presented with pain/tenderness, swelling/
Volume 91 (suppl 6A)
induration, erythema, warmth, or purulent discharge. The distribution of clinical signs and symptoms was similar between the two treatment groups at the time of enrollment. A total of 621 organisms were isolated from 477 patients prior to treatment (Table II). The most commonly isolated pathogens were gram-positive microorganisms, accounting for approximately three-fourths of the pathogens isolated, with staphylococci comprising the majority. Gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa, accounted for 18% of all pathogens isolated. Baseline pathogens were evenly distributed between the two treatment groups. Susceptibility testing revealed that 86% of the 621 organisms were susceptible to both temafloxacin and ciprofloxacin. Of the staphylococci from initially evaluable patients, 4% of S. a’areus (7 of 173), 14% of Staphylococcus epidermidis (15 of 106), and 18% of other species of coagulase-negative staphylococci (3 of 17) were resistant to oxacillin/methicillin. For those isolates that were methicillin resistant on susceptibility testing, all but one isolate of S. aureus was susceptible to temafloxacin and ciprofloxacin. In the temafloxacin group, 101 patients were clinically unevaluable. Reasons included no baseline pathogen (n = 40), missed examination (n = 22>, pathogen not susceptible (n = 13), surgical incision and drainage required (n = 8), insufficient duration of treatment (n = 12), no susceptibility test performed (n = 2), concurrent use of other antibiotics (n = 3), and use of pretreatment antibiotics (n = 1). An additional five patients were unevaluable bacteriologically because of missing cultures. In the ciprofloxacin group, 110 patients were clinically unevaluable. Reasons included no baseline pathogen (n = 37), missed examination (n = 29), pathogen not susceptible (n = 14), surgical incision and drainage required (n = 14), insufficient duration of treatment (n = 9), no susceptibility test performed (n = 5), and selection criteria not met (n = 2). An additional four patients were unevaluable bacteriologically because of missing cultures.
Patient
Demographics
and Diagnoses
/ PARISH and JUNGKIND
Number of Patients Variable
Temafloxacin
Ciprofloxacin
243 14499 (1.51
129:lZO (1.11
Total number enrolled Gender (male:female ratro) Race Caucasian Black Other
AgeM
Mean Range Diagnosis Abscess Superficial skin InfectIon Infected skin ulcers Infections of hair folllcleisweat Infected wounds Celluhs Other
TABLE
249
181 37 25
192
45.3 18-87
45.9 17-88
33
88 52
:i
ii gland
ii 25 15 6
ii 20 6
II
Pathogens
Isolated
at Baseline*
Organism
Number
Percentage
Staphylococci
Staphykxoccus aureus Sfaphyiococcussp., Streptococci
coagulase-negativet
Streptococcuspyogenes [group A streptococci) Phemolytic streptococci, Enterococcussp. Enterobacterlaceae
groups B: C, G
229
36.9
174
28.0
21 32 15
3.4 5.2 2.4
:i
2.3 7.7
Eschenchiaco/i Misc. Enterobacteriaceae Nonfermenter and other misc. gram-negative rods
Pseudomonasaerugrnasa
2.9
MISC.gram4egative microorganisms MISC.aerobic gram-positive microorganlsms Total
ii 37
5.3 6.0
621
100.0
*There were 477 mfectlons of skin or skin structure diagnosed tStaphy/ococcus epidermidis Included in this group.
TABLE
Clinical and bacteriologic responses in evaluable patients are summarized in Table III. Clinical success rates (cure plus improvement) were 96% in the temafloxacin group (136 of 142) and 99% in the ciprofloxacin group (138 of 139). The clinical cure rate was quantitatively higher in patients in both treatment groups who had acute versus chronic infections (86% vs 78%, respectively). The clinical cure rate was also higher in patients in both treatment groups who had nonserious versus serious inDecember
ON FLUOROQUINOLONES
TABLE I
Clinical
Clinical and Bacteriologic Response
SYMPOSIUM
at baseline.
Ill and Bacteriologic
Responses
in Evaluable
Patients
Number of Patients (%) Response
Temafloxacin
Ciprofloxacin
Clinrcal Total evaluable Cure Improvement Failure Bacteriologrc Total evaluable Cure Failure
30, 1991
The American
Journal
of Medicine
Volume
91 (suppl
6A)
6A-117s
SYMPOSIUM
ON FLUOROQUINOLONES
I PARISH and JUNGKIND
TABLE IV Bacteriologic Response by Pathogen in Evaluable Patients Number Eradicated/ Number Isolated (%) Microorganism Staphy/acoccusaureus Sfaphykxoccus epidermidis Pseudomonasaeruginosa Streptococcus pyogenes Escherichiaco/i Other Total
Ciprofloxacin
Temafloxacin 14178 (95) 2;;~~$~;!
