The classification of skin and soft tissue infection (SSTI) will ultimately determine therapeutic strategies to be used in the patient. SSTIs are categorized as “uncomplicated” (such as mild cellulitis, a simple abscess, or impetigo) or “complicated” (cSSTIs, including deep soft tissue infections, those requiring surgical intervention [infected ulcers, infected burns, and major abscesses] and those in patients who have significant underlying disease states [comorbidities] that complicate response to treatment). Wounds that are chronic, such as diabetic foot infections (DFIs), can range from superficial to deep and from simple to complicated.
Other factors that might contribute to the complexity of the infection are the patient’s risk factors including: advanced age, poor nutritional status, diabetes, smoking, obesity, infections at a remote body site, colonization with resistant organisms, the use of steroids or other immunosuppressants, and prolonged length of stay (LOS) in a hospital or long-term care (LTC) facility.
Epidemiology Of SSTIs
Staphylococcus aureus was recovered from 45.9% of SSTIs in the SENTRY Antimicrobial Surveillance Program, with 30% of the S. aureus isolates methicillin-resistant (MRSA).22 In DFIs, S. aureus is also the most frequently isolated pathogen, with MRSA increasing in prevalence in these infections, in both the hospital and community.23,24 These diabetic MRSA infections are associated with prolonged LOS and increased economic costs.25-28
Risk factors that predispose a patient to MRSA infections include long LOS, invasive procedures, previous antibiotic use, diabetes, previous MRSA colonization, chronic wounds, and care in a LTC facility.24,29-30
Treatment Strategies
Incision and drainage (I&D) is the mainstay of therapy in any SSTI. Debridement and removal of any foreign body, if there is a foreign body, are of paramount importance in cases of necrotic tissue or the presence of a foreign body. Antibiotic therapy is only adjuvant to surgical therapy. In cases of cellulitis with no necrotic tissue or purulent material, I&D or debridement can be bypassed or delayed until the patient shows no signs of improvement. The clinician must also decide whether to treat the patient as an inpatient or an outpatient.
Special considerations to keep in mind when choosing an antibiotic include the site and severity of infection, and whether it is a healthcare-associated or community-acquired infection. Institution susceptibility patterns must also be considered if the patient is being treated as an inpatient. In addition, the severity of the infection, as determined by the local manifestations and systemic symptoms, the patient’s risk factors, and comorbidities, must be factored in. The dilemma of starting empiric therapy with a narrow-spectrum agent, a broad-spectrum agent, or one that covers resistant organisms continues to persist. When treating patients with DFIs, broad-spectrum therapy is generally indicated for severe infections.31 Definitive antimicrobial therapy should be based on cultured organisms and their susceptibility patterns.
While several antibiotics have activity against MRSA, only a few are FDA-approved for treating MRSA SSTIs. This group of antibiotics includes vancomycin, linezolid, daptomycin, and tigecycline (see Table 2). Non–FDA-approved agents with some activity against MRSA include trimethoprim/sulfamethoxazole, clindamycin, minocycline, rifampin, some of the fluoroquinolones, quinupristin/dalfopristin (Q/D), and doxycycline. Dalbavancin is currently under FDA review for approval for the treatment of MRSA SSTIs.
Of the FDA-approved antibiotics, vancomycin is the most commonly used, as it has been available the longest and is the one with which clinicians are most familiar. A bactericidal glycopeptide that was discovered in 1956 and introduced clinically in 1958, vancomycin was quickly overshadowed by other anti-staphylococcal antibiotics due to its nephrotoxicity and potential to cause Red-man syndrome. It became clinically important in the mid-1980s with the emergence of MRSA.32
Vancomycin, linezolid, daptomycin, and tigecycline are all approved for the treatment of MRSA SSTIs.33-36 Vancomycin is also approved for multiple other indications. Linezolid also has approval for the treatment of DFI and pneumonia. All of the approved agents are administered intravenously. Linezolid can be given orally or intravenously at the same dose of 600 mg every 12 hours.34 Vancomycin is dosed 1 g every 12 hours and is dose adjusted based on the weight and renal function of the patient, and based on susceptibility patterns.33 Q/D is dosed 7.5 mg/kg every 12 hours.37
Daptomycin is given only once a day, at a dose of 4 mg/kg of body weight.35 Tigecycline is given as a fixed dose of 50 mg every 12 hours after an initial loading dose of 100 mg.36 Dalbavancin, another new anti-MRSA agent, is currently under FDA review. It has been dosed at 1000 mg once and 500 mg 1 week later in phase 3 trials.38
The advantages of each of these antibiotics are outlined in Table 3.33-38 Clinicians are very familiar with vancomycin and feel comfortable using it. Q/D was never widely used, except at a time when none of the others were available, and it was mostly used to treat vancomycin-resistant Enterococcus (VRE) infections. Pharmacoeconomic studies with linezolid have shown that patients can start with or switch to the oral formulation, have IV catheters removed quickly, and be discharged home earlier.39,40
Also, Weigelt and colleagues have demonstrated that linezolid is superior to vancomycin for the treatment of MRSA SSTIs, including surgical site infections (SSIs).41,42 Daptomycin is bactericidal. Tigecycline has a broad spectrum of antimicrobial activity against gram-positive and gram-negative organisms, and is given at a fixed dose. Dalbavancin is given only once a week and it is also bactericidal.
