- The rise of antibiotic resistance underlines the need for the development of new therapies to treat skin and soft tissue infections (SSTIs) with activity against pathogens commonly associated with these conditions, including drug-resistant strains.1
- There is a need to improve antibiotic utilization and patient outcomes.2,3
- There is a need to increase appropriate use of oral antibiotics to reduce cost and length of hospitalization.2
- The risk of Clostridioides difficile and other serious side effects should be minimized.2,4
The emergence of C. difficile as a major cause of healthcare-associated infection is largely facilitated by excessive antibiotic use. The use of virtually every antibiotic can lead to C. difficile infections (CDI), which can cause life-threatening disease.2,4 Antibiotic risk factors include the number of antibiotics used, duration of antibiotic use and the use of high-risk antibiotics. Elderly patients and patients with irritable bowel disease, immunocompromising conditions, renal disease or previous history of CDI are at increased risk.2,11
For patients with SSTIs, current Infectious Diseases Society of America (IDSA) guidelines recommend antibiotics targeted toward S. aureus and streptococcal species.12 In clinical practice, however, studies have demonstrated frequent use of broad-spectrum antibiotics which may contribute to the emergence and spread of antibiotic resistance.13 IDSA guidelines for the management of CDI recommend antibiotic stewardship measures including targeted antibiotic restrictions to control CDI rates. Antibiotics to be targeted should be based on the local epidemiology and the C. difficile strains present. Restriction of high-risk antibiotics such as fluoroquinolones, clindamycin, and cephalosporins should be considered.4
A meta-analysis of comparative observational studies was performed to determine the association between antibiotic class and the risk of CDI in the community setting. This study found that clindamycin (odds ratio [OR] 16.8), fluoroquinolones (OR 5.5) and cephalosporins (OR 5.7) were associated with the highest risk of CDI, whereas tetracyclines were low risk (OR 0.92).14 These findings are consistent with other published meta-analysis and case studies that examined the risk of CDI associated with antibiotic use.15-17
Variation in Risk of CDI Associated with Different Antimicrobial Classes14
A simple 4-point index (pictured below) summarizing the meta-analysis results was developed in a post hoc exploratory analysis; the index was equal to 1 for tetracyclines; 2 for sulfonamides, macrolides, and penicillins; 3 for cephalosporins, monobactams, carbapenems and fluoroquinolones; and 4 for clindamycin. Each 1-point increase in the index was associated with a 2.4-fold increase in the odds of acquiring C. difficile.14
The spread of MRSA in the last decades has impacted the therapeutic approach for SSTIs which is reflected in the 2014 IDSA SSTI guidelines.12 The IDSA has also published guidelines that specifically focus on the treatment of MRSA infections including SSTIs.18 Additionally, the CDC has issued guidance on the outpatient management of SSTIs in the era of community-acquired (CA)-MRSA.19 The antibiotic treatment recommendations are consistent across the three documents, while the IDSA MRSA guidelines and CDC SSTI recommendations provide additional information about individual antibiotics that may assist clinicians in selecting the optimal treatment based on a variety of patient and disease characteristics.18,19
Adequate knowledge of the adverse effect profile of each antibiotic is important for guiding, monitoring, and managing adverse events to reduce the risk of toxicities that may negatively impact patient outcomes.2,3,12,20 Treatment may be complicated in patients with proven and serious allergies to beta-lactams and sulfonamides.21-23 Another potential challenge of antibiotic therapy is dose adjustments and drug monitoring. Many patients with SSTI have comorbidities and are older, which may affect drug pharmacokinetics and increases the risk for potential drug-drug interactions.24,25
Related to disease characteristics, the distinction between purulent and non-purulent SSTIs has a major impact on the recommended antibiotic treatment regimens with the IDSA SSTI treatment guidelines making a clear distinction between these two types of SSTI. 12 However, in clinical practice this distinction is not always readily apparent to healthcare providers. Circumstances may prevent the culturing of purulent material when present or cultures may be obtained after an antibiotic was prescribed, leading to confusion about appropriate treatment.26
The IDSA SSTI guidelines also recommend an antibiotic that is effective against both MRSA and streptococci in patients whose cellulitis is associated with penetrating trauma, evidence of MRSA infection elsewhere, nasal colonization with MRSA, injection drug use, or severe infection.12 Therefore, clinicians often seek to prescribe an empiric treatment regimen with reliable activity against both streptococci and MRSA.27
The CDC recognizes the diagnostic uncertainty regarding MRSA and streptococci and provides additional guidance on the clinical management of MRSA in the community, with a focus on SSTIs.19
- Clindamycin is approved by the US Food and Drug Administration (FDA) for the treatment of serious infections due to S. aureus and S. pyogenes and the guidelines recommend clindamycin as potential treatment option for both purulent and non-purulent infections.12,18,28 Although not specifically approved for treatment of MRSA infection, clindamycin has become widely used for treatment of SSTI in the community.18