76180 (951 31137(84)
616(100) 212(100) 47147(100) 1591168 j95)
45147(96) 1631175 (931
515(100) 212(100) 414 (100)
TABLE V Most Frequently Reported Adverse Events, Including Those Only Remotely Related to Treatment Number of Events (%) Adverse Event Nausea Diarrhea Dizziness
Temafloxacin (n = 243)
16(7) “L 1:;
Ci rofloxacin Pn = 249)
:: Iii 8 (3)
fections (88% vs 64%, respectively). Both regimens were comparable in producing improvement in signs and symptoms in >93% of patients. Bacteriologic cure rates were 93% in both treatment groups. When bacteriologic response was analyzed by pathogen, there were no significant between-group differences in eradication rates (Table IV). The overall eradication rate (for all pathogens) was 95% (159 of 168) for the temafloxacin group and 93% (163 of 175) for the ciprofloxacin group. Safety Evaluation All 492 patients were evaluated for safety. In both treatment groups, as shown in Table V, the most common adverse events were nausea (7% and 8% in the temafloxacin and ciprofloxacin groups, respectively), diarrhea (5% and 6%, respectively), and dizziness (3% in both groups). Most adverse events were mild to moderate in severity. Treatment was discontinued in 31 patients because of adverse events or concurrent conditions. Of the 20 patients who stopped temafloxacin, 14 (70%) had events that were probably related to treatment; the remainder had remotely related events (n = 4) or concurrent conditions (n = 2). Events considered probably related consisted of gastrointestinal (GI) disturbances (n = 12), dizziness (n = 3), headache (n = 2), rash (n = 2), photosensitivity (n = l), chills (n = l), sweating (n = l), 6A-118s
December 30, 1991
The American Journal of Medicine
restlessness (n = l), sedation (n = l), or pharyngitis (n = 1). All of these events resolved after discontinuation of temafloxacin except for one case of severe GI upset. Of the 11 patients who stopped ciprofloxacin, nine (82%) had events that were probably or possibly related to treatment; the remainder had remotely related events or concurrent conditions (one each). Events that were probably or possibly related consisted of GI disturbances (n = S), headache (n = 2), dizziness (n = 2>, central nervous system stimulation (n = l), anxiety (n = l), weakness (n = l), and metallic taste (n = 1). All events resolved after discontinuation of ciprofloxacin. In a patient who also experienced weakness and nausea, abnormal renal function was detected on study day 6, which normalized on day 13. This event was considered mild in severity and possibly related to ciprofloxacin. Concomitant hydrochlorothiazide/ triamterene (Dyazidem) and captopril (Capote+) were identified as possible contributing factors. Overall, there were no clinically significant trends in changes from pretreatment to post-treatment chemistry or hematology parameters. The only significant differences between treatment groups (p ~0.05) were mean changes in serum creatinine (+8.80 vs +4.4 PmoliL), total protein (-2.62 vs -1.08 g/L), and albumin (-2.42 vs -0.50 g/L) in the temafloxacin versus ciprofloxacin groups, respectively. The reason for these differences is unclear.
COMMENT Penicillin had been considered effective therapy for the treatment of skin and skin structure infections until the evolution of penicillin-resistant S. aureus. Since then, researchers and clinicians have been searching for safe and effective antimicrobials in this setting. The fluoroquinolone class of antibiotics has the advantage of a spectrum of activity comparable to many parenteral agents. They are thus useful for mixed infections and also may potentially be used for both inpatients and outpatients with skin or skin structure infections. Temafloxacin is absorbed rapidly and nearly completely after oral administration and has excellent tissue penetration characteristics. Temafloxacin penetrates skin tissue, and the area-under-thecurve (AUC) for blister fluid approximates that found in plasma. The elimination half-life of temafloxacin in both plasma and blister fluid is 7-8 hours, which allows for a convenient twice-daily dosing schedule [6]. The findings of a rabbit model of infected fibrin clots exemplify in vivo differences between temafloxacin and ciprofloxacin. Both
Volume 91 (suppl 6A)
SYMPOSIUM
temafloxacin and ciprofloxacin produced high peak serum and clot levels in this model, but the longer elimination half-life of temafloxacin resulted in higher AUCs in both serum (11.9 vs 5.4 pg/ mL.hour) and clot (10.1 vs 5.7 pg.hour/mL) [15]. Temafloxacin has been shown to have a favorable therapeutic index in an experimental model of infections caused by common skin pathogens [16]. Suspensions containing multiples of the median lethal dose (LD,,,) of bacteria were injected intraperitoneally into mice. The dose of temafloxacin (2.2 mg/kg) required to protect 50% of animals with the median effective dose (ED& from death due to S. aureua (10,649) was much lower than that of ciprofloxacin (30.1 mg/kg), even though MIC values were 0.06 and 0.12 pg/mL, respectively. Likewise, MIC values against S. pyoyenes (C203) were within one dilution, but the EDjo values for temafloxacin and ciprofloxacin were 12.5 and ~100 mglkg, respectively. This discrepancy between in vitro and in vivo results is presumably a reflection of the favorable pharmacokinetic profile of temafloxacin. In this study, temafloxacin 600 mg b.i.d. was highly effective in the treatment of bacterial infections of the skin or skin structure. Clinical response and bacteriologic cure rates were 96% and 93%, respectively, which were comparable to those in patients treated with ciprofloxacin, 99% and 93%, respectively. Temafloxacin 600 mg b.i.d. was as effective as ciprofloxacin 750 mg b.i.d. in adults with bacterial infections of the skin or skin structure. Both regimens produced clinical and bacteriologic response rates of 93% or higher and were well tolerated. Additional studies are warranted to delineate the role of temafloxacin in the management of serious skin and skin structure infections and in additional dermatologic entities, such as acne and gramnegative folliculitis.
