Updated Antibiotic Guidance for Skin and Soft Tissue Infections and Diabetes-Related Foot Infections

This post was researched and written by Dr. Jonathan Ryder, Assistant Professor and previous UNMC ID Fellow. Dr. Ryder is also Associate Medical Director of the Nebraska Medicine Antimicrobial Stewardship Program and Associate Hospital Epidemiologist. Here, Dr. Ryder shares key changes the Antimicrobial Stewardship Program has recently made in guidance on the treatment of SSTIs.

The Nebraska Medicine Antimicrobial Stewardship Program has published updated local guidance on the management of patients with skin and soft tissue infections (SSTI) and diabetes-related foot infections (DFI). This includes conditions such as non-purulent cellulitis, abscesses, necrotizing skin soft tissue infections, and bite wounds. These changes are due to new 2023 IDSA guidelines on the management of diabetes-related foot infections as well as updates in the microbiology for these infections since the 2014 IDSA guidelines for SSTI.

In this post, we highlight the key changes we have made to our guidance and the rationale behind these changes.

So Long to Clindamycin

Two of the most common pathogens for SSTI and DFI are beta-hemolytic Streptococci (including group A Streptococci [GAS] and group B Streptococci [GBS]) and Staphylococcus aureus. Unfortunately, resistance to clindamycin is rising significantly in these pathogens. Per surveillance data from the Centers for Disease Control, resistance to clindamycin was found in 34.4% of invasive GAS and 51.4% of invasive GBS.¹ For Staphylococcus aureus, our 2024 antibiogram shows over 25% resistance to clindamycin.² Given these high rates of resistance to clindamycin, clindamycin is no longer recommended for empiric treatment of SSTIs or DFI. 

However, there are other reasons why clindamycin has fallen out of favor. Clindamycin is associated with high rates of adverse effects, in particular gastrointestinal side effects in over 20%.³ Specifically, antibiotic-associated diarrhea is found in over 13% of patients.³ Clindamycin is also associated with the highest risk of Clostridioides difficile infection (CDI) compared to other antibiotics, with one study demonstrating 25 times higher odds of CDI when receiving clindamycin.^4,5 Clindamycin is also dosed 3-4 times per day, which can make adherence challenging for patients. In a systematic review assessing adherence to therapy, 3-times-daily dosing was associated with only 65% adherence, while 4-times-daily was 51%.⁶ Thus, clindamycin is also a poor choice for SSTI and DFI given its high rate of adverse events and poor adherence to therapy. 

But What about Patients with Penicillin Allergies?

Clindamycin has frequently been used as an alternative choice in patients with penicillin allergies; however, a better understanding of antibiotic allergies provides more alternatives. New guidelines for management of antibiotic allergies were released in 2022.⁷ In collaboration with our allergy experts, local guidance for management of penicillin allergy and other beta-lactam allergy were developed. Within the new SSTI and DFI guidance, penicillin allergy guidance is provided for each scenario. Reference to these documents is helpful for finding alternative regimens. Generally speaking, even in the presence of a severe IgE-mediated penicillin allergy (e.g., anaphylaxis), first-line regimens for cellulitis, such as intravenous cefazolin, can still be used.

Alternative Options Exist with Increased Accessibility

Other options for patients with beta-lactam allergy include trimethoprim-sulfamethoxazole (TMP-SMX) and linezolid. Historically, TMP-SMX has been avoided in non-purulent SSTI due to concerns about high rates of resistance to TMP-SMX in GAS. However, this concern about resistance has been found to be a myth .⁸ Older studies found high rates of resistance to TMP-SMX in vitro as a result of methodologic problems. After these problems were corrected, TMP-SMX susceptibility rates were very high for GAS. In clinical studies, TMP-SMX has performed well in the treatment of SSTI.⁹ TMP-SMX has been a preferred alternative when allergy precludes first-line regimens.

Linezolid has excellent Staphylococcal and Streptococcal activity, but concerns have existed regarding cost and serotonin syndrome. Fortunately, the price of linezolid has decreased substantially, although there can be variation between outpatient pharmacies on price (ensuring patients can access the drug at a lower price is key for prescribing linezolid outpatient).¹⁰ Regarding serotonin syndrome, the risk for this adverse event in patients receiving linezolid is exceedingly low, even in patients on selective serotonin reuptake inhibitors.⁸ In patients with serious infections, a careful weighing of risks/benefits is warranted. Regardless, linezolid remains a much safer and more effective option compared to clindamycin, especially as an alternative agent in patients with severe penicillin allergies.

