Ryan Stevens, PharmD, BCPS

 encompass a broad spectrum of diseases affecting skin and underlying subcutaneous tissue, fascia, or muscle that can range in severity from mild to life threatening.

Clinical trials using this terminology leave some ambiguity in interpretation because of the use of heterogeneous, broad inclusion criteria attributed to a lack of standardized nomenclature and monitoring parameters.

 To provide consistency in the identification of infections for which a treatment effect can be reliably estimated, in October 2013 the FDA released a guidance document that introduced the term 

acute bacterial skin and skin structure infections

 (ABSSSI) and defined quantifiable efficacy end points.

ABSSSI include cellulitis/erysipelas, wound infections, and major cutaneous abscesses with a lesion surface area of equal to or greater than 75 cm

, measured by the area of edema, induration, or redness.

 Excluded from the definition are some skin and skin structure infections of very mild severity, very high severity, or those appearing from specific causes or in specific hosts. Such conditions include animal or human bites, burn wounds, chronic wound or diabetic food infections, ecthyma gangrenosum, impetigo, minor cutaneous abscesses, myonecrosis, and necrotizing fasciitis.

Suboptimal treatment of ABSSSI, resulting from failure to recognize risk factors, misclassification of severity, misdiagnosis, or using the wrong duration or type of antibiotics, may lead to infection recurrence and/or treatment failure.

This review summarizes the treatment of ABSSSI by focusing on typical pathogens expected, based on severity classification and patient risk factors, and provides associated recommendations for treatment.

Pathogens that should be suspected in various ABSSSI depend on the severity classification and patient risk factors. Abscesses and cellulitis/erysipelas are typically caused by gram-positive bacteria. However, other pathogens can be encountered depending on the location of infection and other risk factors.

 The presence of purulence typically indicates a high probability that 

, as opposed to a streptococcal spp, may be involved. In wound infections, the anatomical location of the wound plays a significant role in determining the microbiologic differential.

 For example, gram-negative organisms are typically seen in wound infections of the lower or perianal abdominal area, whereas methicillin-resistant 

 (MSSA) are more predominant in wound infections following surgery of the extremities, head, neck, or trunk.

The guideline-recommended empiric antibiotic regimens differ for nonpurulent and purulent infections, because of known differences in causative pathogens. For purulent infections, empiric oral antibiotic regimens for mild or moderate disease include oral agents with activity against 

, including MRSA and MSSA, such as doxycycline or trimethoprim-sulfamethoxazole.

 For patients with moderate or severe purulent infections requiring inpatient admission, intravenous (IV) agents include ceftaroline, daptomycin, linezolid, or vancomycin, with vancomycin representing the typical first-line agent.

 As in all infectious syndromes, special care should be given to the appropriate stewardship of antimicrobial agents when making therapy selections.

Empiric antibiotic regimens for nonpurulent cellulitis and erysipelas should primarily target streptococcal spp given the predominance of this organism in the syndrome. For outpatient management of mild or moderate infections, optimal agents include either oral first-generation cephalosporins (ie, cefadroxil or cephalexin) or a penicillin (ie, amoxicillin or penicillin). Clindamycin can be used for patients with known, severe β-lactam allergy.

For inpatient management of mild or moderate infections, the optimal first-line IV option is a first-generation cephalosporin, such as cefazolin, although such other agents as ceftriaxone, nafcillin, or penicillin also provide an appropriate empiric spectrum of activity. Clindamycin or vancomycin can be used in patients unable to tolerate β-lactams.

Patients with nonpurulent disease who have a history of MRSA infections should be considered for empiric treatment with vancomycin or another agent that will cover MRSA.

As previously indicated, treatment of wound infections varies based on the anatomical location of the wound and expected flora at the wound site. In general, oral antimicrobial regimens should include antistreptococcal agents, such as cephalexin, and anti-MRSA agents, such as trimethoprim-sulfamethoxazole. IV vancomycin provides appropriate coverage of gram-positive organisms for patients admitted to the hospital.

 Infected wounds of the abdominal, perianal, or urogenital regions should include empiric coverage for enteric anaerobes and gram-negative pathogens.

