By Giordano, Philip A; Elston, Dirk; Akinlade, Bolanle K; Weber, Kurt; Et al
Key words: Cefdinir – Cephalexin – Uncomplicated skin and skin structure infections – USSSI
ABSTRACT
Objectives: To compare the efficacy and safety of cefdinir to that of cephalexin In adolescents and adults with mild to moderate uncomplicated skin and skin structure infections (USSSI).
Research design and methods: This was an investigator-blinded, multicenter study In which patients at least 13 years of age with USSSI were randomized to receive 10 days of cefdinir 300 mg twice dally (BID) or cephalexin 250 mg four times daily (QID). Patients were evaluated at baseline, by telephone on Days 3-5, and during office visits on Days 12-14 (end-of-therapy [EOT] visit) and Days 17- 24 (test-of-cure [TOC] visit).
Main outcome measures: Clinical response was evaluated at the TOC visit. Patient reported outcomes, Including a usefulness questionnaire, were also assessed.
Results: Three hundred and ninety-one patients were treated. The treatment groups were well matched with regard to demographic characteristics and types of infection. Abscess(es) (26%), wound infection (24%), and cellulitis (21%) were the most common infections. At the TOC visit, the clinical cure rate for both treatment groups was 89% (151/170 for cefdinir and 154/174 for cephalexin) in clinically evaluable patients (95% Cl for difference in cure rates [-6.7 to 7.3]). In the intent-to-treat analysis, cure rates were 83% for cefdinir vs. 82% for cephalexin. Clinical cure rates for infections caused by methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureusmre 93% (37/40) and 92% (35/38) for cefdinir vs. 91% (29/32) and 90% (37/41) for cephalexin (p > 0.999 comparing treatment groups for MSSA; p > 0.999 for MRSA). The usefulness questionnaire demonstrated that cefdinir was more highly rated in the mean composite score (87.4 vs. 83.6, p = 0.04), with the difference primarily due to the respondents’ preference for the convenience of taking the study medication (mean score 93.5 vs. 74.1 for cephalexin, p
Conclusions: This study demonstrated that empiric coverage of USSSIs with cephalosporin therapy remains an appropriate clinical strategy. MRSA infections responded well in both arms of the study, suggesting that the choice of a cephalosporin did not adversely affect patient outcome. However, cephalosporins do not have accepted, clinically relevant in vitro activity against MRSA. Hence, the clinical response rates seen in this study against MRSA infections must be interpreted with caution. Cefdinir was more highly rated than cephalexin in a composite usefulness assessment.
Introduction
Uncomplicated skin and skin structure infections (USSSI) such as impetigo, erysipelas, cellulitis, folliculitis, furunculosis, wound infection, and simple abscesses are frequently encountered in the ambulatory care setting1. USSSIs are commonly caused by Staphylococcus aureus, Streptococcus pyogenes, and other streptococci2. They must be distinguished from complicated skin infections, which involve deeper soft tissue or require significant surgical intervention, such as infected ulcers, burns, and major abscesses, or involve a significant underlying disease state that complicates the response to treatment. Superficial infections or abscesses in anatomical sites, such as the rectal area, where the risk of anaerobic or Gram-negative pathogen involvement is high are also considered complicated skin infections3. In clinical practice, empiric antibiotic treatment for USSSI is typically initiated at the time of the initial visit, regardless of whether a culture is performed. Abscesses are treated with incision and drainage (I&D), with antibiotics playing a secondary role4.
Because USSSIs are confined to the superficial layers of the skin and seldom result in hospitalization, they can generally be treated with an oral antibiotic with coverage against the most common Gram- positive pathogens. Among the antimicrobial agents recommended for treating USSSIs, penicillinase-stable β-lactam agents possess good microbiological activity against methicillin-susceptible strains of S. aureus (MSSA) and streptococci5. Oral cephalosporins with proven clinical efficacy for USSSIs remain the most common class of antibiotics used for the treatment of USSSIs6,7 and include cefprozil, cefuroxime axetil, cefadroxil, cefdinir, cephalexin8-14. Semisynthetic penicillins and the penicillin-β-lactamase inhibitor combination, amoxicillin-clavulanate, are also used5. In addition, fluoroquinolones, tetracyclines, trimethoprim- sulfamethoxazole, macrolides, and lincosamides have demonstrated clinical efficacy in the treatment of USSSI5.