Changes in Management of Necrotizing Soft Tissue Infection

Another common indication for clindamycin has been adjunctive antitoxin therapy for necrotizing soft tissue infections due to GAS or Clostridium species. However, there has been debate about whether clindamycin should be replaced by linezolid, which has similar in vitro antitoxin activity.¹¹ The crux of this debate involves the increasing GAS resistance to clindamycin, a lower risk of CDI with linezolid, and replacing empiric vancomycin (and its associated risk of acute kidney injury) with linezolid. Since publishing this debate, two small retrospective studies have demonstrated linezolid and clindamycin have similar efficacy, but replacing clindamycin (and vancomycin) with linezolid reduced a composite risk of death, CDI, and acute kidney injury in one of these studies.^12,13 Another study found a lower risk of acute kidney injury with this switch as well.¹⁴

Shorter is Better

The new guidance documents include updated antibiotic durations. For non-purulent cellulitis, antibiotic durations of 5-6 days are now the standard.¹⁵ For necrotizing soft tissue infections without concurrent bacteremia or cellulitis, antibiotic therapy can likely be stopped within 48 hours of the final debridement.¹⁶ Several changes in duration for DFI have also been incorporated from the 2023 IDSA guidance.

Conclusion

The management of patients with SSTI and DFI is changing due to increasing resistance, myth busting, and improved understanding of antibiotic allergies. Our updated guidance accounts for these changes by moving away from clindamycin, recommending more linezolid and TMP-SMX use, and shortening antibiotic durations.

References

1. US Centers for Disease Control and Prevention. ABCs Bact Facts Interactive Data Dashboard. Accessed May 3, 2024, 2024. https://www.cdc.gov/abcs/bact-facts-interactive-dashboard.html
2. Nebraska Medicine Antimicrobial Stewardship Program. Antibiograms. Accessed May 3, 2024, 2024. https://www.unmc.edu/intmed/divisions/id/asp/antibiograms.html
3. Neu HC, Prince A, Neu CO, Garvey GJ. Incidence of diarrhea and colitis associated with clindamycin therapy. J Infect Dis. Mar 1977;135 Suppl:S120-5. doi:10.1093/infdis/135.supplement.s120
4. Miller AC, Arakkal AT, Sewell DK, Segre AM, Tholany J, Polgreen PM. Comparison of Different Antibiotics and the Risk for Community-Associated Clostridioides difficile Infection: A Case-Control Study. Open Forum Infect Dis. Aug 2023;10(8):ofad413. doi:10.1093/ofid/ofad413
5. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. May 2013;57(5):2326-32. doi:10.1128/aac.02176-12
6. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. Aug 2001;23(8):1296-310. doi:10.1016/s0149-2918(01)80109-0
7. Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. Dec 2022;150(6):1333-1393. doi:10.1016/j.jaci.2022.08.028
8. McCreary EK, Johnson MD, Jones TM, et al. Antibiotic Myths for the Infectious Diseases Clinician. Clin Infect Dis. Oct 13 2023;77(8):1120-1125. doi:10.1093/cid/ciad357
9. Bowen AC, Carapetis JR, Currie BJ, Fowler V, Jr., Chambers HF, Tong SYC. Sulfamethoxazole-Trimethoprim (Cotrimoxazole) for Skin and Soft Tissue Infections Including Impetigo, Cellulitis, and Abscess. Open Forum Infect Dis. Fall 2017;4(4):ofx232. doi:10.1093/ofid/ofx232
10. Cheap Generic Drugs. NEJM Journal Watch. Accessed May 3, 2024, 2024. https://blogs.jwatch.org/hiv-id-observations/index.php/hey-insurance-companies-and-pharmacies-stop-messing-around-with-cheap-generic-drugs/2024/04/26/
11. Cortés-Penfield N, Ryder JH. Should Linezolid Replace Clindamycin as the Adjunctive Antimicrobial of Choice in Group A Streptococcal Necrotizing Soft Tissue Infection and Toxic Shock Syndrome? A Focused Debate. Clin Infect Dis. Sep 3 2022;doi:10.1093/cid/ciac720
12. Heil EL, Kaur H, Atalla A, et al. Comparison of Adjuvant Clindamycin vs Linezolid for Severe Invasive Group A Streptococcus Skin and Soft Tissue Infections. Open Forum Infect Dis. Dec 2023;10(12):ofad588. doi:10.1093/ofid/ofad588
13. Dorazio J, Chiappelli AL, Shields RK, et al. Clindamycin Plus Vancomycin Versus Linezolid for Treatment of Necrotizing Soft Tissue Infection. Open Forum Infect Dis. Jun 2023;10(6):ofad258. doi:10.1093/ofid/ofad258
14. Lehman A, Santevecchi BA, Maguigan KL, et al. Impact of Empiric Linezolid for Necrotizing Soft Tissue Infections on Duration of Methicillin-Resistant Staphylococcus aureus-Active Therapy. Surg Infect (Larchmt). Apr 2022;23(3):313-317. doi:10.1089/sur.2021.329
15. Lee RA, Centor RM, Humphrey LL, et al. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. Jun 2021;174(6):822-827. doi:10.7326/m20-7355
16. Lyons NB, Cohen BL, O’Neil CF, Jr., et al. Short Versus Long Antibiotic Duration for Necrotizing Soft Tissue Infection: A Systematic Review and Meta-Analysis. Surg Infect (Larchmt). Jun 2023;24(5):425-432. doi:10.1089/sur.2023.037