ACKNOWLEDGMENT Thus study was supported
by a grant from Abbott
Laboratories,
Abbott
Park, Illinois.
December
ON FLUOROQUINOLONES
/ PARISH and JUNGKIND
Acknowledgment IS made to the other investigators who parbcipated In thus study: Filmore Bagatell, M.D.. Phoenix, Arizona; Lloyd Cleaver, D.O., Kirksvrlie, MISsouri; James Glower, M.D., Jacksonvrlle, FlorIda; Manuel Morman, M.D., Rutherford, New Jersey; Robert Nim!os, M.D., Sun City West, Arrzona; Francis Pren, M.D., Honolulu, Hawaii; Marvin Rappaport M.D., Beverly Hrlls, Caiifornra; Eduardo Tschen, M.D., Albuquerque, New Mexrco; Gerald Wachs, M.D., Summrt, New Jersey; Vincent Falanga, M.D., Mlamr, Florida; Larry GlIderman, M.D., Pembroke Pines, FlorIda; Gene Graff D.O., Woodinvale, Washington: Sister Karen Sue Heath, M.D., Dillon, South Carolina; Merlin Kampfer, M.D., Phoenix, Arizona; and Larry E. Mrllikan, M.D., New Orleans, LouIslana.
REFERENCES 1. Duhring LA. A practical treatise on drseases of the skin. Phrladelphia, Pennsylvanra: JB Lipprncott; (187? 281-91) 1982: 288-304. 2. Witkowski JA, Parish LC. Bacterial skrn infections: management of common streptococcal and staphylococcal lessons. Postgrad Med 1982; 73: 176-8. 3. Fuchs P. in vitro activrty of temafloxacin agarnst gram-positive COCCI, including MRSA. Am J Med 1991; 91 (Suppl 6A): 15-8. 4. Hardy D. In vitro activrty of temafloxacin against gram-negatrve bacteria: an overview. Am J Med 1991; 91 (Suppl 6A): 19-23. 5. Granneman GR. Mulbple dose pharmacokinetics of temafloxacrn. Antimrcrob Agents Chemother 1991; rn press. 6. Nye K, Shi YG, Andrews JM, Ashby JP, Wise R. The In-vitro actrvrty, pharmacoklnetics and trssue penetratron of temafloxacrn. J Antlmicrob Chemother 1989; 24: 415-24. 7. Llcitra CM, Brooks RG, Sieger BE. Clrnical efficacy and levels of ciprofloxacin in tissue in patients wrth soft tissue Infection. Anhmrcrob Agents Chemother 1987; 31: 805-7. 8. Ball AP. Overvrew of clrnrcal experience wrth ciprofloxacrn. Eur J Clin Microbial 1986; 5: 214-9. 9. Arcieri G. Griffith E. Gruenwaldt G, et a/. A survey of clrnical experience with crprofloxacrn, a new qurnolone antrmrcrobral. J Clin Pharmacol 1988; 28: 179-89. 10. Parish LC, Asper R. Systemrc treatment of cutaneous lnfectrons: a comparative study of ciprofioxacin and cefotaxime. Am I Med 1987; 82 (Suppl 4A): 227-9. 11. P’rez-Ruvalcaba JA, Qulntero-P’rez NP, Morales-Reyes JJ, et a/. Double-blrnd comparison of crprofloxacin wrth cefotaxlme in the treatment of skin and skin structure infections. Am J Med 1987; 82 (Suppl 4A): 242-6. 12. Thadepallr H, Mathar D, Chuah SK, Bansal MB. Ciprofloxacrn versus ceftazidtme in skrn and soft tissue infections. J Chemother 1989; 1: 30-4. 13. Gentry LO, Khoshdel A. Intravenous/oral crprofloxacin versus Intravenous ceftazrdime III the treatment of serious gram-negative infections of the skin and skin structure. Am J Med 1989; 87 (Suppl 5A): 13X-1355. 14. Domrnguer J, Palma F, Vega ME. Prospective, controlled, randomrzed non-bllnd comparrson of intravenous/oral clprofloxacrn wrth rntravenous ceftazrdrme In the treatment of skin and soft-tissue Infections. Am J Med 1989; 87 (Suppl 5A): 135S137s. 15. Turcotte A, Bergeron MG. Penetratron and rn VIVO actrvlty of temafloxacrn and ciprofloxacin rn infected fibrin clots [Abstract No. 6981. In: Program and Abstracts of the 30th Annual InterscIence Conference on Anhmicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta. Georgia. 16. Hardy DJ, Swanson RN, Hensey DM, ei a/. Comparatrve antibacterral actrvitres of temafloxacrn hydrochlorrde (A-62254) and two reference fluoroqurnolones. Antrmicrob Agents Chemother 1987; 31: 1768-74.
