Critical Care Medicine

Infections following organ transplantation (Including Solid Organ and Hematopoietic Stem cell): Cutaneous, mucocutaneous, and soft tissue infections

Cellulitis, soft tissue infection, skin lesions, necrotizing fasciitis, pyomyositis, myonecrosis, rash, catheter exit-site infection

Synonyms

Skin and soft tissue infections in the immunocompromised host; deep soft tissue infections in the immunocompromised host

Related conditions

Impetigo, bullous impetigo, erysipelas, lymphangitis, venous stasis, lymphedema, septic thrombophlebitis, Group A streptococcal infection, staphylococcal infection, MRSA, tunnel infection, meningococcemia, disseminated gonococcal infection, Pseudomonas, Aeromonas, Rocky Mountain spotted fever, venous stasis ulcers, Clostridium, gas gangrene, progressive synergistic gangrene, Fournier's gangrene, fasciitis, ecthyma gangrenosum, purpura, purpura fulminans, graft-vs-host disease of the skin, drug rash, Sweet’s syndrome, DRESS syndrome, hives, angioedema, ulceration, abscess, decubitus ulcer, pressure ulcer, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, vasculitis, embolic lesions, cutaneous eruption, Janeway lesions, Osler's nodes, macular rash, petechiae, papular rash, maculopapular rash, vesicular rash, subcutaneous nodules, erythema nodosum, zoster, herpes zoster, shingles, herpes simplex, Fusarium, cryptococcosis, blastomycosis, histoplasmosis, sporotrichosis, nodular lymphangitis, Mycobacterium marinum, toxic shock syndrome, Vibrio vulnificus, filariasis, anthrax, tularemia.

1. Description of the problem

What every clinician needs to know

The skin and soft tissue may provide important clues to either a localized or systemic infection in an immunocompromised patient. The skin and soft tissue may be the primary focus of the infection; may be a sign of a systemic or disseminated infection; or may be a manifestation of an infection with another primary localization. Recognition of types of skin lesions can help guide empiric therapy, and a skin biopsy with appropriate cultures may be diagnostic even where other cultures are negative. Recognition of rapidly progressive soft tissue infections such as clostridial myonecrosis and invasive Group A streptococcal infection is crucial in facilitating emergent life-saving surgical procedures.

Clinical features

Skin rashes related to infection may be macular, papular, maculopapular, petechial, purpuric, vesicular, nodular, ulcerating or some combination of these. The involved area may be localized, multifocal, or diffuse (covering the entire body). Cellulitis is a localized infection of the soft tissues characterized by erythema, warmth and swelling, often though not always involving the lower extremity. Regional lymphadenopathy and lymphangitic streaking may or may not be present. Erysipelas is a more well-demarcated erythematous process frequently involving the face.

Cellulitis is most commonly caused by Group A beta-hemolytic streptococci or Staphylococcus aureus (including MRSA), but may be caused by a wide variety of organisms including Gram-negative bacilli (especially in neutropenic or diabetic patients) or fungi (particularly Cryptococcus). Systemic symptoms (fevers, chills, drenching sweats) may or may not be present depending on the underlying cause.

Trauma under water (e.g. in a lake) can suggest the Gram-negative bacteria Aeromonas or Plesiomonas, or Pseudomonas; bullous lesions with exposure to infected water or shellfish may suggest Vibrio vulnificus (which can cause devastating sepsis in the presence of underlying liver disease.)

Rapid progression, desquamation, bullae, crepitance, severe pain and presence of hemodynamic instability can be signs of an emergent process requiring immediate surgical intervention. Deep soft tissue infection such as necrotizing fasciitis or pyomyositis may present with severe pain in an extremity and may occur initially without overlying skin changes or with nonspecific erythema. Pain out of proportion to physical findings is a clue.

Development of bullae or crepitance is worrisome for Clostridium, toxin-producing Group A streptococcal infection, Vibrio vulnificus or other virulent organisms. Consider Vibrio vulnificus if there has been contact with infected shellfish or water. Scrotal or perineal pain and swelling with or without overlying skin changes should suggest Fournier's gangrene (necrotizing fasciitis of the groin and genital area), which is a surgical emergency, particularly in a patient with diabetes or renal failure, or who is postoperative.

Meningococcal infection may be manifested by few too multiple petechiae or by a widespread purpuric rash that is almost confluent in some areas ("purpura fulminans"). Other causes of purpura fulminans include pneumococcal and staphylococcal infections and Capnocytophaga canimorsus (related to dog bite in a splenectomized patient).

