Safety and efficacy of lomefloxacin and cefaclor in the treatment of skin and skin structure infections

International Journal of Antimicrobial Agents 2 (1992) 55-60

55

© 1992Elsevier SciencePublishers BV 0924-8579/92/$15.00 ANTAGE 00043

Safety and efficacy oflomefloxacin and cefaclor in the treatment of skin and skin structure infections G. A m a y a - T a p i a , J. A n d r a d e - V i l l a n u e v a , A. F l o r e s - G a x i o l a , G. A g u i r r e - A v a l o s , R. M o r f i n - O t e r o , S. E s p a r z a - A h u m a d a a n d E. R o d r i g u e z - N o r i e g a Infectious Diseases Division, Hospital Civil de Guadalajara, Instituto de Patologia Infecciosa y Experimental 'Dr. Francisco Ruiz Sanchez', Universidad de Guadalajara, Jalisco, Mexico

(Accepted 17 September 1992)

Introduction Primary bacterial skin and skin structure infections are c o m m o n infectious syndromes that are frequently seen in the pediatric population and have distinctive clinical characteristics based on the infecting bacteria, which are helpful for the selection of initial therapy [1]. In contrast, secondary bacterial skin and skin structure infections occur more often Correspondence to." Dr E. Rodriguez-Noriega,Apartado Postal 2-788, Guadalajara, Jalisco, Mexico.

in adults, do not have special manifestations based on the infecting organism, and the presentation is associated basically with the pre-existing lesion [1,29]. Gram-positive bacteria are frequent pathogens of primary skin infections and of a substantial percentage of secondary bacterial skin and skin structure infections [1]. Enterobacteriaceae, previously reported as c o m m o n pathogens for skin and skin structure infections occurring only in abnormal hosts, have increased in importance and are now repeatedly isolated in all secondary bacterial skin and

56 skin structure infections, including some that appear as primary skin infections [3,4,6,7,12,14-16,1820,22-24,28]. The increasing role of Enterobacteriaceae and other Gram-negative aerobic bacteria as etiologic factors in skin and skin structure infections has prompted the search for alternative therapies, which have included some of the orally and intravenously administered quinolones [4,6,7,15,18-20,23,24,28]. The newer quinolones, with their broad spectrum of antibacterial activity and adequate penetration into most tissues, including the skin and its structures, have produced effective responses in moderate and severe skin and skin structure infections caused by Gram-positive and Gram-negative aerobic bacteria [7,19,20,23,24,28]. Lomefloxacin is a new difluorinated quinolone with a wide antibacterial spectrum and a long halflife that allows once-a-day administration [2,8,9,11,17,21,25,30,31]. Lomefloxacin is rapidly absorbed through the gastrointestinal tract after oral administration and achieves appropriate concentrations in the skin and its structure, making it a candidate for the treatment of skin and skin structure infections caused by susceptible bacteria [2,21,25,30,31]. This report presents the results of once-daily oral administration of lomefloxacin in comparison with oral cefaclor in a randomized, single-blind study.

Patients and Methods Patient selection Adult patients with superficial secondary bacterial skin and skin structure infections were eligible to participate in this study. Secondary bacterial skin and skin structure infections were defined as infections occurring after trauma or wounds to the skin, those accompanied by redness, swelling, tenderness and purulent discharge, and those with a positive Gram stain and a culture in which one or more secondary bacterial skin and skin structure pathogens were identified. Patients with a terminal illness, allergy to quinolones, elevated serum creatinine level (i.e. > 5 times the upper limit of normal), hepatic disease, history of seizure disorders, or those who

were immunosuppressed, receiving antacid therapy, or requiring concomitant non-steroidal anti-inflammatory therapy were excluded. Female patients were allowed to participate if they had a negative pregnancy test before enrollment. Also excluded from the study were patients who had received other antimicrobials if they had total or partial response, and those suspected of being bacteremic. All patients provided informed consent.