30, 1991
The Amerrcan
Journal
of Medrcrne
Volume
91 (suppl
6A)
6A-119s
CHARLES
PARISH,
M.D.,
DONALD
L.
JUNGKIND,
Ph.D., fhi/ade/phia, Pennsyhania
Temafloxacin is an investigational fluoroquinolone with in vitro activity against common skin pathogens and a favorable pharmacokinetic profile. A randomized, double-blind, multicenter study was conducted in 492 patients to compare the safety and efficacy of temafloxacin 600 mg with ciprofloxacin 750 mg for the treatment of bacterial infections of the skin or skin structure. Both drugs were given twice daily for 7-28 days. The most common diagnoses were abscess and superficial skin infection, which were usually caused by staphylococci. In evaluable patients, clinical success (cure plus improvement) rates were 96% in the temafloxacin group and 99% in the ciprofloxacin group. Bacteriologic eradication rates were 95% and 93% in the temafloxacin and ciprofloxacin groups, respectively. Both regimens were well tolerated. Temafloxacin appears to be safe and effective for the management of bacterial infections of the skin and skin structure.
S
kin and skin structure infections are most commonly caused by gram-positive bacteria such as
Streptococcus
pyogenes,
Staphylococcus
aureus,
and coagulase-negative staphylococci. Gram-negative pathogens are sometimes implicated, causing serious and more difficult to treat infections [1,2]. Temafloxacin is an investigational fluoroquinolone, which, like other members of its class, has improved microbiologic and pharmacokinetic features in comparison with the prototype quinolone, nalidixic acid. Temafloxacin has broad-spectrum antimicrobial activity against clinically important gram-positive and gram-negative pathogens. The majority of skin pathogens including S. aureus (90% minimum inhibitory concentration [MI&J = 0.25 pg/mL), S. pyogenes (MICgO = 0.5 PgimL), and most Enterobacteriaceae (MICSO 51 pg/mL) are inhibited by clinically achievable concentrations of temafloxacin [3,4]. Temafloxacin follows a linear pharmacokinetic profile and has excellent tissue penetration characteristics. At steady state, maximum and minimum plasma concentrations, per 100 mg of temafloxacin, are approximately 1 and 0.5 pg/mL, respectively [5]. Thus, following administration of 600 mg b.i.d., the plasma steady-state maximum and minimum concentrations are approximately 6 and 3 PgimL, respectively, well above the MIC& values for common skin pathogens. Concentrations of temafloxacin in blister fluid follow similar pharmacokinetics
F-51. The objective of this study was to evaluate the safety and efficacy of temafloxacin 600 mg b.i.d. in the treatment of bacterial infections of the skin or skin structure. Ciprofloxacin was selected as the reference fluoroquinolone, having previously demonstrated efficacy for the management of these infections U-141.
PATIENTSAND METHODS From the Department of Dermatology and Clinical Microbiology Laboratory, Jefferson Medical College, Thomas Jefferson Unlverslty, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Lawrence Charles Parish, M.D., 1819 John F. Kennedy Boulevard, Philadelphia, Pennsylvania 19103.