Since most therapy for USSSI is empiric5, culture and susceptibility testing, with subsequent modification of therapy, if indicated, is generally reserved for patients with recurrent or recalcitrant USSSI, or for those at high risk of infection with methicillin-resistant S. aureus (MRSA). However, the strains of MRSA that are emerging as an increasingly common cause of community- acquired (CA) skin infections15-17 differ from the hospital- acquired (HA) strains. The CA-MRSA strains are more likely to present as purulent infections such as abscess or furunculosis and to occur in patients without the typically described risk factors for HA-MRSA18. These CA-MRSAs are genetically distinct from HA strains, and contain the gene for Panton-Valentine leukocidin (pvl) toxin, which has been associated with necrotizing pneumonia and necrotic abscesses19.
This study compared the efficacy, tolerability, and safety of cefdinir with that of cephalexin in adolescents and adults with mild to moderate USSSI. Both study drugs are approved in the US for the treatment of such infections20,21.
Patients and methods
Study design
The study was a Phase 4, investigator-blinded, randomized, parallel-group, multicenter study conducted in the US. Patients at least 13 years of age with mild to moderate USSSIs were enrolled at 39 sites between March 25, 2005 and July 22, 2005. An institutional review board reviewed and approved the protocol for each investigative site. Written informed consent was obtained before a patient enrolled into the study. For patients who were 18 years of age or younger, written child assent and their parent/legal guardian consent were also obtained, if determined applicable by the institutional review board.
Patients
Eligible patients were at least 13 years old with a mild to moderate USSSI, which included, but was not limited to, cellulitis, erysipelas, impetigo, simple abscess, wound infection, furunculosis, and folliculitis. The clinical diagnosis of an USSSI was based on the presence of two or more localized signs/symptoms: pain/ tenderness, swelling, erythema, localized warmth, purulent drainage/ discharge, induration, regional lymph node 4 swelling or tenderness, and/or extension of redness. Abscesses surrounded by cellulitis were classified as cellulitis according to the judgment of the physician. Women of childbearing potential were required to have a negative prestudy urine pregnancy test and agree to use effective contraception throughout the study.
Study exclusion criteria included a chronic or underlying skin condition at a site of infection, infections involving prosthetic materials, a wound caused by burn injury or acne vulgaris, abscesses in anatomical sites with a high risk of anaerobic infection (e.g., rectal area), concomitant documented or suspected bacteremia, fungal infection of the nail bed or scalp, immunodeficiency, significant peripheral vascular disease, deep vein thrombosis, or superficial thrombophlebitis. The use of a systemic antibiotic within 7 days (for azithromycin, within 14 days) prior to enrollment or concomitant use during the study was prohibited, as was the use of concomitant topical therapy at the infection site. Patients taking systemic corticosteroids at a dose greater than 15 mg of prednisone (or equivalent) per day for greater than 7 days were excluded.
Antimicrobial therapy
A computer-generated randomization schedule was used to assign patients in a 1:1 ratio to receive either cefdinir capsules 300 mg twice a day (BID) for 10 days (Omnicef, Abbott Laboratories, North Chicago, IL, USA) or cephalexin capsules 250 mg four times per day (QID) for 10 days (Keflex, Eli Lilly and Company, Indianapolis, IN, USA). Study drug containers were dispensed in increasing numerical sequence at each investigative site as patients were enrolled to assure random a\ssignment of the treatment regimens according to the randomization schedule. Local lesion care measures, such as daily dressing change and the use of cleansing agents (e.g., non- antibacterial soap, water, saline) were permitted. Purulent lesions were treated by incision and drainage when appropriate by the investigator.