Rocky Mountain Spotted Fever (due to Rickettsia rickettsii) starts with fever, headache and malaise; the rash may occur several days into the illness; history of a tick bite or residence in/travel to an endemic area is helpful.

Toxic shock syndrome (due to toxin-producing staphylococci or streptococci) may be accompanied initially by a diffuse, blanching, macular erythrodermic sunburn-like rash; 8-10 days later, peripheral desquamation of the distal digits may confirm the diagnosis.

A dark lesion on an extremity may represent ecthyma gangrenosum (usually a sign of Pseudomonas in a neutropenic patient, but occasionally occurs with other Gram-negative or fungal infections). Embolic-appearing lesions can be clues to endocarditis or disseminated infection. Fusarium is a fungal pathogen that is particularly likely to cause skin lesions, often involving the toes, and may be accompanied by positive blood cultures. Zygomycetes (including Mucor), Aspergillus and other molds may cause dark skin lesions that are particularly ominous when they involve the nose or oropharynx as rapid spread to the brain (rhinocerebral mucormycosis) may ensue in a neutropenic or diabetic patient.

Disseminated zoster infection (widespread vesicular eruption) occurs in immunocompromised patients who have previously had varicella (chickenpox) and who reactivate the virus but are unable to contain it within a single dermatome. Differential diagnoses include primary varicella (chickenpox), disseminated herpes simplex infection, disseminated enteroviral infection (Coxsackie), or noninfectious etiology (e.g. pustular psoriasis, drug reaction). Involvement of internal organ systems (lungs, liver, central nervous system) may be present.

Ulcerated lesions may relate to venous stasis or leg edema; trauma; surgery; pyoderma gangrenosum (a noninfectious condition associated with inflammatory bowel disease and some autoimmune disorders); or infections, including tularemia or (rarely) anthrax.

Presence of Osler nodes, Janeway lesions and conjunctival petechiae strongly suggests endocarditis, although nonspecific embolic-appearing lesions may also occur, or at times no lesions at all.

Nodular lymphangitis is most frequently caused by organisms such as Mycobacterium marinum (aquarium contact) and Sporothrix schenkii (sporotrichosis; classically from injury from a rose thorn).

Catheter-associated infections (with or without bacteremia) may have no exit site manifestations; may have erythema, tenderness, and drainage at the exit site; or may have swelling, erythema, and tenderness along the subcutaneous tunnel of the catheter ("tunnel infection"). Tunnel infections in neutropenic patients may be manifested only by pain and not by erythema, due to lack of WBC to produce inflammation.

Consider ectoparasitic infestation such as lice or scabies in the presence of pruritic rashes and (in the case of scabies) burrows.

Drug rashes due to antimicrobials, anticonvulsants or other medications are common, and in severe cases may lead to manifestations such as Stevens-Johnson syndrome (involving target lesions and/or oral stomatitis) and toxic epidermal necrolysis (involving full-thickness necrosis). DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) may have a fulminant presentation with fever, rash, hypotension, and organ dysfunction.

Although hives and angioedema are characteristic of Type I immediate hypersensitivity reactions, late rashes may occur that are not predicted by skin testing and may be characterized by maculopapular, purpuric or other morphologies rather than hives. Voriconazole may cause a blistering dermatitis in sun-exposed areas.

Key management points

Skin biopsy of embolic-appearing lesions, rashes (to rule out graft-versus-host disease or drug reaction) or other skin lesions can be very helpful and should be sent to the microbiology laboratory for bacterial, fungal, AFB (and sometimes viral) stains and cultures as well as to the pathology laboratory for histopathology and special stains.

2. Emergency Management

Emergency management checklist

  • In the presence of bullous or crepitant soft tissue processes, consider clostridial myonecrosis or invasive Group A streptococcal infection, both of which are surgical emergencies which may require radical amputation of a limb or other emergent surgical debridement to give the patient the best chance for survival. Emergent surgical consultation should be obtained as soon as the suspicion of such diagnoses is raised.

  • Blood cultures and urine cultures should be sent as soon as possible, and broad-spectrum antimicrobial therapy rapidly initiated (see below; particularly if the patient is neutropenic or has suspected deep soft tissue infection).

  • Culture any drainage from the sites of indwelling venous catheters; note whether tenderness, erythema or swelling are present at the site or along the catheter tunnel (if present).

  • If open wounds or ulcerations are present, consider culturing drainage or the wound surface for routine and fungal pathogens, as colonizing organisms can rapidly become infecting organisms in the immunocompromised patient. If bullae are present, a bulla may be unroofed and the material sent for cultures and stains. If boils or carbuncles are present, consider incision and drainage with cultures and stains.