 Empiric oral regimens include amoxicillin-clavulanate or cefdinir and metronidazole. A preferred empiric IV regimen for abdominal, perineal, or urogenital wound infection consists of ceftriaxone and metronidazole.

In attempts to reduce the risk for unintended consequences of antimicrobial use, significant focus has been applied to reducing the duration of antibiotic treatment for many infections, including ABSSSI. Studies continue to emerge showing that shorter courses of antibiotics for cellulitis are just as efficacious as longer durations.

 In 1 such study of patients receiving antibiotic therapy for uncomplicated cellulitis, the results showed no significant differences in the clinical outcomes or treatment failure in those who received 5 days of therapy compared with patients receiving 10 days.

 As such, the most recent guidelines for ABSSSI recommend a duration of 5 days of antibiotic therapy. However, for those who demonstrate delayed clinical improvement (ie, delayed resolution of fever, recession of erythema, or vital sign stability), it may be necessary to extend the antimicrobial duration.

ABSSSI are commonly encountered in clinical practice. The broad scope of patient risk factors, severity of illness, and syndromes can be intimidating factors in determining suspected microbiology, empiric antimicrobial selection, and therapy duration. Key elements involved in these facets of care include the absence or presence of purulence, anatomical location, need for inpatient care or IV antimicrobials, and severity of infection. Careful consideration of these key factors will guide clinicians in their care of patients presenting with ABSSSI (see Table

is an inpatient antimicrobial stewardship pharmacist at Ascension Sacred Heart Hospital in Pensacola, Florida.

is an antimicrobial stewardship/outpatient antimicrobial therapy pharmacist at Mayo Clinic in Rochester, Minnesota.

is a PGY-2 emergency medicine pharmacy resident at Mayo Clinic.

1. Pollack CV Jr, Amin A, Ford WT Jr, et al. Acute bacterial skin and skin structure infections (ABSSSI): practice guidelines for management and care transitions in the emergency department and hospital. 

 2015;48(4):508-519. doi:10.1016/j.jemermed.2014.12.001

2. Tiwari AK, Lal R. Study to evaluate the role of severity stratification of skin and soft tissue infections (SSTIs) in formulating treatment strategies and predicting poor prognostic factors. 

 2014;12(2):125-133. doi:10.1016/j.ijsu.2013.11.014

3. Russo A, Concia E, Cristini F, et al. Current and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections. 

2016;22(suppl 2):S27-36.doi:10.1016/S1198-743X(16)30095-7

4. Acute bacterial skin and skin structure infections: developing drugs for treatment. FDA. October 2013. Accessed June 18, 2021. https://www.fda.gov/files/drugs/published/Acute-Bacterial-Skin-and-Skin-Structure-Infections---Developing-Drugs-for-Treatment.pdf

5. 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. 

2017;4(5):143-161. doi:10.1177/2049936117723228

6. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. 

 2014;59(2):e10-e52. doi:10.1093/cid/ciu444

7. Sartelli M, Guirao X, Hardcastle TC, et al. 2018 WSES/SIS-E consensus conference: recommendations for the management of skin and soft-tissue infections. 

2018;13:58. doi:10.1186/s13017-018-0219-9

8. Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. 

2017;18(1):1-76. doi:10.1089/sur.2016.261

9. Spellberg B. The new antibiotic mantra—“shorter is better.” 

. 2016;176(9):1254-1255. doi:10.1001/jamainternmed.2016.3646

10. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin-structure infections: the ESTABLISH-1 randomized trial. 

. 2013;309(6):559-569. doi:10.1001/jama.2013.241

11. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. 

 2014;14(8):696-705. doi:10.1016/S1473-3099(14)70737-6

12. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. 

2004;164(15):1669-1674. doi:10.1001/archinte.164.15.1669

13. Kannangara DW, Pandya D. Infections in injection drug users: the significance of oral bacteria and a comparison with bacteria originating from skin and environmental sources. 

 January 22, 2020. Accessed June 18, 2021. 

https://www.researchgate.net/publication/338836628_Infections_in_Injection_Drug_Users_The_Significance_of_Oral_Bacteria_and_a_Comparison_with_Bacteria_Originating_from_Skin_and_Environmental_Sources

14. Jenkins TC, Knepper BC, Moore SJ, et al. Microbiology and initial antibiotic therapy for injection drug users and non-injection drug users with cutaneous abscesses in the era of community-associated methicillin-resistant Staphylococcus aureus. 