Drug regimens Patients received either 400 mg lomefloxacin orally once daily or 250 mg cefaclor orally three times daily for 8-14 days. The medication was administered by an independent third party to ensure investigator blinding.

Evaluation Baseline evaluation (Visit 1) was performed within the 48 h preceding the first dose of study medication. This included a medical history and physical examination. Blood samples were obtained for hematologic and biochemical testing, and urine for urinalysis. Specimens for bacteriologic evaluation were obtained by needle aspiration at the point of maximum inflammation, from the leading edge of the lesion, and the available draining material [10]. All specimens were plated onto conventional primary isolation plates. After primary isolation, pathogens were identified and tested for susceptibility to some antibiotics using a microplate method (Microscan, Baxter). All pathogens were re-tested for their antimicrobial susceptibility using both the KirbyBauer procedure and a macrodilution method. All these procedures and tests were repeated 24-72 h after the last dose of the study medication (Visit 2). Upon completion of therapy, if all signs and symptoms related to the infection had disappeared, it was designated as a complete clinical resolution. 'Improvement' indicated a marked reduction in the severity of signs and symptoms of infection. 'Failure' indicated that there was an insufficient decrease in the signs and symptoms of infection. The bacteriologic response 2-4 days post-therapy was graded as 'eradication' when the causative organisms were absent during and at the end of ther-

57 apy, or 'persistence' when the causative organisms were present at the end o f therapy. Based on the clinical and bacteriologic responses, the overall response was assessed as 'cure' in those with complete clinical resolution and bacteriologic eradication, 'partial cure' when there was clinical improvement with bacteriologic eradication, and 'failure' when clinical failure accompanied bacteriologic persistence. Bacteriologic eradication and clinical success rates for the two treatment groups were analyzed using 95% confidence intervals. In addition, efficacy data for the two treatment groups were compared using the Cochran-Mantel-Haenszel and Chi-square tests.

Results The study was conducted as a controlled, randomized, single-blind study in hospitalized patients and outpatients seen at the Hospital Civil de Guadalajara. In total, 80 patients were enrolled and randomized to the two treatment groups: 41 in the lomefloxacin group and 39 in the cefaclor group. Patient age, height, and weight were similar in both groups. Nineteen females and 22 males were included in the lomefloxacin group and 16 females and 23 males in the cefaclor group (Table 1). Concomitant diseases were present in 24.3% o f patients in the lomefloxacin group and in 20.5% in the cefaclor group; these included non-insulin-dependent diabetes mellitus and hypertension. Six patients were excluded from the final evalua-

tion of efficacy; four o f these patients had a bacterial pathogen resistant to cefaclor (three with Pseudomonas aeruginosa and one with Enterobacter amnigenus), one had Streptococcus equisimilis resistant to lomefloxacin and one had an abnormal liver function test on the first evaluation. Patients received lomefloxacin for a m e a n + SD o f 11.8 + 1.4 days and cefaclor for 11.6 _+ 1.3 days (p = 0.375); a m i n i m u m of seven days' therapy was required for evaluability. Staphylococcus aureus was the most frequent pathogen in both groups, with Streptococcus pyogenes, coagulase-negative staphylococci, and Escherichia coli following in frequency (Table 2). All pathogens (39 from 37 evaluable patients) were eradicated in the lomefloxacin group, and two pathogens persisted in the cefaclor group (Table 2). Clinical responses were similar in both the lomefloxacin and the cefaclor groups (Table 3). The initial white blood cell (WBC) count from patients in the lomefloxacin group was (mean + SD) 9800 + 5700, and that o f the cefaclor patients was 9000 + 3500 (p = 0.375). At the end o f treatment, the WBC count in the lomefloxacin group was 7000 + 1700 (versus initial WBC count p -- 0.005), with an end of treatment WBC count in the cefaclor group o f 7300 + 2200 (versus initial WBC count p = 0.01). Adverse events occurred in three patients (4.0%). Two (5.4%) patients on lomefloxacin developed mild, self-limited diarrhea, and one patient in the cefaclor group (2.7%) developed moderate epigastric pain.

