Complicated SSTIs: Identifying Infections Promptly Saves Lives

Skin and soft tissue infections vary from the easily treatable to complicated, even dangerous, cases.

Bacteria are always looking for new places to call home. Little breaches in human local defense—as small as skin cuts and hair follicle trauma— allow bacteria to overrun and create pus and inflammation in surrounding tissues, referred to as skin and soft tissue infections (SSTIs).

SSTIs include impetigo, folliculitis, furunculosis, carbunculosis, and trauma-related wound infections. With functioning immune defenses, most patients will combat the infection and establish protective immunity against the strain. In uncomplicated cases that fail to resolve, oral or topical antibiotics can clear up the problem quickly.^1,2

Sometimes, even with a small skin breach, the offending bacteria will penetrate the epidermis, dermis, and subcutaneous tissues. Bacteria can enter circulating lymph and blood and form abscesses elsewhere. Antibiotic treatment is then necessary to stop the pain and inflammation, and to prevent the spread of infection.^1,2 Among treated patients whose infections resolve, approximately 20% will experience infection flares later, indicating they did not acquire protective immunity.³

If the primary or secondary infection becomes deep-seated and tenacious, it is classified as a complicated skin and soft tissue infection (cSSTI), which includes cellulitis, necrotizing fasciitis, myonecrosis, and toxic shock syndrome. Although it may help to be able to define these more precisely, no universal grading system exists. Clinicians are challenged and patients are frustrated by cSSTIs because they are usually timeconsuming and costly to treat.

Note that necrotizing infections may involve the deep fascia and muscle, tissues below the actual skin structure.⁴ Predisposing factors include mechanical damage to the skin, dry/irritated skin, immunocompromise, chronic venous or lymphatic insufficiency, and chronic neuropathy.^1,2

A Growing Threat

In 2001, emergency departments reported approximately 1.5 million visits for cSSTIs; by 2005, they reported 3.5 million. The epidemiology and frequency of cSSTIs, which are heavily influenced by the increase in infections caused by community-associated methicillin- resistant Staphylococcus aureus (MRSA), have changed in the last decade. S aureus accounts for approximately 40% of all cSSTIs. It mutates at such a rapid rate that its epidemiology in terms of causative strains and antibiotic susceptibility cannot be predicted reliably. Psuedomonas aeruginosa is the second-most common cause of cSSTIs (11%), with the remainder divided among countless other pathogens.^4-6

Of most concern to microbiologists and public health officials is antibiotic resistance; nearly half of S aureus infections are antibiotoic resistant.^5,6 Methicillin is no longer used in the United States, but in its day, it was effective against penicillin-resistant strains of staph and other microbes that produce penicillinase; penicillinase cannot cleave methicillin. Due primarily to indiscriminate antibiotic use, hospitalor community-acquired MRSA bacterial isolates that excrete a penicillin-binding protein are now commonplace, present in more than 30% of infections.^3,7-9 Emergency departments report that of community-acquired infections, a full 59% involve MRSA.¹⁰ And, communityacquired MRSA in an SSTI often leads to antibiotic-resistant pneumonia.¹¹

Necrotizing cSSTIs, an infection that infectious disease specialists classify separate from other cSSTIs, have increased remarkably since 2005. This special class of SSTIs is defined by their aggressive nature, the numerous pathogens involved, and the high likelihood of limb loss or death (~24%). They require prompt diagnosis, immediate and appropriate antibiotic therapy, and skilled surgical debridement.

Necrotizing infections are usually caused by mixed pathogens—4, on average—typically beginning in an existing indolent site. The infection may start in a perirectal infection, colonic lesion, intravenous drug injection site, trauma, chronic diabetic ulceration, and/ or other skin infection. They tend to be gas-producing and spread along fascia (fibrous connective tissue separating or binding muscles and organs) and fascial planes where the blood supply is less robust.^4,12 Less frequently, a single, more virulent pathogen produces exotoxins that cause rapidly progressive necrosis. In both types of necrotizing infection, patients report pain out of proportion to the observed lesions.¹³

The several signs and clinical findings specific to a necrotizing infection occur late in the disease’s course, so clinicians need to maintain a high index of suspicion. In patients who have a serious underlying disease, previous hospital admissions, animal contact and bite history, injection drug use (especially methamphetamine, which is closely associated with MRSA), or recent travel, cSSTI may differ from that typically seen in the community.^4,14

Treat Quickly, Think Locally

Treatment must include empiric antibiotics while culture results are in process and surgical drainage. Bacterial resistance has complicated the choice of empiric therapy, and prescribers need to be aware of local epidemiology and pathogen susceptibility. If a cSSTI develops in the rectum, genital tract, diabetic foot, or burned tissues, poly-infection with Gram-positive and Gram-negative organisms and anaerobes is more likely.⁴ In any situation where systemic involvement appears probable, any and all necessary tests to determine the extent of involvement are appropriate.