This was a randomized, double-blind, multicenter (16 centers) trial. Patients were randomly assigned to receive temafloxacin 600 mg b.i.d. or ciprofloxatin 750 mg b.i.d., both given orally for 7-28 days. Adults (218 years of age) with bacterial infections of the skin or skin structure were eligible for the
SYMPOSIUM
ON FLUOROQUINOLONES
/ PARISH and JUNGKIND
study. Women who were pregnant or nursing and patients with any of the following conditions were excluded from enrollment: skin infection caused by bacteria resistant to temafloxacin or ciprofloxacin; skin lesion requiring surgical drainage or debridement; quinolone hypersensitivity; concurrent antacids, theophylline, systemic or topical antibiotic, investigational drug therapy, steroids, or chemotherapy; or renal or hepatic impairment. Informed consent was obtained prior to study enrollment. Patients were discontinued from the study if any of the following occurred: no pathogen isolated in pretreatment culture, organism isolated from pretreatment culture resistant to temafloxacin or ciprofloxacin, or an adverse event necessitating discontinuation of the study drug. Patients were evaluated as follows: (a) within 48 hours prior to treatment (pretreatment); (b) during treatment (if receiving more than 11 days of therapy); (c) within 48 hours after the last dose (posttreatment); and (d) at 5-9 days after the last dose (follow-up). Medical and physical examinations, culture and susceptibility determination, and dermatologic assessments were performed at each evaluation period. Infections were classified as acute if they occurred within 3 weeks of initiation of drug therapy; otherwise, they were considered to be chronic. Standard clinical laboratory evaluations were done at the pre- and post-treatment examinations. Evaluation of the clinical response occurred at the 5-9 day follow-up visit. Clinical, Bacteriologic,
and Safety Evaluations
Specimens for culture were obtained according to standard procedures. The method for obtaining the sample (for example, swab, needle aspirate) depended on the condition of the infected skin. In vitro susceptibility was determined by disk-diffusion methods recommended by the National Committee for Clinical Laboratory Standards. Susceptibility to temafloxacin was defined as a diameter ~20 mm; resistance was defined as a diameter ~16 mm. Susceptibility to ciprofloxacin was defined as a diameter of ~21 mm; resistance was defined as a diameter ~15 mm. Clinical response was based on the signs and symptoms of skin infection at the time of the followup visit and was categorized as cure (complete resolution), improvement (improvement without complete resolution), failure (no improvement or worsening), or unevaluable (indeterminable because of concomitant antibiotic therapy or patient noncompliance). To be clinically evaluable, patients had to receive a minimum of 3 days’ therapy to be considered a treatment failure or 5 days to be considered a cure. 6A-116s
December 30, 1991
The American Journal of Medicine
Bacteriologic response was based on culture results at the post-treatment and follow-up visits and was categorized as eradication (absence of pretreatment pathogen or no specimen available to culture), persistence/failure (noneradication of original pathogen), or unevaluable (indeterminable because of missing cultures, concomitant antibiotic, or noncompliance). Adverse events observed by the investigators were recorded according to onset, duration, severity, etiology, relationship to study drug, and action taken. Each adverse event was rated by the investigator as mild (transient and easily tolerated), moderate (discomforting and causing interruption of patient’s usual activities), or severe (considerable interference with usual activities and potentially incapacitating or life-threatening). Data Analysis
All statistical tests were two-tailed with p ~0.05 as the breakpoint for statistical significance. Demographic variables were summarized with descriptive statistics. Comparability of patients assigned to treatment groups and among investigators was assessed by two-way analysis of variance (for example, age, height, and weight) or MantelHaenszel test (for example, gender and race). For overall comparison, efficacy variables were analyzed with Fisher’s exact test. For investigator interactions, efficacy variables were analyzed by the Breslow-Day test of homogeneity. For vital signs and laboratory data, a one-way analysis of variance was performed on the change from pre- to posttreatment. Within each treatment group, shifts of laboratory values with respect to normal ranges were assessed by Stuart-Maxwell or McNemar’s test.
RESULTS A total of 492 patients from 16 centers were enrolled into the study. There were no differences betw,een treatment groups on the basis of demographic variables or diagnoses (Table I). Overall, the male:female ratio was 1.5:1 in the temafloxacin group and l.l:l in the ciprofloxacin group. The mean ages were 45.3 and 45.9 years in the two groups, respectively. Within individual investigator sites, differences in mean age were detected; however, this was attributed to small sample size. Otherwise, there were no differences within individual investigator sites, so data were combined and analyzed according to treatment groups. The most common diagnoses were abscess and superficial skin infection (Table I). Most infections were mild to moderate in severity. The majority of patients presented with pain/tenderness, swelling/
Volume 91 (suppl 6A)
induration, erythema, warmth, or purulent discharge. The distribution of clinical signs and symptoms was similar between the two treatment groups at the time of enrollment. A total of 621 organisms were isolated from 477 patients prior to treatment (Table II). The most commonly isolated pathogens were gram-positive microorganisms, accounting for approximately three-fourths of the pathogens isolated, with staphylococci comprising the majority. Gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa, accounted for 18% of all pathogens isolated. Baseline pathogens were evenly distributed between the two treatment groups. Susceptibility testing revealed that 86% of the 621 organisms were susceptible to both temafloxacin and ciprofloxacin. Of the staphylococci from initially evaluable patients, 4% of S. a’areus (7 of 173), 14% of Staphylococcus epidermidis (15 of 106), and 18% of other species of coagulase-negative staphylococci (3 of 17) were resistant to oxacillin/methicillin. For those isolates that were methicillin resistant on susceptibility testing, all but one isolate of S. aureus was susceptible to temafloxacin and ciprofloxacin. In the temafloxacin group, 101 patients were clinically unevaluable. Reasons included no baseline pathogen (n = 40), missed examination (n = 22>, pathogen not susceptible (n = 13), surgical incision and drainage required (n = 8), insufficient duration of treatment (n = 12), no susceptibility test performed (n = 2), concurrent use of other antibiotics (n = 3), and use of pretreatment antibiotics (n = 1). An additional five patients were unevaluable bacteriologically because of missing cultures. In the ciprofloxacin group, 110 patients were clinically unevaluable. Reasons included no baseline pathogen (n = 37), missed examination (n = 29), pathogen not susceptible (n = 14), surgical incision and drainage required (n = 14), insufficient duration of treatment (n = 9), no susceptibility test performed (n = 5), and selection criteria not met (n = 2). An additional four patients were unevaluable bacteriologically because of missing cultures.
