Resistant Pathogen-associated Skin and Skin-structure Infections: Antibiotic Options

Daniel Curcio


Expert Rev Anti Infect Ther. 2010;8(9):1019-1036. 

In This Article

MDR Pathogens in cSSSI: Epidemiology & Microbiology

Multidrug-resistant bacteria have settled in many hospitals and contribute to increased morbidity, patient length-of-stay and, ultimately, mortality rates.[19,20]

In 2010, the Tigecycline Evaluation and Surveillance Trial (TEST) published worrisome rates of nosocomial bacterial resistance: 13% of all enterococci were VRE, 41% of all staphylococi were MRSA, 18% of all Klebsiella pneumoniae were ESBL-producing, 38% of all Acinetobacter spp. and 15% of all P. aeruginosa were meropenem-resistant and 37% of all Enterobacter cloacae were third-generation cephalosporins resistant (Table 2).[201]

Rice recently reported these as the 'ESKAPE' pathogens in order to emphasize that they currently cause the majority of worldwide hospital infections and effectively 'escape' the effects of antibacterial drugs (Table 2).[21]

In this scenario, the risk of mortality rises markedly if primary empirical therapy fails to cover the pathogens subsequently shown to be present in severe infections.[21–24] Failure often reflects inadequacy against MRSA and multi-resistant Gram-negative bacteria,[23] and the risk of this inadequacy must rise as multi-resistance becomes more prevalent. Even in infections where there is little or no risk of early mortality, inadequate therapy is associated with worse outcomes or delayed resolution, as shown for intra-abdominal infections[25] and even cSSSIs.[26,27]

The microbial causes of cSSSI in hospitalized patients and the weight of the evidence on global data have been recorded over some years in the SENTRY Antimicrobial Surveillance Program database.[27] Globally, S. aureus was the dominant pathogen, ranking highest in North America (44.6%), higher than in Europe (37.5%) and Latin America (33.5%). P. aeruginosa constituted more than 10% of pathogens for all regions, ranking second in North America and Europe but third in Latin America (in 2004, P. aeruginosa ranked third for all regions). E. coli ranked second in Latin America each year, third in Europe each year except for 2004, when it rose to second, and fourth each year for North America. Enterococcus spp. occurred more frequently in North America (9.3%) compared with Latin America (6.8%) and Europe (6.1%). Enterobacteriaceae isolates (Enterobacter spp., Klebsiella spp. and Proteus mirabilis) ranked fifth to eighth in North America, and at positions four to nine in the other regions. Unexpectedly, the β-hemolytic Streptococcus spp. group was only the seventh ranking pathogen in North America and Europe, and tenth in Latin America. Acinetobacter spp., an increasingly important Gram-negative pathogen, ranked highest in occurrence in Latin America (ninth) and tenth in Europe (Table 3).

Among Gram-positive bacteria, resistance has become a clinically relevant concern, especially with S. aureus. The incidence of S. aureus has increased dramatically throughout the world as a cause of nosocomial infections. In the USA, MRSA accounts for up to 21% of all nosocomial cSSSI.[28] In a National Healthcare Safety Network study, 30% of postoperative infections in the USA were caused by S. aureus, and nearly 50% of these were MRSA.[29]

Although initially recognized as an important nosocomial pathogen, MRSA is now endemic in the community outside hospitals.[30] CA-MRSA is endemic in the community, differs from nosocomial MRSA in virulence mechanisms and antibiotic susceptibility, and exhibits diverse and unique pathological characteristics. Although they often present as minor skin and soft-tissue infections, CA-MRSA infections can be severe and invasive. CA-MRSA is often extremely virulent, which may be due to the presence of bacteriophage-associated genes for Panton–Valentine leukocidin (PVL), although this is debated.[31] Risk factors for CA-MRSA acquisition typically involve increased frequency of contact with infected and colonized individuals. Groups at risk include children, military personnel, prison inmates, men who have sex with men and athletes (Table 4). However, more and more patients without identifiable risk factors are being infected with CA-MRSA.[32] CA-MRSA typically carries SCCmec staphylococcal cassette chromosome type IV or V, which are smaller and carry fewer resistance genes than other SCCmec types; for that reason, CA-MRSA is frequently susceptible to agents active against nosocomial MRSA, including vancomycin, linezolid and daptomycin, but is also susceptible to cotrimoxazole and rifampicin (100%), clindamycin (95%), tetracycline (92%), fluoroquinolones (60%) and erythromycin.[31,32]