To maintain investigator blinding, the study drug was dispensed by an unblinded third person who did not participate in the assessments of clinical response. Furthermore, the patient was instructed not to disclose any details about the study drug (e.g., dosing frequency, taste, appearance, or packaging) to the investigator.
Study procedures
Patients were evaluated during visits conducted at baseline (within 48 h of study enrollment), following the completion of treatment (study Days 12-14; end-of-therapy [EOT] visit), and at a follow-up visit (study Days 17-24; test-of-cure visit [TOC]) or within 48 h of study discontinuation for patients who were prematurely withdrawn from the study. In addition, patients were contacted by telephone during treatment (study Days 3-5); a clinic visit was scheduled if the patient’s symptoms had not improved or had worsened at that time. Patients were assessed for adverse events during the telephone call and at all clinic visits.
A specimen for culture was obtained at baseline prior to the initiation of study drug and at any time thereafter, as clinically indicated. A specimen was obtained at the TOC visit, if culturable material was available. For abscess(es) and other purulent lesions, the specimen was obtained by swab from the base of the lesion during I&D or from purulent material that was spontaneously draining from lesions that did not require I&D. For uncomplicated cellulitis and erysipelas, leading-edge needle aspiration was conducted after cleansing with normal saline or sterile water to prevent surface contamination. Specimens were sent to a central laboratory, and minimum inhibitory concentrations (MICs) for isolated pathogens were determined for cephalosporins and other antibiotics using broth microdilution according to Clinical Laboratory Standards Institute (CLSI) methods22,23. In addition, isolates of S. aureus were tested for susceptibility to oxacillin to differentiate MSSA from MRSA using the CLSI criteria22,23. MRSAs were confirmed using the latex agglutination test (PBP2′ test kit for the detection of PBP2′, Oxoid Ltd., Basingstoke, Hants, UK). Culture results were provided to investigators to manage individual patients, on request only.
Other assessments
Patients completed three outcomes questionnaires related to the treatment of their skin infections. In a self-assessment questionnaire, patients assessed their USSSI symptoms at all visits and during the on-treatment telephone call. A questionnaire was administered at the EOT visit, in which patients rated the usefulness of study drug based on their USSSI symptom improvement, medication side effects, and convenience in taking the medication; each response was rated using a scale from 0 (least useful) to 100 (most useful) and a composite score was calculated from the three individual scores. At both the EOT and TOC visits, patients were questioned about their use of healthcare resources since their previous evaluation.
In addition, patients completed a daily diary assessing medication compliance, USSSI symptom severity, activity limitations, other problems related to the infection (e.g., lack of sleep, reduced productivity/ concentration), number of hours of paid work missed (by patients or caregivers), and use of non-routine baby- sitting.
Outcome measures
Efficacy
The investigators evaluated clinical and microbiological responses at the TOC visit or at premature discontinuation. Patients were considered a clinical cure if their signs and symptoms had improved or resolved, and additional systemic antimicrobial therapy was not required. Patients were considered a clinical failure if they experienced persistent or worsening signs and symptoms, had onset of new USSSI signs/symptoms at the baseline infection site following at least 72 h of antibiotic therapy, or needed additional antimicrobial therapy for the skin infection. An indeterminate clinical response was assigned when evaluation was impossible (e.g., no follow-up examination, use of confounding medications, or premature discontinuation due to an adverse event or protocol violation).