- In vitro rates of susceptibility to clindamycin are higher among CA-MRSA than they are among hospital-associated MRSA, although there is variation by geographic region and recent surveillance data show resistance rates are over 25%.10,18 Some S. aureus isolates have inducible clindamycin and special testing is required. The D-zone test is recommended for detection of inducible clindamycin resistance and is now readily available. If empiric clindamycin therapy has been initiated and inducible clindamycin resistance is detected, response to therapy should be closely assessed.18
- Clostridium difficile–associated disease may occur more frequently, compared with other oral agents.18,19
- Doxycycline is FDA-approved for the treatment of SSTI due to S. aureus, although not specifically for those caused by MRSA. Although tetracyclines have in vitro activity, data on the use of tetracyclines for the treatment of MRSA SSTIs is limited to relatively small case series.18
- Tetracycline resistance in CA-MRSA isolates is primarily associated with the TetK efflux pump which confers resistance to tetracycline and inducible resistance todoxycycline.18 Doxycycline is not recommended for the treatment of non-purulent SSTIs as clinical activity against group A streptococcus is unknown and resistance rates in S. pyogenes approach 20%.10,12,19
- Tetracyclines should not be used during second and third trimester of pregnancy and in children up to the age of 8 years.18,19
- TMP-SMX is not FDA-approved for the treatment of S. aureus infections. However, because 95%–100% of CA-MRSA strains are susceptible in vitro, it has become an important option for the outpatient treatment of purulent SSTIs.12,18 TMP/SMX has demonstrated efficacy in randomized controlled trials in the treatment of uncomplicated SSTIs where MRSA is a major pathogen.18,29
- Similar to doxycycline, TMP/SMX may not provide reliable coverage against
S. pyogenes and clinical experience in the treatment of non-purulent SSTIs such as cellulitis is limited.18,19
- Caution is advised when using TMP-SMX to treat elderly patients, particularly those receiving concurrent inhibitors of the renin-angiotensin system and those with chronic renal insufficiency, because of an increased risk of hyperkalemia. TMP-SMX is not recommended in pregnant women in the third trimester, or in infants younger than 2 months of age.18
- Linezolid is FDA-approved for adults and children for the treatment of SSTI due to
S. aureus including MRSA, S. pyogenes, and S. agalactiae.18
- Linezolid resistance is rare, although an outbreak of linezolid-resistant MRSA infection has been described.18
- Linezolid has been associated with myelosuppression, neuropathy and lactic acidosis during prolonged therapy. Linezolid is a weak, nonselective, reversible inhibitor of monoamine oxidase and has been associated with serotonin syndrome in patients taking concurrent selective serotonin receptor inhibitors.18,19
Due to the limitations of the antibiotics listed above, clinicians may choose to prescribe combination therapy to cover both S. aureus and S. pyogenes. Combinations such as cephalexin plus TMP/SMX requires frequent dosing throughout the day.30,31 While combination therapy may expand the pathogens covered, patient adherence may suffer because of the high pill burden associated with frequent dosing. Poor adherence to antibiotic therapy may lead to suboptimal clinical outcomes in patients with SSTIs.32
The IDSA Guideline on the Implementation of an Antimicrobial Stewardship Programs recommends implementation of programs to increase both appropriate use of oral antibiotics for initial therapy and the timely transition of patients from intravenous (IV) to oral antibiotics. The findings of many studies have shown that programs aimed to increase the use of oral antibiotics are associated with reduced drug costs and length of hospital stay without compromising efficacy or safety.2
The vast majority of SSTI patients have mild to moderate severity disease and rarely suffer serious complications. The most common reason for hospital admission is administration of IV antibiotics.33 Considering treatment options for outpatient parenteral administration and/or IV to oral transitions, a substantial proportion of emergency department (ED) patients hospitalized for SSTI could instead be safely and effectively managed as outpatients.
Given the complexity of SSTIs, inappropriate management resulting from misdiagnosis, under/overestimation of severity, failure to recognize risk factors, or use of inappropriate antibiotics, is not uncommon. The consequences of inadequate therapy include treatment failure and infection recurrence, both of which have implications for patient quality of life.6
Recognizing patient and disease risk factors is key to avoiding treatment failure. Among patients treated in EDs in the US, initial treatment failure is associated with a variety of patient-level factors, including drug/ alcohol abuse, obesity, inadequate drainage of infection, and age ≥65 years.6 Longer duration of infection before seeking treatment, larger lesion size, and inappropriate antibiotic selection also increase the probability of treatment failure.6,9 Among outpatients, lack of compliance with antibiotic treatment or underestimation of baseline infection severity contributes to the failure of initial therapy.6
S. aureus is the most common cause of SSTI in the US and recurrent infections are commonly reported after initial infection. Recurrent infections occur in nearly half of all patients with S. aureus SSTI, and the emergence of multi-drug resistant isolates limits available antimicrobial therapies. Epidemiologic and environmental factors, such as exposure to healthcare, age, household contacts with S. aureus SSTI, and contaminated household fomites are associated with recurrence. Individuals with comorbid conditions that predispose to S. aureus infections, such as diabetes mellitus and chronic renal failure are also at greater risk for recurrence.34
- Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States. Available from: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf (accessed October 24 2020).
- Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-77.