Patient
Demographics
and Diagnoses
/ PARISH and JUNGKIND
Number of Patients Variable
Temafloxacin
Ciprofloxacin
243 14499 (1.51
129:lZO (1.11
Total number enrolled Gender (male:female ratro) Race Caucasian Black Other
AgeM
Mean Range Diagnosis Abscess Superficial skin InfectIon Infected skin ulcers Infections of hair folllcleisweat Infected wounds Celluhs Other
TABLE
249
181 37 25
192
45.3 18-87
45.9 17-88
33
88 52
:i
ii gland
ii 25 15 6
ii 20 6
II
Pathogens
Isolated
at Baseline*
Organism
Number
Percentage
Staphylococci
Staphykxoccus aureus Sfaphyiococcussp., Streptococci
coagulase-negativet
Streptococcuspyogenes [group A streptococci) Phemolytic streptococci, Enterococcussp. Enterobacterlaceae
groups B: C, G
229
36.9
174
28.0
21 32 15
3.4 5.2 2.4
:i
2.3 7.7
Eschenchiaco/i Misc. Enterobacteriaceae Nonfermenter and other misc. gram-negative rods
Pseudomonasaerugrnasa
2.9
MISC.gram4egative microorganisms MISC.aerobic gram-positive microorganlsms Total
ii 37
5.3 6.0
621
100.0
*There were 477 mfectlons of skin or skin structure diagnosed tStaphy/ococcus epidermidis Included in this group.
TABLE
Clinical and bacteriologic responses in evaluable patients are summarized in Table III. Clinical success rates (cure plus improvement) were 96% in the temafloxacin group (136 of 142) and 99% in the ciprofloxacin group (138 of 139). The clinical cure rate was quantitatively higher in patients in both treatment groups who had acute versus chronic infections (86% vs 78%, respectively). The clinical cure rate was also higher in patients in both treatment groups who had nonserious versus serious inDecember
ON FLUOROQUINOLONES
TABLE I
Clinical
Clinical and Bacteriologic Response
SYMPOSIUM
at baseline.
Ill and Bacteriologic
Responses
in Evaluable
Patients
Number of Patients (%) Response
Temafloxacin
Ciprofloxacin
Clinrcal Total evaluable Cure Improvement Failure Bacteriologrc Total evaluable Cure Failure
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The American
Journal
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Volume
91 (suppl
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SYMPOSIUM
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I PARISH and JUNGKIND
TABLE IV Bacteriologic Response by Pathogen in Evaluable Patients Number Eradicated/ Number Isolated (%) Microorganism Staphy/acoccusaureus Sfaphykxoccus epidermidis Pseudomonasaeruginosa Streptococcus pyogenes Escherichiaco/i Other Total
Ciprofloxacin
Temafloxacin 14178 (95) 2;;~~$~;!