Microbiologic responses included patient bacteriological cure rate and target pathogen eradication rate. Bacteriologic response was assigned using the following definitions: eradication, absence of the pretreatment pathogen in a post-treatment specimen; presumed eradication, clinical cure with absence of culturable material at the primary infection site; persistence, growth of the pretreatment pathogen in a culture taken at a post-treatment visit; presumed persistence, clinical failure with absence of culturable material at the primary infection site; new infection, isolation of a new pathogen from a specimen obtained after the initiation of study drug; and indeterminate, microbiologic response could not be assigned. Target skin pathogens were S. pyogenes and S. aureus, as well as other recognized skin-related pathogens (Streptococcus agalactiae, Streptococcus uberis, Streptococcus dysgalactiae, Pseudomonas aeruginosa, Pasteureua multocida). The patient bacteriological cure rate was the percentage of clinically and bacteriologically evaluable patients in whom all target pathogens were eradicated or presumed to be eradicated. The target pathogen eradication rate was the percentage of all evaluable pretreatment target pathogens eradicated or presumed to be eradicated.
Safety and compliance
Investigators monitored patients throughout the study for adverse events and recorded their severity and relationship to the study drug. All study patients who received at least one dose of the study drug were included in the safety analysis. Patients were asked to return their study drug container at the end of treatment, and the third-party individual who dispensed the study drug to patients counted unused study medication to assess treatment compliance.
Data analysis
Assuming a clinical cure rate of [approximate] 85% in each treatment group and a clinical evaluability rate of 70%, at least 380 patients were to be enrolled. This sample size would provide approximately 80% power to ensure that the 2-tailed 95% CI around the difference in response between treatments would remain within the lower bound of -0.125 for establishing non-inferiority between treatments. Statistical analyses were conducted using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).
Characteristics of treatment groups at baseline were compared using Fisher’s exact test for gender and race; one-way analysis of variance (ANOVA) for age; and the Cochran-Mantel-Haenszel test for the infection diagnosis. Baseline data on clinical signs and symptoms were compared between treatment groups using the Cochran- Mantel-Haenszel test.
Three data sets were analyzed for efficacy: the clinically evaluable (per-protocol) patient population, the clinically and bacteriologically evaluable patient population, and the intent-to- treat (ITT) patient population. All patients who received at least one dose of the study drug and had a clinical diagnosis of USSSI supported by clinical signs and symptoms were included in the ITT population. In addition to this requirement, patients in the clinically evaluable population must have taken at least 80% of the study drug to be considered a clinical cure (3 days for those classified as a clinical failure) and received no prohibited medications during study participation (as described in the Patients section). In addition to the previous requirements, clinically and bacteriologically evaluable patients were also required to have at least one pre-treatment target pathogen isolated from the primary infection site culture.
The clinical cure rate at the TOC visit in the clinically evaluable patient population was the primary efficacy endpoint. Patient bacteriological cure rate and pathogen eradication rate were secondary study endpoints. The treatment-group differences for clinical cure rate (clinically evaluable and ITT populations), patient bacteriologic cure rate (clinically and bacteriologically evaluable, and ITT populations), and pathogen eradication rate (clinically and bacteriologically evaluable, and ITT populations) at the TOC visit were analyzed using Fisher’s exact test. Binomial 95% CIs, based on the normal approximation for the binomial distribution, were computed for the difference between treatment groups. The treatment groups were compared based on clinical cure rate and patient bacteriological cure rate by infection diagnosis using the Cochran-Mantel-Haenszel test.
The treatment groups were also compared based on responses to the usefulness questionnaire (using one-way ANOVA), patient self- assessment (using the Cochran-Mantel-Haenszel test), and health care resource utilization (using Fisher’s exact test) in the clinically evaluable population. Patient diary data in the clinically evaluable population were compared using the Chi-square test (categorical data) and the t-test (continuous data). The incidence of adverse events was compared using Fisher’s exact test.