Discussion TABLE 1 Patient characteristics Characteristic

Lomefloxacin Cefaclor (n = 41) (n = 39)

Mean + SD age (years) 45.4+ 19.5 Sex ratio (female/male) 19/22 Mean + SD weight (kg) 66.2+ 9.5 Severityof infection Mild 3 Moderate 29 Severe 9

p value

39.7 + 21.7 0.375 16/23 64.4 + 11.1 0.375 1 33 5

The increasing pathogenic role that bacteria such as Enterobacteriaceae have in skin and skin structure infections in the normal host has caused re-evaluation o f the selection o f antibiotics for initial or empiric therapy [4,6,7,15,18-20,23,24,28]. The importance of non-traditional pathogens in skin and skin structure infections is increased by the large population of adults with non-insulin-dependent diabetes mellitus who frequently experience mixed secondary bacterial skin and skin structure infections [5,13,26,27].

58 TABLE 2 Bacteriologic response by organism Cefaclor (n = 37)

Lomefloxacin (n = 37) Persistence

Total

Eradication

Persistence

Total

13

0

13

27

1

28

-

-

-

S. p y o g e n e s

6

0

6

S. h y i c u s h y i c u s

4

0

4

S. s a n g u i s

-

-

E. coli

4

0

S. cohni

-

-

E. cloacae

1

0

1

S. equisimilis

1

0

1

Pathogen

Eradication

S. a u r e u s S. c a p i t i s

S. epidermidis

1

1 -

-

-

-

-

2

1

2

-

-

1 4

2

1

1

-

1

1

1

1

K. cryocrencens

1

0

1

S. m o r b i l l o r u m

1

0

1

-

1 1

0 0

1 1

-

-

K. oxytoca

1

0

1

1

-

P. vulgaris

1

0

1

-

S. i n t e r m e d i u s

2

0

2

3

-

3

S. f a e c a l i s

1

0

1

-

-

-

Diphtheroids sp.

1

0

1

-

-

39

0

39

38

2

Pasteurella

sp.

Group B streptococci

Total

TABLE 3 Responses to treatment Response

Lomefloxacin (n = 37) n

Clinical Resolution Improvement Failure Bacteriologic Eradication Persistence Overall Cure Partial cure Failure

33 4 0 37 0 31 6 0

Cefaclor (n = 37) (%)

(%)

(89.2) (10.8) (100) (83.7) (16.2)

33 4 0

(89.2) (10.8)

35 2

(94.6) (5.4)

31 5

(83.7) 03.5) (2.7)

1

-

-

1 -

40

M o d e r a t e - t o - s e v e r e s e c o n d a r y bacterial skin a n d skin s t r u c t u r e infections, especially in an a b n o r m a l host, usually require h o s p i t a l i z a t i o n , aggressive int r a v e n o u s t h e r a p y with agents c a p a b l e o f c o v e r i n g m i x e d infections involving S . a u r e u s a n d E n t e r o bacteriaceae, and surgical debridement [4,6,7,15,18,23]. A c o n t i n u i n g p r o b l e m , especially in the diabetic p a t i e n t with skin a n d skin s t r u c t u r e infections, is the lack o f efficacy o f m o s t single-agent regimens against a n a e r o b i c flora [20]. In o r d e r to o v e r c o m e the lack o f a truly multiples p e c t r u m antibiotic, c o m b i n a t i o n t h e r a p y , e m p l o y ing one agent with g o o d c o v e r a g e o f G r a m - p o s i t i v e p a t h o g e n s a n d a s e c o n d a g e n t with a g o o d G r a m negative s p e c t r u m o f action, can be used. T h e n e w e r q u i n o l o n e s offer some a d v a n t a g e s in the t r e a t m e n t o f skin a n d skin s t r u c t u r e infections.