  • If HSV or VZV is suspected, a viral swab kit should be used for PCR, DFA or culture for these pathogens, since conventional culture swabs may be inhibitory to viruses. Viral swabs should be placed in appropriate media according to kit instructions (e.g. a tube of M4 media) and transported to the lab immediately for maximal yield. A Tzanck prep of a vesicle scraping can be stained to look for multinucleated giant cells, which are signs of HSV or VZV.

  • If a drug rash/reaction is suspected, stop the suspected agent(s) and if continued antibiotic therapy is needed (e.g. for broad-spectrum coverage for neutropenic fever), use alternative agents from unrelated categories of drugs; consider steroids for severe rashes.

  • If petechiae and/or purpura are present in the setting of hemodynamic instability, consider meningococcemia (or overwhelming pneumococcal, staphylococcal, streptococcal, Capnocytophaga or other sepsis).

  • Mark the extent of a soft tissue process (e.g. cellulitis) with a marker, in order to determine whether it is progressing or regressing on subsequent exams.

  • Emergent surgical consultation if clostridial myonecrosis, invasive Group A strep infection or other deep soft tissue infection (necrotizing fasciitis, pyomyositis) is suspected.

  • If the above deep soft tissue infections are suspected, the patient may go emergently to the OR depending on the rate of progression of the process; if the patient is more stable, imaging such as CT or MRI of the area may be performed to rule out deep soft tissue abscesses etc.

  • Note the presence of neutropenia and/or history of splenectomy which predispose to a variety of overwhelming infections.

3. Diagnosis

Diagnostic criteria and tests

Cultures of blood, urine, catheter sites (if drainage), wounds and ulcerations (if any) should be performed. Viral swabs for HSV and VZV PCR, DFA, or cultures should be performed if herpes simplex or zoster infection are suspected.

Bullous lesions can be unroofed and the fluid sent for Gram stain and culture, but surgical management of a suspected Clostridium or invasive Group A strep infection should not be delayed if the results are not immediately received.

Consider skin biopsy with routine bacterial, fungal and mycobacterial cultures and special stains (occasionally viral cultures or immunostains as well), particularly for lesions that appear embolic or are singular or few in number.

Make sure to obtain a differential on the CBC: a) for neutrophil count and b) for eosinophilia, which can be a sign of allergic drug reaction and also of graft-versus-host disease

Consider CT or MRI of an involved area (e.g. an extremity) if the patient is stable and if deep soft tissue infection or drainable abscess is suspected.

Other noninvasive testing which can be helpful includes sedimentation rate and CRP (usually highly elevated in endocarditis or disseminated infection, for example); urine Histoplasma antigen; fungal antibody panel; Aspergillus galactomannan antigen; beta-d-glucan; blood cryptococcal antigen; and fungal and mycobacterial isolator blood cultures. Bone marrow biopsy (with fungal and mycobacterial stains and cultures as well as histopathology) may be helpful in the diagnosis of disseminated fungal or mycobacterial infection.

Consider brain imaging and LP in the presence of mental status changes; if an LP is performed, include Gram stain and culture, fungal stain and fungal culture, cryptococcal antigen, AFB stain and culture, VDRL, and PCRs for HSV, VZV, CMV, EBV, human herpesvirus-6, and other viruses if indicated (such as JC virus, West Nile virus, enterovirus). Cytology on the CSF should be obtained if malignancy is a possibility.

Obtain a history of recent environmental exposures if possible: e.g. exposure to infected shellfish or water (Vibrio vulnificus); cleaning of an aquarium (Mycobacterium marinum); injury from a rose thorn (sporotrichosis); exposure to sexually transmitted disease (disseminated gonococcal infection); dog bite in a splenectomized patient (Capnocytophaga canimorsus).

Obtain a history of recently initiated medications in case of suspected drug reaction, and review the entire medication list (with particular attention to beta-lactam antibiotics, vancomycin and sulfa-containing antibiotics).

Establishing the diagnosis

Diagnoses such as cellulitis and erysipelas are generally made by physical examination and clinical impression; microbiologic confirmation may or may not be obtainable as most of these processes are not bacteremic and cultures may be no growth. Response to therapy is often confirmatory.

Disseminated infections are most commonly diagnosed by blood cultures or by tissue biopsy with special stains and cultures, as well as serologies and antigen testing (at times) for fungal infections.

Toxic shock syndrome due to staphylococci is frequently not accompanied by positive blood cultures, while blood cultures are positive in at least 50% of those with toxic shock due to streptococci.