The disadvantages of each of these drugs are also outlined in Table 3.33-38 Vancomycin has been associated with nephrotoxicity and Red-man syndrome, and the development of resistant organisms such as VRE, vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). It requires therapeutic drug monitoring, skilled nursing staff for IV line care, and has been associated with treatment failures (see below). Q/D can only be given through a central IV line and has been associated with myalgias and arthralgias. Linezolid has been associated with reversible hematologic abnormalities, mainly thrombocytopenia, which is most often seen with greater than 14 days of therapy, and Enterococcus species develop resistance with prolonged use. Daptomycin has limited indications, has been shown to be ineffective in pneumonia, and has been associated with myalgias.43 Tigecycline has a 30% incidence of nausea and vomiting.
Decreased Effectiveness Of Vancomycin
Difficulties have emerged with vancomycin therapy over the past 30 years, resulting in its decreased effectiveness. Even though vancomycin affects cell wall synthesis of gram-positive organisms, it is slowly bactericidal, meaning its killing is slower than that of b-lactam antibiotics. Other issues include poor tissue penetration and a gradual increase in the minimum inhibitory concentrations (MICs) among MRSA over the past 30 years. In fact, VISA organisms have been described with MICs of 4 mcg/mL to 8 mcg/mL, and VRSA with MICs of greater than 32 mcg/mL have been described in the United States and Japan.44-46
A recent study by Moise-Broder and colleagues demonstrated that as the MICs of the MRSA organisms increase, the clinical failure rate also increases.47 They found that an MIC of vancomycin for MRSA of 0.5 mcg/mL was associated with a 22% failure rate, and that an MIC of 2.0 mcg/mL of vancomycin was associated with a failure rate around 50%.46
Another entity that can result in vancomycin treatment failures is heteroresistance in MRSA. Heteroresistance is when some MRSA isolates have MICs in the susceptible range but have subpopulations that grow on vancomycin >4 mcg/mL.48 Basically, the MRSA isolates are made up of a mixed population of organisms, some of which are susceptible to vancomycin and are killed, and some of which are resistant to vancomycin and continue to grow. Unfortunately, heteroresistance is not reported to clinicians by clinical microbiology laboratories, and routine testing for heteroresistance in MRSA isolates is not commonly performed.
Review Of Clinical Trials In Complicated SSTIs
Data from prospective, randomized trials exist for the use of these antibiotics in cSSTIs. Nichols and colleagues published the results of 2 studies, 1 comparing Q/D with oxacillin and 1 comparing Q/D with cefazolin.49 A total of 893 patients were enrolled (450 patients in the Q/D arm and 443 in the comparator arm). Clinical success in the Q/D arm and the comparator arm was 68.2% and 70.7%, respectively. For MRSA infections, the cure rates were higher for Q/D (77.8%) than the comparators (50.0%).49 Statistical conclusions could not be made due to the small number of patients in the subset analysis. Q/D never received FDA approval for the treatment of MRSA infections.
Linezolid for the treatment of SSTIs has been studied extensively.50,51 A recent prospective, randomized, multinational trial compared linezolid with vancomycin in 1200 hospitalized patients with cSSTIs suspected to be caused by MRSA.41 Vancomycin could be switched to one of the antistaphylococcal penicillins orally or intravenously if methicillin-susceptible S. aureus (MSSA) was recovered from the infection site. Linezolid could be started orally or switched to the oral formulation at any time over the course of treatment. Treatment was continued for 4 to 14 days and the primary end point was clinical cure, defined as resolution of the signs and symptoms of infection. In the study, health economic outcomes were evaluated, including LOS, weekly discharge rate, and the duration of IV therapy.