Results
Three hundred and ninety-two patients with USSSI were randomized to receive the study drug and 391 patients took at least one dose of the study drug (191 in the cefdinir treatment group and 200 in the cephalexin treatment group). The two treatment groups were well matched with regard to demographic characteristics, types of infection (Table 1), and pretreatment clinical signs and symptoms. Abscess(es) (26%), wound infection (24%), and cellulitis (21%) accounted for the majority of infections, with no significant difference in incidence between treatment groups.\Patient disposition
All 391 randomized and treated patients were included in the ITT population (Table 2). The clinically evaluable population for clinical efficacy analyses excluded 47 patients: 23 due to noncompliance with their assigned treatment regimen, 14 for receiving prohibited medications during study participation, 12 for not returning for the TOC visit, 6 for not meeting the admission criteria, 5 for having a confounding disease, and 4 for a mistimed TOC visit (a patient could have been excluded for multiple reasons, making the sum of reasons for exclusion greater than 47) (Table 2). In addition to the reasons cited for patients being clinically unevaluable, 15 and 18 patients in the cefdinir and cephalexin groups, respectively, were excluded from the clinically and bacteriologically evaluable analyses because of a negative culture at baseline.
Table 1. Characteristics of all treated patients at baseline
Table 2. Disposition of patients
Pretreatment pathogens
A total of 170 (89%) of the 191 cefdinir-treated patients and 179 (90%) of 200 cephalexin-treated patients had a positive skin culture. Of 488 isolates obtained at baseline, 197 were target skin pathogens. The incidence of target skin pathogens was as follows: S. aureus (171 [87%]), S. agalactiae (11 [6%]), S. pyogenes (7 [4%]), P. aeruginosa (4 [2%]), S. uberis (2 [1%]), P. multocida (1 [0.5%]), and S. dysgalactiae (1 [0.5%]). The 171 S. aureus isolates included 90 (53%) that were resistant to oxacillin (MRSA), which were most commonly cultured from abscesses. MIC^sub 90^ values of cefdinir and cephalothin, used as a surrogate for cephalexin23, were 1.0 g/mL and 0.5 g/mL, respectively, against MSSA and 8.9 g/mL and 4.0 g/mL, respectively, against MRSA. Culture results could be provided to investigators to manage individual patients. However, only 16 culture results were requested (i.e., four clinical cures, nine clinical failures, and three indeterminate clinical responses); of these 16 culture results, seven revealed an infection caused by MRSA (i.e., four clinical cure, two clinical failures, and one indeterminate clinical response).
Table 3. Clinical cure rate by infection diagnosis at the test- of-cure visit in clinically evaluable patients
Clinical response
There were no statistically significant differences between the treatment groups in clinical response. At the TOC visit, the clinical cure rate for both treatment groups was 89% among clinically evaluable patients (151/170 for cefdinir and 154/174 for cephalexin; 95% CI for difference in cure rates [-6.7 to 7.3]) and 88% among clinically and bacteriologically evaluable patients (136/ 155 for cefdinir and 137/156 for cephalexin 95% CI [-7.7% to 7.5%]). In the ITT population, the clinical cure rate was 83% (158/191) for cefdinir and 82% (163/200) for cephalexin, 95% CI [-6.7% to 9.1%].
The clinical cure rate by infection diagnosis in the clinically evaluable population ranged from 70% to 100%, with no statistically significant difference between treatment groups (Table 3). Among clinically and bacteriologically evaluable patients, the clinical cure rates for the cefdinir and cephalexin groups were 93% (37/40) and 91% (29/32), respectively, for infections caused by MSSA (p > 0.999) and 92% (35/38) and 90% (37/41), respectively, for infections caused by MRSA (p > 0.999); many of these were abscesses that had been incised and drained before start of therapy. For infections caused by S. pyogenes (p > 0.999) the clinical cure rates were 100% (2/2) and 75% (3/4) for the respective treatment groups.
Seven of 79 patients with MRSA-associated infections were clinical failures. Of these, three had been treated with cefdinir and four with cephalexin. In these seven patients, MRSA was isolated as the sole pathogen in six patients and was isolated along with S. epidermidis and Bacillus species in one patient (cefdinir group). The infections associated with these failures were furunculosis (one cefdinir), wound infection (one cefdinir), cellulitis (one cefdinir and two cephalexin), and abscess (two cephalexin). Of the seven MRSA- related clinical failures, four patients had repeat cultures performed at the TOC visit. All four patients had MRSA isolated at this repeat culture, with Enterobacter aerogenes co-isolated with MRSA in one of these patients (cefdinir group). All seven patients with MRSA evaluated as clinical failures were also classified as bacteriological failures.