The spectrum of disease caused by CA-MRSA occurs worldwide and primarily encompasses skin and soft-tissue infections,[33–39] but deep-seated infections such as pyomyositis, osteomyelitis and septic arthritis, and severe infections such as necrotising pneumonia and bacteremia have also been reported.[38] The prevalence and incidence of invasive CA-MRSA infections probably varies geographically. In the USA, for example, 6% of CA-MRSA infections cause invasive disease (pneumonia accounting for 2% overall),[39] and 14% of all invasive MRSA infections are due to CA-MRSA (14% of these invasive infections are CA-MRSA pneumonia).[40]

A worrisome problem to consider is that several authors noted a marked increase in healthcare-associated MRSA infections caused by isolates phenotypically consistent with community-associated CA-MRSA strains.[41,42] Alvarez et al. have recently published that 26 (10.4%) CA-MRSA nosocomial infection-causing strains were detected in 250 MRSA infection isolates in mainly primary bacteremia and surgical site infections in a Colombian hospital.[41] Similarly, Maree et al. have found among 352 patients with nosocomial MRSA isolates, an increase of CA-MRSA phenotype from 17% in 1999 to 56% in 2003 (p < 0.0001).[42] In summary, MRSA strains with molecular characteristics of CA-MRSA strains should be considered as an important cause of serious healthcare-associated infection.

Concerning VRE, Dahms et al. published a matched control study showing that use of third-generation cephalosporins alone (p = 0.05) or concurrently with vancomycin (p = 0.05) was a risk factor for VRE infection in surgical patients.[43] Similarly, Elizaga et al. have demonstrated that the presence of a decubitus ulcer is identified as a risk factor for skin colonization with VRE in 28% of the elderly people admitted to long-term care facilities.[44]

Gram-negative pathogens are often cultured in cSSSIs; P. aeruginosa is the second most frequently isolated pathogen collected from cSSSI, behind only S. aureus.[45] According to the 2003 National Nosocomial Infections Surveillance System (NNIS) study, a 32% increase in P. aeruginosa resistance to quinolones and imipenem occurred in the USA over a period of 4 years.[46] Among other Gram-negative species, ESBL is cause for concern, having been isolated in approximately 7.1% of E. coli and 11.3% of Klebsiella species causing cSSSI.[45] Treatment of serious infection with ESBL-producing isolates is challenging because the organisms are resistant to multiple antibiotics.[11] Clinical failures have been reported in several outcome studies when β-lactams were used to manage serious infections due to pathogens that produce ESBLs.[47,48] These isolates are commonly resistant to extended-spectrum cephalosporins and aztreonam, as well as aminopenicillins, ureidopenicillins and narrow-spectrum cephalosporins.[49] Carbapenems and cephamycins are stable against these enzymes and are currently the only options for treatment.[50] However, possible widespread empirical therapy with carbapenems is of concern, because the frequency of imipenem-resistant P. aeruginosa and Acinetobacter spp. increased significantly when these agents were used to treat outbreaks due to ESBL-producing organisms.[51–53]

Acinetobacter baumannii infections are typically encountered in hospitalized patients, particularly those who are critically ill.[54] Specific characteristics of affected patients include advanced age, presence of serious underlying diseases, immune suppression, major trauma or burn injuries, performance of invasive procedures, as well as presence of indwelling catheters, support with mechanical ventilation, extended hospital stay and previous administration of antibiotics.[54] In this context, A. baumannii is gaining importance as a cause of nosocomial infections (e.g., bacteremia and ventilator-associated pneumonia), but reports of SSSIs are uncommon. A recent report by the National Healthcare Safety Network identified a prevalence of 0.6% of SSSIs due to A. baumannii in US hospitals during the period January 2006–October 2007.[29]

Guerrero et al. have published a case series of severe wound infections due to A. baumannii occurring in military personnel in Iraq and Afghanistan.[55] They found that the four unique features associated with necrotizing SSSI associated with A. baumannii were: it occurs in hosts with underlying comorbidities (e.g., nursing home residents, obese patients, and those with end-stage renal disease, trauma, cirrhosis or HIV); it is often accompanied by bacteremia; multiple drug resistance and the presence of co-pathogens frequently complicated treatment (64% of cases); and the cases reported here and in our article required surgical debridement (84% of cases) and led to substantial mortality (~30%). Similarly, Sebeny et al. have performed a retrospective study of patients with A. baumannii-associated SSSIs associated with war trauma.[56] Their cases presented cellulitis with a 'peau d'orange' appearance with overlying vesicles and, when untreated, progressed to necrotizing infection with bullae (hemorrhagic and nonhemorrhagic) and all the isolates were MDR. Clinical success was achieved in most of the patients with debridement and carbapenem therapy, however, antimicrobial resistance poses great limits for therapeutic options in these patients, especially if the isolates are resistant to the carbapenems.


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