Clostridial myonecrosis or crepitant cellulitis may be confirmed by unroofing a bulla and visualizing large Gram-positive rods on a Gram stain, but the diagnosis should be immediately suspected on exam, and emergent surgical consultation should not be delayed pending the Gram stain result.

Other possible conditions

Medication-associated rashes are common particularly with beta-lactam antibiotics, vancomycin, and sulfa-containing antibiotics, but can occur with virtually any antimicrobial. Non-antibiotic medications may also cause rashes and may mimic infectious processes, for example in a neutropenic patient receiving a new anticonvulsant.

Acute graft-versus-host disease in the hematopoietic stem cell transplant recipient (and occasionally the solid organ transplant recipient) often involves the skin (with or without liver or GI tract involvement). Skin GVHD is graded I-IV and ranges from patchy erythema (often seen first on the hands and back) to diffuse, bright-red desquamating erythroderms. Skin biopsy is diagnostic but therapy often is started on clinical grounds with biopsy results pending.

Erythema nodosum and vasculitic lesions (palpable purpura) may have noninfectious causes such as autoimmune diseases and medications.

Confirmatory tests

As listed above, the most important confirmatory tests are often the blood cultures and skin biopsy, with appropriate stains and cultures, but other confirmatory testing may include echocardiography to detect infectious endocarditis, serologies and antigen testing for fungal infections such as histoplasmosis, chest and abdominal CT scans to detect nodules or other signs of disseminated infection, and occasionally a dilated retinal exam (which may reveal evidence of disseminated candidiasis, toxoplasmosis, tuberculosis, etc).

Eosinophilia in the peripheral blood or eosinophils seen on urine stain can support the diagnosis of a drug reaction. Peripheral blood eosinophilia can also be a feature of graft-versus-host disease.

4. Specific Treatment

For the febrile neutropenic patient with a skin lesion or lesions, initiate broad-spectrum coverage, including at least one agent active against Gram-negative bacteria including Pseudomonas (see section on Infections in Transplant Recipients: Presenting Without Localizing Signs).

Presence of ecthyma gangrenosum is frequently indicative of Pseudomonas though other organisms (Gram-negative, Staphylococcus aureus) may mimic it. Prevailing antimicrobial resistance patterns at particular centers should inform the choice of initial empiric broad coverage. Inclusion of vancomycin should be considered if the center has a high rate of MRSA and/or if a catheter-related infection is suspected.

For suspected toxin-producing Group A streptococcal infection, while obtaining emergent surgical consultation, inclusion of clindamycin in the regimen is helpful in terms of limiting toxin production (as it inhibits bacterial protein synthesis) and also avoids the problem of using a cell-wall active agent when the bacterial inoculum is so high that the rate of bacterial replication slows (the Eagle effect).

Many clinicians use penicillin (a cell-wall active agent) together with clindamycin in this situation. Addition of IVIg has also been shown to be helpful in streptococcal toxic shock syndrome, presumably through neutralization of bacterial toxin.

Suspected Clostridium perfringens infection (gas gangrene, myonecrosis) requires emergent surgical consultation, but antimicrobial coverage should be started simultaneously. Antibiotics that cover Clostridium perfringens and similar species include high-dose penicillin, imipenem, ampicillin-sulbactam, piperacillin-tazobactam, and clindamycin. On the other hand, cephalosporins, quinolones, metronidazole, aminoglycosides, oxacillin, vancomycin, and aztreonam do not have adequate Clostridium perfringens coverage.

Suspected meningococcemia coverage is generally with a 3rd-generation cephalosporin; vancomycin is often added until resistant pneumococcal infection is ruled out.

Drugs and dosages

Dosages of antimicrobials should be maximal within the indicated range (especially for neutropenic or septic patients), but should be adjusted for renal dysfunction according to the manufacturers' instructions. The following list includes some commonly used antibiotics in this setting, though it is not comprehensive; doses given are for normal renal function and should be adjusted for renal dysfunction according to the manufacturer's nomogram.

  • Acyclovir 5 mg/kg IV Q8h (mucosal HSV in an immunocompromised patient); 10 mg/kg IV Q8h (for disseminated zoster in an immunocompromised patient or one unable to take oral medications); acyclovir 400 mg po BID (e.g.) for prophylaxis.

  • Amphotericin B Lipid Complex (ABLC) or Liposomal Amphotericin B - prophylaxis 3 mg/kg/day, treatment 5 mg/kg/day (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone, normal saline).

  • Amikacin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 8 and peak 28-35 mcg/ml (for pneumonia or sepsis).

  • Anidulafungin 200 mg IV loading dose followed by 100 mg IV once daily.

  • Azithromycin 500 mg daily.