Six of 72 patients with MSSA-associated infections were clinical failures. Of these, three in each group had been treated with cefdinir and cephalexin. The infections associated with these failures were cellulitis (one cefdinir and one cephalexin), paronychia (two cefdinir), and impetigo (two cephalexin). Of the six MSSA-related clinical failures, four patients had repeat cultures performed at the TOC visit. All four patients had MSSA isolated at this repeat culture, with other organisms co-isolated with MSSA in all of these patients (i.e., Bacillus species and E. cloacae in two patients; Prevotella bivia in one patient; and Pantoea species, S. epidermidis, and Stentrophomonas maltophilia in one patient).
Microbiologic response
The treatment groups were similar based on patient bacteriological cure rates in the clinically and bacteriologically evaluable patients: 87% (135/155) for cefdinir and 86% (134/156) for cephalexin in patients with any isolate at baseline. In patients infected with target skin pathogen(s) the bacteriological cure rates were 92% (79/86) and 89% (70/79), p = 0.601, 95% CI [-6.5 to 13.0] for the respective treatment groups. As was observed with the clinical cure rates in the clinically evaluable population, there was no significant difference between treatment groups based on patient bacteriological response stratified by infection diagnosis. No between-group differences were observed for patient bacteriological cure rate (any isolate, target skin pathogen, and S. aureus or S. pyogenes) in ITT patients (data not shown).
Table 4. Eradication rates at the test-of-cure visit for pathogens isolated from clinically and bacteriologically evaluable patients
Of the target skin pathogens isolated at baseline from clinically and bacteriologically evaluable patients, 87% were eradicated or presumed eradicated in each treatment group at the TOC visit (95% CI, -9.0% to 9.7%) (Table 4). Eradication rates for MSSA, MRSA, and S. pyogenes were 93%, 89%, and 100%, respectively, for cefdinir and 88%, 88%, and 75%, respectively, for cephalexin. There was good correlation between clinical response and bacteriological eradication of pathogens, with discordant results based on clinical and bacteriological responses in only four patients (one cefdinir and three cephalexin), who were each classified as a clinical cure, but had documented bacterial persistence based on repeat culture.
There was no significant increase in MIC (> 2-fold dilution) in any organisms isolated at follow-up that were originally present at baseline (average of 15.3 6.95 days between specimen collections). Among patients from whom a bacterial isolate was obtained after baseline, 11 patients in the cefdinir group had 18 new isolates not found at baseline, the most common being S. epidermidis (three patients). Thirteen patients in the cephalexin group had 18 new isolates, the most common being S. epidermidis (four patients), Enterobacter faecalis, and Peptostreptococcus magnus (two patients each).
Other outcomes
In the usefulness questionnaire, completed at the EOT visit, cefdinir was more highly rated in the composite assessment (87.4 vs. 83.6, p = 0.04), primarily due to a statistically significant preference for the convenience of taking cefdinir compared with cephalexin (93.5 vs. 74.1, p
Safety
Only one patient each in the cefdinir group (diarrhea) and the cephalexin group (gastroenteritis) experienced a treatment-related adverse event that led to premature discontinuation of the study drug. The most common treatment-related adverse events were diarrhea (10% cefdinir, 4% cephalexin, p = 0.017), nausea (3% and 6%, respectively, p = 0.203), and vaginal mycosis (3% and 6% of females, respectively, p = 0.500). Most adverse events were mild or moderate in intensity and resolved rapidly without intervention. No patient experienced a treatment-related serious adverse event during his/ her participation in the study.