- Centers for Disease Control and Prevention. Core elements of antibiotic stewardship. August 15, 2019. Available from: https://www.cdc.gov/antibiotic- use/core-elements/index.html (accessed October 09 2020).
- McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
- Esposito S, Noviello S, Leone S. Epidemiology and microbiology of skin and soft tissue infections. Curr Opin Infect Dis. 2016;29(2):109-115.
- Pulido-Cejudo A, Guzmán-Gutierrez M, Jalife-Montaño A, et al. Management of acute bacterial skin and skin structure infections with a focus on patients at high risk of treatment failure. Ther Adv Infect Dis. 2017;4(5):143-161.
- Anderson DJ, Kaye KS, Chen LF, et al. Clinical and financial outcomes due to methicillin resistant Staphylococcus aureus surgical site infection: a multi-center matched outcomes study. PLoS One. 2009;4(12):e8305.
- Diekema DJ, Pfaller MA, Shortridge D, et al. Twenty-year trends in antimicrobial susceptibilities among Staphylococcus aureus from the SENTRY antimicrobial surveillance program. Open Forum Infect Dis. 2019;6:S47-S53.
- Ruhe JJ, Smith N, Bradsher RW, et al. Community-onset methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: impact of antimicrobial therapy on outcome. Clin Infect Dis. 2007;44(6):777-784.
- JMI Keystone Surveillance Database. Paratek Pharmaceuticals, Inc. Available from: https://paratek-keystone.com/.
- Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548.
- Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):147-159.
- Jenkins TC, Knepper BC, Moore SJ, et al. Antibiotic prescribing practices in a multicenter cohort of patients hospitalized for acute bacterial skin and skin structure infection. Infect Control Hosp Epidemiol. 2014;35(10):1241-1250.
- Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326-2332.
- Brown KA, Langford B, Schwartz KL, et al. Antibiotic prescribing choices and their comparative C. difficile infection risks: a longitudinal case-cohort study. Clin Infect Dis. 2021;72(5):836-844.
- Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68(9):1951-1961.
- Tariq R, Cho J, Kapoor S, et al. Low Risk of Primary Clostridium difficile Infection With Tetracyclines: A Systematic Review and Metaanalysis. Clin Infect Dis. 2018;66(4):514-522.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285-292.
- CDC. Outpatient management of skin and soft tissue infections in the era of community associated MRSA. September 2007. Available from: https://www.cdc.gov/mrsa/pdf/flowchart-k.pdf. (accessed February 19 2021).
- Morency-Potvin P, Schwartz DN, Weinstein RA. Antimicrobial Stewardship: How the Microbiology Laboratory Can Right the Ship. Clin Microbiol Rev. 2017;30(1):381-407.
- Blumenthal KG, Peter JG, Trubiano JA, et al. Antibiotic allergy. Lancet. 2019;393(10167):183-198.
- Sakoulas G, Geriak M, Nizet V. Is a Reported Penicillin Allergy Sufficient Grounds to Forgo the Multidimensional Antimicrobial Benefits of beta- Lactam Antibiotics? Clin Infect Dis. 2019;68(1):157-164.
- Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498-2505.
- Giarratano A, Green SE, Nicolau DP. Review of antimicrobial use and considerations in the elderly population. Clin Interv Aging. 2018;13:657-667.
- Ramakrishnan K, Salinas RC, Agudelo Higuita NI. Skin and Soft Tissue Infections. Am Fam Physician. 2015;92(6):474-483.
- Daly JM, Ely JW, Levy BT, et al. Primary care clinicians’ perspectives on management of skin and soft tissue infections: an Iowa Research Network study. J Rural Health. 2011;27(3):319-328.
- Pallin DJ, Camargo CA, Jr., Schuur JD. Skin infections and antibiotic stewardship: analysis of emergency department prescribing practices,2007-2010. West J Emerg Med. 2014;15(3):282-289.
- Clindamycin prescribing information. Available from: https://www.drugs.com/pro/clindamycin-capsules.html. (accessed January 06 2021).
- Bowen AC, Carapetis JR, Currie BJ, et al. Sulfamethoxazole-Trimethoprim (Cotrimoxazole) for Skin and Soft Tissue Infections Including Impetigo, Cellulitis, and Abscess. Open Forum Infect Dis. 2017;4(4):ofx232.
- Moran GJ, Krishnadasan A, Mower WR, et al. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. JAMA. 2017;317(20):2088-2096.
- Pallin DJ, Binder WD, Allen MB, et al. Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial. Clin Infect Dis. 2013;56(12):1754-1762.
- Eells SJ, Nguyen M, Jung J, et al. Relationship between Adherence to Oral Antibiotics and Postdischarge Clinical Outcomes among Patients Hospitalized with Staphylococcus aureus Skin Infections. Antimicrob Agents Chemother. 2016;60(5):2941-2948.
- Talan DA, Salhi BA, Moran GJ, et al. Factors associated with decision to hospitalize emergency department patients with skin and soft tissue infection. West J Emerg Med. 2015;16(1):89-97.
- Montgomery CP, David MZ, Daum RS. Host factors that contribute to recurrent staphylococcal skin infection. Curr Opin Infect Dis. 2015;28(3):253-258.