76180 (951 31137(84)
616(100) 212(100) 47147(100) 1591168 j95)
45147(96) 1631175 (931
515(100) 212(100) 414 (100)
TABLE V Most Frequently Reported Adverse Events, Including Those Only Remotely Related to Treatment Number of Events (%) Adverse Event Nausea Diarrhea Dizziness
Temafloxacin (n = 243)
16(7) “L 1:;
Ci rofloxacin Pn = 249)
:: Iii 8 (3)
fections (88% vs 64%, respectively). Both regimens were comparable in producing improvement in signs and symptoms in >93% of patients. Bacteriologic cure rates were 93% in both treatment groups. When bacteriologic response was analyzed by pathogen, there were no significant between-group differences in eradication rates (Table IV). The overall eradication rate (for all pathogens) was 95% (159 of 168) for the temafloxacin group and 93% (163 of 175) for the ciprofloxacin group. Safety Evaluation All 492 patients were evaluated for safety. In both treatment groups, as shown in Table V, the most common adverse events were nausea (7% and 8% in the temafloxacin and ciprofloxacin groups, respectively), diarrhea (5% and 6%, respectively), and dizziness (3% in both groups). Most adverse events were mild to moderate in severity. Treatment was discontinued in 31 patients because of adverse events or concurrent conditions. Of the 20 patients who stopped temafloxacin, 14 (70%) had events that were probably related to treatment; the remainder had remotely related events (n = 4) or concurrent conditions (n = 2). Events considered probably related consisted of gastrointestinal (GI) disturbances (n = 12), dizziness (n = 3), headache (n = 2), rash (n = 2), photosensitivity (n = l), chills (n = l), sweating (n = l), 6A-118s
December 30, 1991
The American Journal of Medicine
restlessness (n = l), sedation (n = l), or pharyngitis (n = 1). All of these events resolved after discontinuation of temafloxacin except for one case of severe GI upset. Of the 11 patients who stopped ciprofloxacin, nine (82%) had events that were probably or possibly related to treatment; the remainder had remotely related events or concurrent conditions (one each). Events that were probably or possibly related consisted of GI disturbances (n = S), headache (n = 2), dizziness (n = 2>, central nervous system stimulation (n = l), anxiety (n = l), weakness (n = l), and metallic taste (n = 1). All events resolved after discontinuation of ciprofloxacin. In a patient who also experienced weakness and nausea, abnormal renal function was detected on study day 6, which normalized on day 13. This event was considered mild in severity and possibly related to ciprofloxacin. Concomitant hydrochlorothiazide/ triamterene (Dyazidem) and captopril (Capote+) were identified as possible contributing factors. Overall, there were no clinically significant trends in changes from pretreatment to post-treatment chemistry or hematology parameters. The only significant differences between treatment groups (p ~0.05) were mean changes in serum creatinine (+8.80 vs +4.4 PmoliL), total protein (-2.62 vs -1.08 g/L), and albumin (-2.42 vs -0.50 g/L) in the temafloxacin versus ciprofloxacin groups, respectively. The reason for these differences is unclear.
COMMENT Penicillin had been considered effective therapy for the treatment of skin and skin structure infections until the evolution of penicillin-resistant S. aureus. Since then, researchers and clinicians have been searching for safe and effective antimicrobials in this setting. The fluoroquinolone class of antibiotics has the advantage of a spectrum of activity comparable to many parenteral agents. They are thus useful for mixed infections and also may potentially be used for both inpatients and outpatients with skin or skin structure infections. Temafloxacin is absorbed rapidly and nearly completely after oral administration and has excellent tissue penetration characteristics. Temafloxacin penetrates skin tissue, and the area-under-thecurve (AUC) for blister fluid approximates that found in plasma. The elimination half-life of temafloxacin in both plasma and blister fluid is 7-8 hours, which allows for a convenient twice-daily dosing schedule [6]. The findings of a rabbit model of infected fibrin clots exemplify in vivo differences between temafloxacin and ciprofloxacin. Both
Volume 91 (suppl 6A)
SYMPOSIUM
temafloxacin and ciprofloxacin produced high peak serum and clot levels in this model, but the longer elimination half-life of temafloxacin resulted in higher AUCs in both serum (11.9 vs 5.4 pg/ mL.hour) and clot (10.1 vs 5.7 pg.hour/mL) [15]. Temafloxacin has been shown to have a favorable therapeutic index in an experimental model of infections caused by common skin pathogens [16]. Suspensions containing multiples of the median lethal dose (LD,,,) of bacteria were injected intraperitoneally into mice. The dose of temafloxacin (2.2 mg/kg) required to protect 50% of animals with the median effective dose (ED& from death due to S. aureua (10,649) was much lower than that of ciprofloxacin (30.1 mg/kg), even though MIC values were 0.06 and 0.12 pg/mL, respectively. Likewise, MIC values against S. pyoyenes (C203) were within one dilution, but the EDjo values for temafloxacin and ciprofloxacin were 12.5 and ~100 mglkg, respectively. This discrepancy between in vitro and in vivo results is presumably a reflection of the favorable pharmacokinetic profile of temafloxacin. In this study, temafloxacin 600 mg b.i.d. was highly effective in the treatment of bacterial infections of the skin or skin structure. Clinical response and bacteriologic cure rates were 96% and 93%, respectively, which were comparable to those in patients treated with ciprofloxacin, 99% and 93%, respectively. Temafloxacin 600 mg b.i.d. was as effective as ciprofloxacin 750 mg b.i.d. in adults with bacterial infections of the skin or skin structure. Both regimens produced clinical and bacteriologic response rates of 93% or higher and were well tolerated. Additional studies are warranted to delineate the role of temafloxacin in the management of serious skin and skin structure infections and in additional dermatologic entities, such as acne and gramnegative folliculitis.