Discussion
This study of cephalosporin therapy for USSSI demonstrated comparable clinical cure rates of 89% in clinically evaluable patients for cefdinir and cephalexin at the TOC visit conducted approximately 3 weeks after the completion of a 10-day treatment course, and outcomes were similar between groups for each infection diagnosis. In the ITT analysis, which provides a more realistic and unbiased assessment of clinical effectiveness in a clinical practice setting than does a per-protocol analysis24, the two study drugs were also comparable with regard to clinical outcomes. Clinical outcomes were similar between groups for each infection diagnosis. The clinical cure rates for purulent infections in the clinically evaluable group ranged from 85% to 100%, and the clinical cure rates for cellulitis ranged from 84% to 90%. In a similarly designed study conducted almost a decade ago by Tack et al., the clinical cure rates at the TOC visit in clinically and bacteriologically evaluable patients were 88% among cefdinir-treated patients (300mg BID for 10 days) and 87% among cephalexin-treated (500mg QID for 10 days) patients12, prior to the emergence of more widespread CA-MRSA infection.
MRSA represented 46% of all target skin \pathogens in this study. Most MRSA were isolated from purulent infections (69 of 90 isolates) with the highest number found isolated from abscesses. In recently published studies16,17, S. aureus was the most frequently isolated pathogen from culturable skin lesions with the majority of the isolates being methicillin resistant.
MRSA is considered resistant to both study drugs25, although MIC^sub 90^s for cefdinir and cephalothin (as a surrogate for cephalexin) were 8 g/mL and 4 g/mL, respectively. However, the clinical cure rate of patients infected with MRSA was 92% and 90%, respectively, in the cefdinir and cephalexin groups. The finding that MRSA infections responded at least as well as MSSA infections, despite the use of a β-lactam agent, is in agreement with previous studies26,27. For example, Fridkin et al. observed that treatment of CA-MRSA infections with an antibiotic lacking activity against MRSA was not associated with adverse outcomes28. This suggests that successful treatment for abscesses caused by MRSA is based primarily on I&D, more so than on antibiotic selection4,29.
The clinical cure rates for cellulitis were 90% and 84%, respectively, in the cefdinir and cephalexin treatment groups. For cellulitis, most are caused by streptococci regardless of the non- specific isolation of a different pathogen (e.g., MRSA) by culture. Furthermore, in this study many cases of abscesses with associated cellulitis were categorized as cellulitis. This is reflected by the low rate of recovery from cellulitis of S. pyogenes, the primary pathogen in uncomplicated cellulitis, and a high rate of S. aureus, which is less frequently involved. Cephalosporins remain active against streptococci5. Despite this fact, a retrospective review of uncomplicated cellulitis by Madaras-Kelly revealed a 40% failure rate with cephalexin30. However, in the study microbial cultures were obtained in
The study limitations, as previously described, include: all enrolled patients were required to have a specimen for culture collected at baseline, which is likely to have skewed the enrollment of patients towards those with abscesses (26% of all entry diagnoses); the results of culture in patients with USSSIs are often non-specific; in some patients entering the study with a diagnosis of cellulitis, the cellulitis was associated with an abscess; and, since most MRSAs in this study were isolated from purulent infections, I&D, spontaneous drainage, and needle aspiration are likely to have contributed to clinical response for purulent infections, and in particular MRSA-associated infections, where the drugs have limited antibacterial activity.
Both study drugs were well tolerated, with only one patient in each treatment group discontinuing the study prematurely due to a treatment-related adverse event. Despite a statistically significant difference in the incidence of diarrhea between treatment groups, there was a similar rate of discontinuation from the study due to this adverse event (one patient in each treatment group) and similar patient opinion of the impact of medication side effects.
Conclusions
Both study drugs provided comparable clinical response in this population of adolescents and adults with USSSIs. Patients rated cefdinir as more useful overall for treating their infection, likely influenced by the strong preference for the convenience of taking cefdinir twice daily as compared with taking cephalexin four times daily.