It is of interest to note that 52% of the patients in the linezolid arm of the study were initiated on oral rather than IV linezolid. Overall clinical cure rates in the clinically evaluable (CE) patient population were 94.4% for linezolid and 90.4% for vancomycin (P=0.023). In the microbiologically evaluable (ME) MRSA subgroup, the cure rates were 88.6% for linezolid and 66.9% for vancomycin (P<0.0001) (see Figure 4).41 In addition, patients receiving linezolid had a reduced LOS and duration of IV treatment compared with vancomycin, and this, too, was statistically significant.40
Patients with SSIs (n=135) were evaluated in a secondary analysis of this 1200-patient study. MRSA was isolated in 34 patients in the linezolid arm and in 31 patients in the vancomycin arm. Linezolid clinical cure rates were higher than vancomycin in the CE patients (98% for linezolid and 87% for vancomycin, P=0.06). Microbiologic cure rates were superior for linezolid compared with vancomycin (87% for linezolid and 48% for vancomycin; P=0.0022) in the MRSA cohort.42
Daptomycin was studied in 2 international, multicenter, randomized, double-blind studies in cSSTI.52 Patients received either daptomycin or vancomycin, which could be switched to one of the antistaphylococcal penicillins if MSSA was isolated from the site of infection. The primary end point was resolution of clinical signs and symptoms. Both studies demonstrated equivalence of daptomycin to the comparator. Major subgroups that were evaluated included wound infection, major abscess, ulcer infection, and other infection. The cure rates for all of these groups were very similar between daptomycin and the comparator. Thus, it was concluded from the 2 studies that daptomycin was as efficacious as the comparator.52
Tigecycline was studied in cSSTI and compared with vancomycin plus aztreonam. Clinical cure rates were similar between tigecycline and vancomycin plus aztreonam in the overall population as well as in the following subgroups: soft tissue infections, abscesses, infected ulcers, and burns. Cure rates for the MRSA subgroup were 78.1% in the tigecycline group and 75.8% in the vancomycin plus aztreonam groups, but only 65 MRSA isolates were identified in this study.53 Essentially, tigecycline was shown to be equivalent to vancomycin plus aztreonam.
Dalbavancin is currently under FDA review for the treatment of gram-positive infections. It is a semisynthetic, IV glycopeptide, a cousin of vancomycin. In a phase 3, noninferiority study, patients with cSSTIs, including infections known or suspected to be due to MRSA, were randomized to receive dalbavancin (1000 mg IV on Day 1 and 500 mg IV on Day 8) or linezolid (600 mg IV or PO q12h for 14 days). Dalbavancin and linezolid demonstrated comparable clinical efficacy in the CE population (88.9% and 91.2%, respectively).38 Both treatments yielded successful microbiologic responses in excess of 85% among ME patients for all pathogens combined, for all S. aureus strains, and for MRSA.
Review Of Clinical Trials In DFIs
Of the newer antimicrobials, linezolid was compared with ampicillin/sulbactam or amoxicillin/clavulanate in a multicenter, open-label trial for the treatment of DFIs. In the 371 patients enrolled, the success rates for linezolid and the comparators were statistically equivalent overall (81% for linezolid vs 71% for comparators), but were statistically higher in patients with foot ulcers (81% for linezolid vs 68% for comparators; P=0.018).54
Patients with DFIs in the daptomycin cSSTI studies were prospectively stratified to daptomycin or the control groups. Of the 1092 patients enrolled in the clinical trials, 133 had an infected diabetic ulcer. Clinical success rates were not statistically different between the study groups (66% for daptomycin versus 70% for comparators).55
Figure 4. Clinical Success Rates of Linezolid vs Vancomycin in cSSTIs Presumed or Known
|  | | CE=clinically evaluable; cSSTI=complicated skin and soft tissue infection; ME=microbiologically evaluable; MRSA=methicillin-resistant Staphylococcus aureus. |
In another DFI study, patients with DFIs were randomized to ertapenem or piperacillin/tazobactam. Clinical response rates were similar for the 2 groups (94% for ertapenem versus 92% for piperacillin/tazobactam).56
Of note, in all of these DFI studies, the numbers of MRSA infections were relatively low.
Conclusion
Gram-positive aerobes are the most common organisms in hospitalized patients with SSTI. S. aureus is the most common gram-positive aerobe among these infections with MRSA as the most common pathogen. The increased prevalence of MRSA is seen in the hospital as well as the community. In choosing an antimicrobial, assessment of the infection and patient for special considerations must be completed. CA-MRSA strains are showing resistance to more antimicrobial classes, and b-lactam antibiotics can no longer be considered first-line therapy for community-acquired SSTIs.
For more serious infections, there are several antimicrobial options available that have very good MRSA coverage. These are linezolid, daptomycin, and tigecycline. |