2015;22(8):993-997. doi:10.1111/acem.12727

Articles

Consider key elements of acute bacterial skin and skin structure infection to help patients manage this broad range of diseases.

Scratch Beneath the Surface: ABSSSI

Patient-reported allergy to penicillin antibiotics is a common scenario during health care encounters, with an estimated population prevalence of roughly 8% to 12%.

 Primary reactions to penicillin antibiotics include rash, itching, nausea and vomiting, shortness of breath, and anaphylaxis.

Despite the high population prevalence, 80% to 90% of those reporting a penicillin allergy will have a negative response to penicillin skin testing.

 Thus, with a true rate of penicillin allergy likely much lower than that reported by patients, health care professionals are often placed in a predicament regarding the selection of empiric antimicrobial therapy to treat a wide array of infectious conditions.

Often, when patients are labeled as having a penicillin allergy, providers are forced to approach the scenario conservatively and simply avoid using beta-lactams.

 This strategy will frequently lead to suboptimal regimens, including therapies that may be inferior to beta-lactam—based regimens or those that may have unnecessarily broad or inappropriately narrow spectrums of activity.

It is important to ascertain a patient’s reported reaction and reaction timing with regard to administration to help indicate whether the allergy represents an immunoglobin (IgE)-mediated reaction, a delayed-onset reaction, an adverse effect, or simply an intolerance.

 If a patient’s penicillin allergy is determined by reaction severity or allergy testing to represent a true allergy, then the clinician is faced with the challenge of determining and interpreting the rate of allergic cross-reactivity from the penicillin class to the other beta-lactam classes (ie, cephalosporins, carbapenems, and mono-bactams). Understanding the possible cross-reactivity will help a provider assess the risk to the patient and ultimately decide whether a nonpenicillin beta-lactam should be used.

For cephalosporins, the rate of cross-reactivity with penicillins is lower than previously believed. A common myth is that about 10% of patients with a penicillin allergy history will experience an allergic reaction if administered a cephalosporin. This rate derived from early cross-reactivity studies seems to have been caused, at least partially, by contamination of early preparations of cephalosporins with trace amounts of penicillin G.

 However, more recent observational studies have found cross-reactivity rates of between 0.17% and 0.7%.

 In 1 prospective study, the rate of cross-reactivity among subjects with a positive penicillin skin test was 6%.

It appears that cross-reactivity between penicillins and cephalosporins is more likely associated with structurally similar side chains rather than the beta-lactam ring itself.

 For instance, amoxicillin has a side chain identical to that of first-generation cephalosporins cefadroxil and cefprozil, whereas ampicillin has a side chain identical to that of first-generation cephalosporins cephalexin and cephradine, as well as to that of cefaclor, a second-generation cephalosporin. This is in direct contrast to later-generation cephalosporins, where there is little to no side chain similarity to those side chains seen in the penicillin class.

 Risk of cross-reactivity may still remain a concern even with dissimilar side chains; therefore, it is prudent to avoid other beta-lactams in patients with a history of IgE-mediated or severe non—IgE-mediated reactions to penicillins, especially in the absence of skin testing or documentation of successful receipt of other beta-lactams.

Aztreonam is less immunogenic and is associated with fewer allergic reactions compared with other beta-lactams. It can be used safely in patients allergic to other beta-lactams due to dissimilarities in the chemical structure. In vitro data, skin tests, and patient challenge studies found no risk of cross-reactivity to other beta-lactam allergies.

 The exception to this rule appears to be ceftazidime, which has an identical side chain to that of aztreonam; therefore, the risk of cross-reactivity between these 2 agents exists and should be avoided.

With regard to the carbapenems, the overall rate of hypersensitivity reactions encountered in the general population is thought to be less than 3%.

 Carbapenems and penicillins do not share common side chains; therefore, the primary structural similarity that may confer allergic cross-sensitivity to those with a true penicillin allergy is the molecule’s bicyclic core.