  • Aztreonam 1-2 g IV Q6-8h.

  • Caspofungin 70 mg IV x 1 dose then 50 mg IV Q12h.

  • Cefazolin g IV Q8h.

  • Cefepime 2 g IV Q8 h.

  • Ceftazidime 1-2 g IV Q8h.

  • Ceftriaxone 1 g IV Q24h (higher for endocarditis or meningitis).

  • Ciprofloxacin 400 mg IV Q12h.

  • Clindamycin 600-900 mg IV Q8h.

  • Colistimethate 100-125 mg IV Q6-12h (generally reserved for MDR organisms - especially important to adjust for renal dysfunction - watch for nephrotoxicity).

  • Cytomegalovirus immune globulin (CMVIg) 100 mg/kg-150 mg/kg IV (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone; dosing schedules vary; used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis).

  • Daptomycin 6 mg/kg IV Q24h.

  • Filgrastim (G-CSF) 300 mcg SQ or 480 mcg SQ can be administered daily as needed for neutropenia in the solid organ transplant recipient (it does not appear to precipitate rejection in this setting). Filgrastim should be used under the guidance of a hematologist in the HSCT recipient. When filgrastim is stopped, the WBC count may fall by up to 50%.

  • Fluconazole 100-400 mg IV Q24h.

  • Foscarnet - follow manufacturer's nomogram.

  • Ganciclovir 5 mg/kg IV Q12h (therapy) or 5 mg/kg IV Q24h (prophylaxis).

  • Gentamicin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Imipenem 500-1000 mg Iv Q6h.

  • Intravenous immunoglobulin (IVIg) 400 mg/kg IV per dose; number and timing of doses varies; with acetaminophen/diphenhydramine (and sometimes hydrocortisone) premedication - used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis.

  • Isavuconazole 372 mg po/IV Q8h for 6 doses, then 372 mg po/IV Q24h.

  • Itraconazole 200 mg Q12h.

  • Levofloxacin 500 mg-750 mg IV Q24h.

  • Linezolid 600 mg IV Q12h.

  • Meropenem 500 mg IV Q6h-1 gram IV Q8h.

  • Micafungin 100-150 mg IV Q24h.

  • Moxifloxacin 400 mg IV Q24h.

  • Oxacillin 1-2 g IV Q4-6h.

  • Piperacillin-tazobactam 3.375 grams IV Q6h-4.5 grams IV Q6h.

  • Posaconazole Extended – release formulation preferred: 300 mg po Q12 x 2 doses, then 300 mg po daily. If necessary to administer via tube, use the liquid formulation, 200 mg po four times daily (treatment dose) or 200 mg po three times daily (prophylaxis) – which must be given with food containing fat.

  • Tigecycline 100 mg IV x 1 dose followed by 50 mg IV Q12h.

  • Tobramycin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Trimethoprim-sulfamethoxazole one double-strength po daily or thrice weekly for Pneumocystis prophylaxis; 15-20 mg/kg/day of the trimethoprim component (divided Q6h) for treatment of Pneumocystis pneumonia.

  • Vancomycin 1-1.5 grams IV Q12h with subsequent pre-dose levels and appropriate adjustment.

  • Valganciclovir 900 mg po BID for treatment and 450 mg po BID (or 900 mg po daily) for prophylaxis.

  • Voriconazole 6 mg/kg po/IV Q12h x 2 doses then 4 mg/kg IV Q12h, with a level on Day 5 (aiming for level 2 – 5).

Note that azole antifungals and some macrolides (erythromycin, clarithromycin) raise the levels of cyclosporine, tacrolimus, sirolimus, and everolimus, and require close monitoring and adjustment of levels and doses of those agents. Azithromycin is the macrolide of choice in the patient receiving cyclosporine, tacrolimus or sirolimus. Also note that aminoglycosides may have enhanced nephrotoxicity in patients receiving cyclosporine or tacrolimus, and alternative agents should be considered if appropriate microbiologically. Assistance of a pharmacist familiar with transplant-related issues is very helpful.

Quinolone resistance is increasingly common in bacterial isolates from immunocompromised patients due to extensive use of quinolones for treatment of infections and for neutropenic prophylaxis. Quinolone resistance is emerging in multiple bacteria including Neisseria meningitidis. This should be taken into account in designing empiric therapy regimens while awaiting culture and susceptibility data.

Refractory cases

In suspected drug rashes when discontinuation of the drug has not resulted in improvement and manifestations are worsening, consider steroid therapy. This is particularly true in the setting of palpable purpura (leukocytoclastic vasculitis) associated with vancomycin, for example.

