Rationale:

• Because gram-positive as well as gram-negative infections occur in immunosuppressed patients with soft tissue infections, treat initially with antibiotics that have activity against both types of microorganisms.
• Although double coverage of Pseudomonas infections is frequently done, clinical trials have failed to substantiate a clinical benefit. Reasons for initiating aminoglycosides for empirical treatment of gram-negative bacilli include a high level of antimicrobial resistance within an institution.

Evidence:

• The clinical signs of infection in the immunosuppressed patient may be subtle or absent due to decreased inflammatory response (21).
• The most likely pathogens during the first 7 days of neutropenia induced by chemotherapy are bacteria such as staphylococci, viridans streptococci, enterococci, and gram-positive rods such as Corynebacterium, Clostriudium, and Bacillus species (21).
• The most likely pathogens after the first 7 days of neutropenia are antibiotic-resistant bacteria and fungi including Aspergillus, Candida, and Rhizopus/Mucor species (21).
• Ticarcillin-clavulanate and piperacillin/tazobactam are effective in treating soft tissue infections caused by both gram-positive and gram-negative bacteria (141).
• Ceftazidime was as effective as tobramycin plus ticarcillin in treating gram-positive, gram-negative, and mixed infections in hospitalized patients with soft tissue infections (142). Monotherapy of Pseudomonas infections appears at least equal to if not superior to dual therapy, in view of the additional toxicity associated with the addition of an aminoglycoside (143; 144).
• Combination antibiotic therapy of Pseudomonas infections does not prevent the emergence of resistance (145).
• Avoid empirical therapy with piperacillin/tazobactam if the patient has been exposed to this antibiotic in the previous month. In one study, 37% of patients exposed to piperacillin/tazobactam in the previous month were subsequently infected with a resistant strain. Furthermore, 64% infected with a piperacillin/tazobactam-resistant Pseudomonas strain in the previous month were reinfected with a resistant strain (146).
• In patients infected with Pseudomonas aeruginosa with APACHE II scores >17, an extended infusion of piperacillin/tazobactam (3.375 g infused over 4 hours three times daily) reduced the mortality rate compared to conventional therapy (12.2% vs. 31.6%, P=0.040) (147).
• Doripenem may possess superior antipseudomonal activity in view of its MIC being two- to four-fold lower than that of meropenem for Pseudomonas aeruginosa (148). Clinical trials showed the clinical cure rate of doripenem for Pseudomonas respiratory infections to be superior to that of imipenem (149). Unlike imipenem, but similar to meropenem, doripenem does not require coadministration of cilastatin.
• In patients with ventilator-associated pneumonia due to gram-negative bacilli, continuous infusion of meropenem resulted in a superior cure rate (90.5%) compared with intermittent administration (59.6%) (150).

Comments:

• The changing spectrum of antibiotic resistance patterns among both gram-negative and gram-positive organisms makes empiric treatment difficult in the immunosuppressed host, but underscores the need for definitive cultures and sensitivities.
• A toxic shock syndrome associated with viridans streptococci has been reported (151).
• Gram-negative bacilli, especially Vibrio vulnificus, may cause a rapidly progressive form of necrotizing fasciitis, which needs to be recognized early to initiate appropriate surgical and antimicrobial therapy targeting the organism. Generally, tetracyclines are recommended to treat this organism (152).
• Patients with cell-mediated immunodeficiency (such as lymphoma, organ recipients, and steroid recipients) are at increased risk of nontuberculous mycobacteria, Nocardia, and fungi. Discussion of these entities is beyond the scope of this module.