Treatment of Multidrug-resistant Gram-Negative Skin and Soft Tissue Infections

Jean-Francois Jabbour; Sima L. Sharara; Souha S. Kanj

Curr Opin Infect Dis. 2020;33(2):146-154.

Conclusion

MDR-GNB plays an important role in SSTIs in immunocompromised and at-risk patients. These infections are associated with high morbidity and prolonged hospital stay. Recently released drugs have shown potent activity against these MDR pathogens, however, their role in the treatment of SSTIs has not been shown in RCTs. In practice, their use has been based on in-vitro susceptibility data and efficacy data extrapolated from their efficacy in other infection sites. With the complexity of the molecular types of MDR-GNB, especially CRE, rapid diagnostic molecular studies are needed to guide therapy.

Various new agents show promise in the treatment of MDR-GNB SSTIs. Clear guidelines on choices of therapy and proper dosing for the directed therapy against MDR-GNB SSTIs are needed. Beyond antibiotic management, anecdotal reports of other modalities of treatment such a phage therapy, antimicrobial peptides, and antibiotic nanotherapy show promising results in the management of challenging MDR infections.

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Cite this: Treatment of Multidrug-resistant Gram-Negative Skin and Soft Tissue Infections - Medscape - Apr 01, 2020.

Table 1. Description of skin and soft tissue infections, associated Gram-negative pathogens, and patient risk factors
Type of infection	Description	Common Gram-negative microbial pathogens	Population at risk
Echthyma gangrenosum	Cutaneous infection that causes hemorrhagic pustules and evolves into a necrotic ulcer	Pseudomonas spp., Stenotrophomonas maltophilia, Enterobacteriaceae	Immunocompromised, malignancy, critically ill
Cellulitis	Acute infection of the skin and subcutaneous tissue that results in erythema, warmth, swelling and tenderness, with possible bullae or systemic symptoms (leukocytosis, fever)	Pseudomonas aeroginosa, Enterobacteriaceae	Previous antibiotic exposure, prolonged hospitalization
Cellulitis in special situations	Cellulitis, can present with ulceration, myonecrosis or rhabdomyolysis	Aeromonas spp.	Traumatic freshwater injury, cirrhosis, diabetes, immunocompromised
	Mild cellulitis, can progress rapidly with bullae, severe myonecrosis, or nectrotizing fasciitis in high-risk individuals	Vibrio vulnificus	Traumatic injury with saltwater, shellfish, or fish, cirrhosis, hereditary hemochromatosis, diabetes
	Cellulitis with possible cutaneous abscesses	Enterobacteriaceae, Pseudomonas aeroginosa, usually polymicrobial	Intravenous drug use
	Metastatic cellulitis – tender, erythematous, warm subcutaneous infiltrates that can be well demarcated	S. maltophilia	Immunocompromised, catheter and device placement
Necrotizing fasciitis	Rapidly progressive inflammation of the fascia, with secondary necrosis of the subcutaneous tissue characterized by erythema, fever and pain out of proportion to skin manifestations	Polymicrobial (Enterobacteriaceae, Pseudomonas aeroginosa)	More common in abdomen or groin (Fournier's gangrene), diabetes, obseity, or immunodeficiency
Diabetic foot infections	Differentiated from uninfected ulcer, usually warm, erythematous, swollen, increasing exudate or pus, inflammatory changes within ulcer bed, could include pain or systemic signs (fever, leukocytosis)	Polymicrobial (Enterobacteriaceae, Pseudomonas spp.)	Uncontrolled diabetes, peripheral vascular disease, chronic wounds, antibiotic exposure
Infected pressure ulcers	Differentiated from uninfected ulcer, could present with new or worsening pain, clinical signs of fever and inflammation	Polymicrobial (Pseudomonas spp., Enterobacteriaceae commonly Proteus mirabilis, Acinetobacter spp.)	Patients in long-term facilities or prolonged hospital stay
Surgical site infections	Infection of a surgical site with signs of erythema, inflammation, pain, purulent drainage, possible systemic symptoms (fever, leukocytosis)	Enterobacteriaceae, Acinetobacter, Pseudomonas spp.	Operations on the axilla, gastrointestinal tract, perineum, or female genital tract
Burn wound infection	May be difficult to distinguish burn wound infection from noninfectious burn erythema, can be confirmed with tissue biopsy	Pseudomonas spp., S.maltophilia, Acenitobacter spp., Enterobacteriaceae	Severe burn injury, prior antibiotic exposure, Gram-negative colonization
Injury in war	Increasing pain, erythema, or discharge from the wound, can be associated with systemtic symptoms (fever, hemodynamic instability)	Pseudomonas spp., A. baumannii, Enterobacteriaceae	Chronic war traumatic wounds, embedded foreign material

Table 2. Activity of novel antibiotic agents against multidrug-resistant Gram-negative pathogens
Novel antibiotic agent	Activity against MDR organisms
Novel antibiotic agent	CRE KPC	CRE MBL	CRE OXA	CRPA	CRAB	SM
Aztreonam–avibactam	++	++^a	++	–	–	++
Cefiderocol	++	++	++	++	++	++
Ceftaroline fosamil–avibactam	++	–	++	–	–	–
Ceftazidime–avibactam	++	–	++	++	–	–
Ceftolozane–tazobactam	–	–	–	++^b	–	+
Eravacycline	++	++	++	–	++	++
Imipenem/cilastatin–relebactam	++	–	+^c	++	–	–
Meropenem–vaborbactam	++	–	–	–	–	–
Murepavadin	–	–	–	++	–	–
Plazomicin	++	+^d	+^e	+	+	–

–, No activity or intrinsic or acquired resistance; +, good activity; ++, excellent and potent activity. CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacteriaceae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; KPC, Klebsiella pneumoniae carbapenemase producers; MBL, metallo-β-lactamase; MDR, multidrug-resistant; SM, Stenotrophomonas maltophilia.
^aActivity diminished against certain Escherichia coli New Delhi Metallo-β-lactamase (NDM) isolates (attributed to novel insertion in PBP3).
^bDecreased activity for carbapenemase-producing strains of CRPA.
^cMixed studies show that relebactam might weakly potentiate the activity of imipenem against OXA-type CREs.
^dActive against producers of Verona integron-encoded metallo-β-lactamase (VIM) and imipenemase (IMP). Not active against NDM primarily because of coproduction of ribosomal methyltransferase enzymes.
^eActive against OXA-type CREs but increased resistance is observed mainly because of 16rRNA methyltransferases.

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