Vasculitic lesions may be associated with noninfectious processes or may accompany hepatitis B, hepatitis C and other infections, and may require therapy of these other processes for resolution.

In culture-negative febrile patients with rash who do not respond to broad-spectrum antimicrobials, consider viral infections such as Coxsackie, measles, parvovirus and rubella.

In "rashless" immunocompromised patients with abdominal pain, elevated liver function tests and/or cutaneous hyperesthesia in the absence of rash, consider the diagnosis of "rashless" zoster and consider empiric high-dose acyclovir therapy.

5. Disease monitoring, follow-up and disposition

Monitoring

The most important feature of monitoring of a skin and soft-tissue infectious process is the daily examination. Extent of the process, development of new lesions, evolution of the lesions (e.g. crusting and drying of zoster lesions, fading of the erythema of cellulitis), development of worsening features such as desquamation or bullae, and the overall status of the patient (fever, hypotension, pressor requirement, resolution of neutropenia, etc) all enter into this assessment and can help guide continuation of therapy or switching therapy.

If any cultures were positive initially (blood, urine, etc.), obtaining repeat cultures will be helpful in documenting control and ultimately resolution of the infection.

For tunnel infections, the catheter should be removed in order to achieve cure. If a catheter exit site infection without symptoms of tunnel infection is managed with the catheter in place initially, monitoring of both the exam and followup cultures is important to determine whether the catheter can be left in place or will require removal.

Wrong diagnosis

If the patient's skin lesions or area of involvement continue to progress or enlarge, or if the patient's overall status deteriorates with worsening fever, hypoxemia, or hypotension, then the initial empiric therapy may not be covering the organism, there may be more than one process present, or there may be a noninfectious component.

If standard antibacterial therapy was administered initially and there is no response, consider fungal etiology (e.g. cryptococcal cellulitis), disseminated viral infection, or atypical bacteria (such as nontuberculous mycobacteria such as M. chelonae or M. abscessus causing nodular skin lesions).

If the patient's rash begins to desquamate or a previous rash confined to the skin begins to involve the oropharynx and other mucous membranes, this is a potential dermatologic emergency; urgent dermatology consultation is helpful if not already obtained.

Drug rashes may persist unchanged or even worsening for one to several days after discontinuation of the offending agent, but if not starting to resolve after several days, discontinuation of other medications and/or administration of steroids should be considered.

Follow-up

If there is a suspected reaction to a medication for which drug levels are available (e.g. vancomycin, aminoglycosides, voriconazole, anticonvulsants, etc), monitoring of drug levels can provide an idea of how long the medication has detectable levels in the system.

Pathophysiology

The skin is a complex organ, including the epidermis, dermis, highly vascular subcutaneous connective tissue and appendages such as hair follicles. Any and all of these can be involved in various infectious processes, as well as the deeper structures such as fascia and muscle.

Erysipelas involves the dermis whereas cellulitis involves deeper layers of subcutaneous tissue. Tinea pedis may predispose to cellulitis by providing a portal of entry for bacteria, particularly in patients with venous insufficiency or who have undergone vein harvesting for coronary artery bypass grafting.

Necrotizing fasciitis, often due to streptococci, staphylococci and other bacteria, progresses rapidly along fascial planes.

Ecthyma gangrenosum, usually associated with Pseudomonas infection, involves bacterial perivascular infection, resulting in an erythematous round or oval lesion that develops an ulcerated center. This usually occurs in neutropenic and/or highly immunocompromised patients, and on histopathology, large numbers of bacilli are present in vessel walls with little host response.

Toxic shock syndrome results in widespread involvement of multiple organ systems because of superantigen pathogenesis (the toxin binds to multiple T cell receptors at the V beta locus) and consequent cytokine release.

Clostridium infection is rapidly progressive and the bullae do not contain host WBC, partially because Clostridium produces a toxin that lyses WBC.

Graft-vs-host disease involves immune system cells (particularly lymphocytes) of the donor that recognize as foreign, then attack cells of an HSCT recipient. Rarely, GVHD can occur after solid organ transplantation, attributed to passenger leukocytes from the donor that were transferred along with the transplanted organ. GVHD after HSCT occurs in a spectrum of severity; after SOT it is typically severe with a high mortality.

Epidemiology

Nearly 40% of necrotizing fasciitis was caused by MRSA in a recent series by Lee et al. The overall mortality rate was 15%. Notably, 62% of these MRSA isolates were resistant to clindamycin, which has implications for empiric therapy.

Epidemiology of necrotizing fasciitis in pediatric patients is different. A large Canadian series identified Group A streptococci as the most common cause, particularly in children under 5 years of age and in association with varicella in the pre-vaccine era.