 The first study that attempted to evaluate the possible cross-reactivity rate from penicillin allergy to carbapenems evaluated the possible cross-reactivity to imipenem.

 This prospective study enrolled 59 total participants and used skin testing only without subsequent systemic administration challenge. The researchers found a cross-reactivity rate to imipenem of 25.6% for those with reported penicillin allergy and 47.4% for those with confirmed penicillin allergy.

 This potential rate of cross-reactivity was alarming; however, this study had a small sample size and used a nonstandard imipenem skin test. These 2 factors led many to evaluate the study’s for clinical application cautiously.

Since this initial study, further studies with varied designs, methodologies, and patient populations have implicated a cross-reactivity rate of somewhere between 0.9% and 11%.

 When further examined, prospective studies that used appropriate penicillin and carbapenem skin testing, and in which patients negative for reaction to carbapenem skin testing received a systemic dose of carbapenem, are likely best positioned to help guide the use of carbapenems in this scenario. In these studies, the rate of true cross-reactivity from a positive penicillin skin test to a positive carbapenem skin test was roughly 1% and patients with negative carbapenem skin testing tolerated system- ic doses of carbapenems without reaction.

 From this data, the rate of true cross-reactivity to carbapenems in patients who are allergic to penicillin appears to be very low.

The following approach can be considered to address beta- lactam antibiotic cross-reactivity concern in the treatment of acute infectious processes. For patients with history of suspected or proven IgE-mediated reaction to penicillin, clinicians should consider an alternative antibiotic or perform desensitization if no reasonable alternatives are available. For patients with a history of non—IgE-mediated reaction, the feasibility of beta-lactam allergy challenge should be determined based on reaction severity and the agent’s side chain similarity. For patients with a history of severe non–IgE-mediated reaction, such as Stevens-Johnson syndrome or hemolytic anemia, use of an alternative antibiotic class should be advised. For patients with a history of nonsevere, non–IgE-mediated reactions to penicillins, cephalosporins and carabapenems need not be avoided; however, consideration should be given to using agents with dissimilar side chains as appropriate.

In conclusion, true rates of cross-reactivity from penicillins to cephalosporins and carabapenems appear to be low. Thus, in clinical settings that lack access to allergy skin testing, thorough consideration of the risk versus benefit of cephalosporin or carbapenem exposure should be considered prior to administration in patients who report a penicillin allergy. Except in the circumstance of IgE-mediated or severe non—IgE-mediated allergy, other beta-lactams should not be avoided and the risk of cross-reactivity may be further reduced by using agents with dissimilar side chains. Aztreonam lacks cross-reactivity to other beta-lactam antibiotics and may be safely given to patient claiming allergy to beta-lactam antibiotics, with the exception of patients allergic to ceftazidime.

RYAN STEVENS graduated with his PharmD from the University of Montana in 2010. He subsequently completed a PGY1 pharmacy practice residency at Alaska Native Medical Center in Anchorage, AK. Following residency, Dr Stevens was employed by Providence Alaska Medical Center as a clinical pharmacist in Adult Critical Care, and he is currently employed there as the Infectious Diseases Clinical Pharmacy Specialist. He is active within his specialty through participation in antimicrobial stewardship activities within the Providence Health and Services system, the Alaska Antimicrobial Stewardship Collaborative, and the Society of Infectious Diseases Pharmacists. 

KHALID ELJAALY, PHARMD, CAPPS, BCPS, MS, is a postdoctoral pharmacy fellow in infectious diseases/antibiotic stewardship in the University of Arizona, Tucson, and a faculty member in the clinical pharmacy department, King Abdulaziz University, Jeddah, Saudi Arabia. He completed his PGY2 pharmacy residency at Beth Israel Deaconess Medical Center in Boston, a hospital affiliated with Harvard Medical School. He is a member of the social media committees of both the Society of Infectious Diseases Pharmacists and the Infectious Diseases Practice and Research Network of the American College of Clinical Pharmacy. His Twitter account is called “Antibiotic Tweets” and his handle is @khalideljaaly. 

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Patient-reported allergy to penicillin antibiotics is a common scenario during health care encounters, with an estimated population prevalence of roughly 8% to 12%. 