59

They have an appropriate spectrum which is capable of covering most of the aerobic flora involved; they can be administered orally; and they have adequate penetration to skin and its structure. These agents will be of value in the treatment of skin and skin structure infections when Enterobacteriaceae or S. a u r e u s are the pathogens involved. As with most available antibiotics, some bacteria, especially anaerobes and some Gram-positive cocci, are not affected. In these situations combination therapy should be used. In this study lomefloxacin demonstrated activity against a large number of Gram-positive pathogens, including S. a u r e u s . The results were similar to those found with regimens specifically targeted at Grampositive organisms, such as the cefaclor used in this evaluation. Resistance to cefaclor in the initially isolated Gram-negative pathogens was responsible for the exclusion of four patients in our study. The use of the newer quinolones in the treatment of skin and skin structure infections will probably help to correct some of the problems arising from the lack of Gram-negative activity of some antibiotic regimens. It is important to note that if severe group A or group B streptococcal cellulitis is suspected by examination or Gram stain, a beta-lactam or macrolide should be used or added to lomefloxacin. Once-daily lomefloxacin therapy of skin and skin structure infections looks promising, but further investigation of its role in Gram-positive infections is required.

Acknowledgements We thank Ma. del Rosario Aceves-Ibarra for the preparation of the manuscript and M. Harker for its revision.

References Bisno AL. Cutaneous infections: microbiologic and epidemiologic considerations. Am J Med 1984;76(Suppl 5a):172179. 2 Chin N-X, Novelli A, Neu HC. In vitro activity of lomeftoxacin (SC-47111, NY-198), a new difluoroquinolone 3-carboxylic acid, compared with those of other quinolones. Antimicrob Agents Chemother 1988;32:656-662. 3 Chow AW, Taylor PR, Yoshikawa TT, Guze IB. A n o s o -

4

5

6 7

8

9

10

11

12

13

14

15

16

17

1

18

19

comial outbreak of infections due to multiple resistant Proteus rnirabilis: role of intestinal colonization as a major reservoir. J Infect Dis 1979;139:621-627. Fass R J, Freimer EH, McCloskey RV. Treatment of skin and soft tissue infections with imipenem/cilastatin. Am J Med 1985;78 (Suppl 6A):110-112. Fierer J, Daniel D, Davis C. The fetid foot: lower extremity infections in patients with diabetes mellitus. Rev Infect Dis 1979;1:210-217. Gentry LO. Treatment of skin, skin structure, bone and joint infections with ceftazidime. Am J Med 1985;79:64-74. Gentry LO, Koshdel A. Intravenous/oral ciprofloxacin versus intravenous ceftazidime in the treatment of serious Gram-negative infections of the skin and skin structure. Am J Med 1989;87(Suppl 5A):132-135. Gros I, Carbon C. Pharmacokinetics of lomefloxacin in healthy volunteers: comparison of 400 milligrams once daily and 200 milligrams twice daily given orally for 5 days. Antimicrob Agents Chemother 1990;34:150-152. Hirose T, Okezaki E, Kato H, Ito Y, Inoue M, Mitsuhashi S. In vitro and in vivo activity of NY-198, a new difluorinated quinolone. Antimicrob Agents Chemother 1987;31:854859. Howe PM, Fajardo JE, Orcutt MA. Etiologic diagnosis of cellulitis: comparison of aspirates obtained from the leading edge and the point of maximal inflammation. Pediatr Infect Dis 1987;6: 685-686. Leroy A, Fillastre JP, Humbert G. Lomefloxacin pharmacokinetics in subjects with normal and impaired renal function. Antimicrob Agents Chemother 1990;34:17-20. Lipsky BA, Hook EW 3rd, Smith AA, Plorde JJ. Citrobacter infections in humans: experience at the Seattle Veterans Administration Medial Center and review of the literature. Rev Infect Dis 1980;2:746-760. Louis TJ, Bartlett JR, Tally FT, Gorbach SL. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann Intern Med 1976;85:461463. Mayhall CA, Camb AV, Gayle WE, Haynes BW Jr. Enterobacter cloacae septicemia in a burn unit center: epidemiology and control of an outbreak. J Infect Dis 1979;136:166-171. McCloskey RV, Goren R, Bissett D, Bently J, Tutlane V. Cefotaxime in the treatment of skin structure. Rev Infect Dis 1982;4 (Suppl):444-447. McManus AT, McCloud CG Jr, Mason A D Jr. Experimental Proteus mirabilis burn surface infection. Arch Surg 1983; 111:291-294. Morrison PJ, Mant TGK, Norman GT, Robinson J, Kunka RL. Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses. Antimicrob Agents Chemother 1988;32:1503-1507. Pankey GA, Katner HP, Valainis GT, Charkson M J, Cortez LM, Dalovisio Jr. Overview of bacterial infections of the skin and soft tissue and clinical experience with ticarcillin plus clavulanate potassium in their treatment. Am J Med 1985;79 (Suppl 5B): 106-115. Parish LC, Asper R. Systemic treatment of cutaneous infec-