Invasive Group A strep infections in the ICU carried a 40% mortality in a series from four Toronto hospitals; 81% required mechanical ventilation, renal dysfunction in 55%, and mortality correlated with APACHE II score and number of dysfunctional organs. Although use of clindamycin and IVIg have been advocated, no difference in mortality was noted with these therapies. Coagulopathy and liver dysfunction were associated with mortality.

In a recent series by Corcoran et al, Fournier's gangrene occurred mainly in males with a mean age of 55%. A Fournier's gangrene severity index incorporating a variety of parameters was highly predictive of mortality (overall mortality was 10%).

Meningococcal infections have been affected by the use of the quadrivalent meningococcal vaccine, but sporadic cases occur. The vaccine does not protect against group B. Persons in crowded environments such as college freshmen and military recruits are at higher risk.

Patients with Vibrio vulnificus infection generally have a history of contact with seawater or raw seafood. Disease is especially severe in those with underlying liver disease or diabetes. There were a number of cases of this infection after Hurricane Katrina.

Prognosis

Time to resolution of skin and soft tissue processes in immunocompromised patients varies widely. Cellulitis frequently may take 1-2 days to start to show improvement or may even extend initially despite appropriate antibiotic therapy, but then should gradually fade in color and diminish in extent over the next 5-14 days. Longer durations of treatment and slower resolutions may be seen in patients with compromised immune systems and with severe venous stasis, especially in the presence of associated skin ulcerations.

Emergent, rapidly progressive infections such as clostridial myonecrosis and Group A streptococcal toxic shock syndrome may be rapidly fatal, or (particularly if the patient undergoes timely emergent surgery), may result in a long, slow recovery with a protracted ICU phase followed by transfer to a regular nursing floor and ultimately to a rehabilitation facility. Repeat debridements may be needed, sometimes multiple times, to stop the spread of the myonecrotic process or to control secondary infection of large open wounds.

Outcome and time to resolution of disseminated infections such as candidiasis, Pseudomonas sepsis and other such infections in the immunocompromised patient are often determined by the overall status of the patient, including rapidity of recovery from neutropenia and degree of immunosuppression, for example. Reduction of immunosuppression, where possible, may speed the resolution of infection.

A patient with proven or suspected disseminated zoster should be monitored daily at least for the first several days to make sure there are no signs of new lesions or visceral spread (liver function tests, pneumonitis, mental status, etc).

Monitoring of the patient with bacterial, fungal or mycobacterial disseminated infection during the recovery phase consists of close clinical followup, repeating blood cultures if they were positive initially and monitoring other sites of involvement (e.g. repeat CT chest for pulmonary nodules, which may coexist with skin lesions in fungal or mycobacterial infections, for example). Fungal, nocardial and mycobacterial infection take months (or sometimes years) to resolve and treatment is often 6-12 months or longer; involvement of an infectious disease specialist with experience in transplant ID is important.

Monitoring of the patient with suspected or proven endocarditis involves monitoring of the EKG (to look for prolongation of the PR interval or development of heart block that may signal the presence of an abscess involving the conduction system); serial echocardiography; and serial blood cultures to document resolution of the bloodstream infection. If blood cultures continue to be positive, if embolization occurs despite appropriate therapy, or if worsening pulmonary edema, valvular insufficiency, or valve ring or myocardial abscess develop, emergent cardiac valvular surgery is indicated.

Special considerations for nursing and allied health professionals.

NA

<b>What's the evidence?</b><b>General</b>DaoudMSGibsonLESuWPD. Skin infections after hemopoietic stem cell or solid organ transplantation. In BowdenRALjungmanP and PayaCV eds, Transplant Infections (Second Edition), Lippincott Williams and Wilkins, Philadelphia, 2003, pp. 163-74.

(Comprehensive review of the wide variety of cutaneous infections in transplant recipients.)

O'ConnellBMAbelEANickoloffBJ et al. Dermatologic complications following heart transplantation. J Heart Transplant1986;430-6.

(Early paper that highlighted the high incidence of both skin infections and malignancies following transplantation.)

ParkerC. Skin lesions in transplant patients. Dermatol Clin1990;8:313-25.

(Helpful review including effects of specific immunosuppressive agents.)

UsatineRPSandyN. Dermatologic emergencies. Am Fam Physician2010;82:773-80.

(Clinically useful description of emergent conditions, including Rocky Mountain spotted fever, necrotizing fasciitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.)