Various guidelines are available for cSSTI treatment. Because few studies have been conducted, the strength of recommendations is rarely grade A (strong recommendation based on highquality evidence). All treatment should be directed at the most likely pathogen, or the pathogen(s) confirmed by culture and sensitivity when possible.

Tissue specimens obtained by biopsy are preferred, because superficial skin swabs or drainage may be contaminated with normal skin flora.^14,15 Incision, drainage, and debridement until healthy skin is seen are almost always used to clean the infected site. The severity and size of the infected site dictates whether oral or parenteral antibiotics are used. Limb- or life-threatening infection, systemic illness, immunosuppression, or very young/very old age are indications for parenteral therapy.^12,15,16

The Future

A major concern is the continuing invasion of multi-drug—resistant pathogens and the lean pharmaceutical development pipeline in this area. Other therapeutic areas are more lucrative for pharmaceutical manufacturers, providing little incentive for antimicrobial innovation. Fortunately, manufacturers use cSSTIs as a testing ground for many antibiotics designed to combat Grampositive pathogens. Several new agents are being tested.¹⁷

Conclusion

Skin infections have many clinical presentations and vary in severity. By necessity, this review is brief and cannot cover all possible complications or considerations. Pharmacists need to remember that there are some limitations when treating cSSTIs, including the lack of a good classification system and few randomized controlled trials to support various treatments. They must also remember that delayed, ineffective, or incomplete treatment can result in serious morbidity.

FDA Definition

Complicating Factors

• Deep or necrotizing, usually requiring surgical intervention, including infected ulcers, infected burns, and major abscesses

• Occur in patients with specific major co-morbidities

• Necessitate hospitalization

• Excludes superficial skin infections lacking necrosis or abscesses treated by incision and drainage alone

• Invasive, life-threatening infections, such as sepsis, abscesses, pneumonia, osteomyelitis, meningitis, and endocarditis

• Hypotension, tachycardia, hypothermia or fever, and altered mental status

• Presence of complicating co-morbidities (peripheral arterial disease, chronic kidney disease, diabetes mellitus)

• Neutropenia

• Ischemia, tissue necrosis, or burns

• Animal bite and water associated infections

CSSTis = complicated skin and soft tissue infections. Adapted from references 2 and 4.

General Type of cSSTI

Treatment Mainstays

Single organism, no necrotizing factor

• Oral or parenteral penicillins, cephalosporins, clindamycin and co-trimoxazole

Polymicrobial infection or simple (nonnecrotizing) treatment failures

• Beta-lactam/beta-lactamase inhibitor combinations

Methicillin-resistant Staphylococcus aureus

• Glycopeptides, linezolid, daptomycin, and tigecycline

Polymicrobial infections needing enhanced anti—Gram-positive activity

• Linezolid, daptomycin, tigecycline, moxifloxacin

CSSTis = complicated skin and soft tissue infections.

Adapted from references 4, 15, and 16.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.

References

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3. Kennedy AD, Otto M, Braughton KR, et al. Epidemic community-associated methicillin-resistant Staphylococcus aureus: recent clonal expansion and diversification. Proc Natl Acad Sci USA. 2008;105:1327-1332.

4. Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother. 2010;65 (suppl 3):iii35-iii44.

5. Pallin DJ, Egan DJ, Pelletier AJ, et al. Increased U.S. emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Ann Emerg Med. 2008;51:291-298.

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11. Shilo N, Quach C. Pulmonary infections and community associated methicillin resistant Staphylococcus aureus: a dangerous mix? Paediatr Respir Rev. 2011;12:182-189.

12. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections: risk factors for mortality and strategies for management. Ann Surg. 1996;224:672-683.

13. Smeets L, Bous A, Heymans O. Necrotizing fasciitis: case report and review of literature. Acta Chir Belg. 2007;107:29-36.

14. Cohen AL, Shuler C, McAllister S, et al. Methamphetamine use and methicillin-resistant Staphylococcus aureus skin infections. Emerg Infect Dis. 2007;13:1707-1713.

15. May AK. Skin and soft tissue infections: the new surgical infection society guidelines. Surg Infect (Larchmt). 2011;12:179-184.

16. May AK, Stafford RE, Bulger EM, et al; Surgical Infection Society. Treatment of complicated skin and soft tissue infections. Surg Infect (Larchmt). 2009;10:467-499.

17. Theuretzbacher U. Future antibiotics scenarios: is the tide starting to turn? Int J Antimicrob Agents. 2009;34:15-20.