Incision and drainage appears to remain the most important therapeutic intervention for purulent infections, especially those caused by MRSA, and should precede antibiotic therapy for these infections whenever possible. Cephalosporins remain an appropriate clinical strategy for the treatment of USSSIs, with the selection between agents ultimately being based on compliance and cost.
Acknowledgment
Declaration of interest: This study was sponsored by Abbott Laboratories. The authors acknowledge the contributions of Victoria Mullally, Andrea Smith, and George E. MacKinnon, III, Ph.D., Abbott Laboratories, and Sandra Noms, PharmD, Noms Communications, for manuscript preparation.
They also acknowledge the investigators who enrolled patients in this study but are not authors of this paper:
Thomas Adams, MD, Murray, KY; Jay Adler, MD, Colorado Springs, CO; Stephen Braden, MD, Bryan, TX; Robert Broker, MD, Simpsonville, SC; Timothy Bruya, MD, CCTI, Spokane, WA; Patricia Buchanan, MD, Eugene, OR; Eric Carter, MD, New York, NY; John Champlin, MD, Carmichael, CA; Shane Christensen, MD, CCRP, West Jordan, UT; Weldon Collins, MD, FAAD, Beaumont, TX; Merra Dewan, MD, Omaha, NE; Jimmy Durden, MD, Tallassee, AL; David Estock, MD, PA, Wilmington, DE; Richard Fei, MD, Lafayette, LA; Thomas Fiel, DO, Tempe, AZ; Chester Fisher, Jr., MD, MPH, Newport News, VA; David George, MD, Louisville, KY; Richard Guzzetta, MD, Clovis, CA; Dan Henry, MD, CCRP, West Jordan, UT; Ronica Kluge, MD, Fort Meyers, FL; James Kratzer, MD, MPH, FAAP, Fresno, CA; Frank Maggiacomo, DO, Cranston, RI; Frank Mazzone, MD, San Luis Obispo, CA; Michael McAdoo, MD, Milan, TN; Carmen Molina, MD, FAAP, Hialeah, FL; Thomas Nolen, MD, FAAFP, Columbiana, AL; Bruce Rankin, DO, CCTI, Deland, FL; Ernie Riffer, MD, Phoenix, AZ; Jeffrey Rosen, MD, Coral Gables, FL; Daniel Rowe, MD, West Palm Beach, FL; Gary Ruoff, MD, Kalamazoo, MI; Renee Scheidell, MD, West Jordan, UT; John Sibille, MD, Sunset, LA; Malcolm Sperling, MD, Fountain Valley, CA; Gary Tarshis, MD, PC, ABFP, Colorado Springs, CO; Randall Watson, MD, West Jordan, UT; Charles White, MD, Lexington, TN; and, Kevin Wingert, MD, Clovis, CA.
* The data summarized in this paper were presented in part during a poster session at the 46th Annual International Conference on Antimicrobial Agents and Chemotherapy, September 27-30, 2006, San Francisco, CA, USA
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3609_4, Accepted for publication: 08 September 2006
Published Online: 30 October 2006
doi:10.1185/030079906X148355
Philip A. Giordano(a), Dirk Elston(b), Bolanle K. Akinlade(c), Kurt Weber(a), Gerard F. Notario(c), Todd A. Busman(c), Mary Cifaldi(c) and Angela M. Nilius(c)
a Orlando Regional Medical Center, Department of Emergency Medicine, Orlando, FL, USA
b Geisinger Medical Center, Danville, PA, USA
c Abbott Laboratories, North Chicago, IL, USA
Address for correspondence: Philip A. Giordano, MD, Oriando Regional Medical Center/ Department of Emergency Medicine, 86 West Underwood Street, Suite 300, Orlando, FL 32806, USA. Tel.: +1 407 237 6329; Fax: +1 407 370 5105; email: [email protected]
Copyright Librapharm Dec 2006
(c) 2006 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.
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