<b>Bacterial infections (including cellulitis, necrotizing fasciitis, pyomyositis, myonecrosis)</b>CorcoranATSmaldoneMCGibbonsEPWalshTJDaviesBJ. Validation of the Fournier's gangrene severity index in a large contemporary series. J Urol2008;180:944-8.

(Explanation of the Fournier's gangrene severity index and its utility in prediction of mortality.)

LeeTCCarrickMMScottBGHodgesJCPhamHQ. Incidence and clinical characteristics of methicillin-resistant Staphylococcus aureus necrotizing fasciitis in a large urban hospital. Am J Surg2007;194:809-12, discussion 812-3.

(Large single-center review that includes helpful information on antimicrobial susceptibility patterns.)

MehtaSMcGeerALowDE et al. Morbidity and mortality of patients with invasive Group A streptococcal infections admitted to the ICU. Chest2006;130:1679-86.

(Prospective, population-based surveillance study over a 10-year period in four university hospitals.)

MerigouDBeylot-BarryMLyS et al. Primary cutaneous Nocardia asteroides infection after heart transplantation. Dermatology1998;196:246-7.

(An unusual but important-to-recognize presentation of nocardiosis.)

MusherDM. Cutaneous manifestations of bacterial sepsis. Hosp Pract1989;24:71-5, 80-2, 92 passim.

(Clinical and pathophysiologic discussion of ecthyma gangrenosum and other skin manifestations of fulminant infection.)

TsaiYHHuangTJHsuRW et al. Necrotizing soft-tissue infections and primary sepsis caused by Vibrio vulnificus and Vibrio cholerae non-O1. J Trauma2009;66:899-905.

(Large series of this unusual infection - 30 patients - which provides important management points.)

WuHMHarcourtBHHatcherCP et al. Emergence of ciprofloxacin-resistant Neisseria meningitidis in North America. N Engl J Med2009;360:886-92.

(Highly concerning report of growing antimicrobial resistance, which will ultimately have implications for post-exposure prophylaxis.)

<b>Fungal skin and soft tissue infections</b>BlairJE. Coccidioidal pneumonia, arthritis, and soft-tissue infection after kidney transplantation. Transpl Infect Dis2004;6:74-6.

(Description of some less well-known manifestations of coccidioidomycosis after transplantation by one of the premier experts on this disease.)

MielePSLevyCSSmithMA et al. Primary cutaneous fungal infections in solid organ transplantation: a case series. Am J Transplant2002;2:678-83.

(Four patients with unusual fungal infections presenting with skin manifestations.)

SunHYAlexanderBDLortholaryO et al. Cutaneous cryptococcosis in solid organ transplant recipients. Med Mycol2010;48:785-91.

(Insights from a multicenter cryptococcosis registry.)

<b>Mycobacterial skin and soft tissue infections</b>UslanDZKowalskiTJWengenackNLVirkAWilsonJW. Skin and soft tissue infections due to rapidly growing mycobacteria: comparison of clinical features, treatment, and suspecptibility. Arch Dematol2006;142:1287-92.

(Large case series of 63 patients from the Mayo Clinic.)

<b>Viral infections with skin involvement</b>ItohMKawaguchiSYagoKShimadaHMuroH. Acute abdominal pain preceding cutaneous manifestations of varicella zoster infection after allogeneic bone marrow transplantation. Tohoku J Exp Med2001;195:61-3.

(Unusual presenation of zoster, important for clinicians to know.)

JeyaratnamDRobsonAMHextallJMWongWMacMahonE. Concurrent verrucous and varicelliform rashes following renal transplantation. Am J Transplant2005;5:1777-80.

(Highlights the need to consider chronic VZV infection even with atypical presentations.)

<b>Noninfectious skin and soft tissue conditions</b>FerraraJLLevineJEReddyPHollerE. Graft-versus-host disease. Lancet2009; 373:1550-61.

(Up-to-date and comprehensive review of this complex topic.)

PatelARTurnerMLBairdK. et al. Voriconazole-induced phototoxicity masquerading as chronic graft-versus-host disease of the skin in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant2009;15:370-6.

(An under-recognized side effect of an antifungal agent in frequent use.)

ZhangYRuizP. Solid organ transplant-associated acute graft-versus-host disease. Arch Pathol Lab Med2010;134:1220-4.

(Most GVHD is seen in HSCT recipients, but SOT recipients can get an unusual and challenging version of this condition.)

Related Resources

You must be a registered member of Cancer Therapy Advisor to post a comment.

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Prostate Cancer Regimens Drugs
Rare Cancers Regimens
Renal Cell Carcinoma Regimens Drugs
Skin Cancer Regimens Drugs
Urologic Cancers Regimens Drugs

Sign Up for Free e-newsletters