60

20

21

22

23

24

25

tions: a comparative study of ciprofioxacin and cefotaxime. Am J Med 1987;82 (Suppl 4a):239-241. Perez-Ruvalcaba JA, Quintero-Perez NP, Morales-Reyes J J, Huitron-Ramirez JA, Rodriguez-Chagollan J J, Rodriguez-Noriega E. Double-blind comparison of ciprofloxacin with cefotaxime in the treatment of skin and skin structure infections. Am J Med 1987;82 (Suppl 4a):242-246. Piddock LJV, Hall MC, Wise R. Mechanism of action of lomefloxacin. Antimicrob Agents Chemother 1990;34: 10881093. Pruitt BA Jr, Colonel MC, McManus AT. Opportunistic infections in severely burned patients. Am J Med 1984;76 (Suppl 3a): 146-154. Quintero-Perez NP, Andrade-Villanueva JF, Leon-Garnica G, Bertin-Montano M, Rodriguez-Noriega E. Efficacy and safety of intravenous ciprofloxacin in the treatment of serious infections. A comparison with ceftazidime. Am J Med 1989;87(Suppl 5a): 198-201. Ramirez-Ronda CH, Saavedra S, Rivera-Vazquez CR. Comparative double-blind study of oral ciprofloxacin and intravenous cefotaxime in skin and skin structure infections. Am J Med 1987;82(Suppl 4a):220--223. Rustige C, Wiedemann B. Antibacterial activity of lomefloxacin in a pharmacokinetic in vitro model. Antimicrob Agents Chemother 1990;34:1107-1111.

26 Sapico FL, Canawati HN, Witte JL, Montgomerie JZ, Wagner FW Jr, Bessman AN. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol 1980;12:413-420. 27 Sapico PL, White JL, Canawati HN, Montgomerie JZ, Bessman AN. The infected feet of a diabetic patient: quantitative microbiology and analysis of clinical features. Rev Infect Dis 1984; 6 (Suppl 1):171-176. 28 SelfPL, ZeloffBA, Sollo D, Gentry LO. Use ofciprofloxacin in the treatment of serious skin and skin structure infections. Am J Med 1987;82 (Suppl 4a):239-241. 29 Sheagren JD. Treatment of skin and skin structure infections in the patient at risk. Am J Med 1984;76 (Suppl 5a): 180-196. 30 Stone JW, Andrews JM, Ashby JP, Griggs D, Wise R. Pharmacokinetics and tissue penetration of orally administered lomefloxacin. Antimicrob Agents Chemother 1988;32:15081510. 31 Wise R, Andrews JM, Ashby JP, Matthews RS. In vitro activity of lomefloxacin, a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988;32:617-622.