ACKNOWLEDGMENT Thus study was supported
by a grant from Abbott
Laboratories,
Abbott
Park, Illinois.
December
ON FLUOROQUINOLONES
/ PARISH and JUNGKIND
Acknowledgment IS made to the other investigators who parbcipated In thus study: Filmore Bagatell, M.D.. Phoenix, Arizona; Lloyd Cleaver, D.O., Kirksvrlie, MISsouri; James Glower, M.D., Jacksonvrlle, FlorIda; Manuel Morman, M.D., Rutherford, New Jersey; Robert Nim!os, M.D., Sun City West, Arrzona; Francis Pren, M.D., Honolulu, Hawaii; Marvin Rappaport M.D., Beverly Hrlls, Caiifornra; Eduardo Tschen, M.D., Albuquerque, New Mexrco; Gerald Wachs, M.D., Summrt, New Jersey; Vincent Falanga, M.D., Mlamr, Florida; Larry GlIderman, M.D., Pembroke Pines, FlorIda; Gene Graff D.O., Woodinvale, Washington: Sister Karen Sue Heath, M.D., Dillon, South Carolina; Merlin Kampfer, M.D., Phoenix, Arizona; and Larry E. Mrllikan, M.D., New Orleans, LouIslana.
REFERENCES 1. Duhring LA. A practical treatise on drseases of the skin. Phrladelphia, Pennsylvanra: JB Lipprncott; (187? 281-91) 1982: 288-304. 2. Witkowski JA, Parish LC. Bacterial skrn infections: management of common streptococcal and staphylococcal lessons. Postgrad Med 1982; 73: 176-8. 3. Fuchs P. in vitro activrty of temafloxacin agarnst gram-positive COCCI, including MRSA. Am J Med 1991; 91 (Suppl 6A): 15-8. 4. Hardy D. In vitro activrty of temafloxacin against gram-negatrve bacteria: an overview. Am J Med 1991; 91 (Suppl 6A): 19-23. 5. Granneman GR. Mulbple dose pharmacokinetics of temafloxacrn. Antimrcrob Agents Chemother 1991; rn press. 6. Nye K, Shi YG, Andrews JM, Ashby JP, Wise R. The In-vitro actrvrty, pharmacoklnetics and trssue penetratron of temafloxacrn. J Antlmicrob Chemother 1989; 24: 415-24. 7. Llcitra CM, Brooks RG, Sieger BE. Clrnical efficacy and levels of ciprofloxacin in tissue in patients wrth soft tissue Infection. Anhmrcrob Agents Chemother 1987; 31: 805-7. 8. Ball AP. Overvrew of clrnrcal experience wrth ciprofloxacrn. Eur J Clin Microbial 1986; 5: 214-9. 9. Arcieri G. Griffith E. Gruenwaldt G, et a/. A survey of clrnical experience with crprofloxacrn, a new qurnolone antrmrcrobral. J Clin Pharmacol 1988; 28: 179-89. 10. Parish LC, Asper R. Systemrc treatment of cutaneous lnfectrons: a comparative study of ciprofioxacin and cefotaxime. Am I Med 1987; 82 (Suppl 4A): 227-9. 11. P’rez-Ruvalcaba JA, Qulntero-P’rez NP, Morales-Reyes JJ, et a/. Double-blrnd comparison of crprofloxacin wrth cefotaxlme in the treatment of skin and skin structure infections. Am J Med 1987; 82 (Suppl 4A): 242-6. 12. Thadepallr H, Mathar D, Chuah SK, Bansal MB. Ciprofloxacrn versus ceftazidtme in skrn and soft tissue infections. J Chemother 1989; 1: 30-4. 13. Gentry LO, Khoshdel A. Intravenous/oral crprofloxacin versus Intravenous ceftazrdime III the treatment of serious gram-negative infections of the skin and skin structure. Am J Med 1989; 87 (Suppl 5A): 13X-1355. 14. Domrnguer J, Palma F, Vega ME. Prospective, controlled, randomrzed non-bllnd comparrson of intravenous/oral clprofloxacrn wrth rntravenous ceftazrdrme In the treatment of skin and soft-tissue Infections. Am J Med 1989; 87 (Suppl 5A): 135S137s. 15. Turcotte A, Bergeron MG. Penetratron and rn VIVO actrvlty of temafloxacrn and ciprofloxacin rn infected fibrin clots [Abstract No. 6981. In: Program and Abstracts of the 30th Annual InterscIence Conference on Anhmicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta. Georgia. 16. Hardy DJ, Swanson RN, Hensey DM, ei a/. Comparatrve antibacterral actrvitres of temafloxacrn hydrochlorrde (A-62254) and two reference fluoroqurnolones. Antrmicrob Agents Chemother 1987; 31: 1768-74.
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The Amerrcan
Journal
of Medrcrne
Volume
91 (suppl
6A)
6A-119s
