When clinicians prescribe an antibiotic to a patient with an established infection, it is expected that the patient will recover. This course of events is particularly anticipated when the host is immunocompetent. It is well recognized, however, that some immunocompromised patients, such as profoundly and persistently leukopenic leukemic patients with an invasive fungal infection, often succumb to their infection despite appropriate antimicrobial chemotherapy.
Failure to respond to antimicrobial treatment is frequently manifested by persistent fever, lack of clinical improvement, and clinical deterioration and/or persistent or worsening laboratory or radiographic abnormalities. The seasoned clinician appreciates, however, that fever can be a manifestation of a noninfectious process, such as an adverse event caused by a drug, chemical thrombophlebitis at an infusion site, deep-venous thrombosis, pulmonary embolism, pulmonary aspiration of gastric contents, neoplasm, or an immunologic disorder. The antimicrobial agents most frequently associated with drug-induced fever include sulfonamides, b-lactam antibiotics, and amphotericin B. Drug fever is usually not accompanied by rash or eosinophilia, and it customarily subsides within 72 hours of discontinuation of the medication.
Resolution of a bacterial infection depends largely on three factors: host defenses, nature of the pathogen, and characteristics of the antimicrobial administered. Failure of resolution of the infection should encourage the clinician to search for factors that would compromise the host, enhance bacterial pathogenicity, or reduce the effectiveness of the prescribed antibiotic.
When a patient is not responding to the designated antibiotic, it is extremely tempting to administer alternative antimicrobial agents with an extended spectrum of inhibitory activity. On occasion, this approach is valid, particularly for a patient who is seriously ill. In general, however, it is preferable for the clinician to consider any host-related features that could be contributing to persistent infection, and to reassess the diagnostic possibilities.
If an infection does not respond to antibiotic treatment alone, the patient should be evaluated for the presence of obstruction, necrotic tissue, hematoma, abscess, or a prosthetic device and, if necessary, corrective action taken. Additional concerns relating to the host that need to be considered are compliance with medication and the presence of an infection in a protected (“privileged”) site. Infections in protected sites, which require treatment with antimicrobials having unique penetration properties, include meningitis, endocarditis, chronic bacterial prostatitis, and endophthalmitis.
An important consideration, when the patient appears not to be responding to antibiotic therapy, is the accuracy of the diagnosis. Gout, thrombophlebitis, and Lyme disease can resemble a traditional bacterial cellulitis; Charcot’s joint often simulates osteomyelitis; and pulmonary infarction, lung cancer, adult respiratory distress syndrome (ARDS), and aspiration of gastric contents can imitate bacterial pneumonia.
The lack of a clinical response can suggest features unique to the offending pathogen. Resistance to the antibiotic prescribed, the presence of multiple organisms (abdominal and pelvic infections as well as infections involving the feet of diabetic patients are typically polymicrobic), and the need to administer combination treatment should be considered when infection persists despite what appears to be appropriate antibiotic treatment.
Results of susceptibility reports generated by automated systems can be false, and this can result in misleading identification of heterogeneous methicillin sodium-resistant staphylococci and b-lactamase-resistant Enterobacteriaceae. It is beneficial to explore this possibility with the microbiology technologist.
Selected infections, including tuberculosis, endocarditis caused by viridans streptococci and enterococci, brucellosis, disseminated Mycobacterium avium complex infection, and life-threatening infection caused by Pseudomonas aeruginosa, require combination antibiotic therapy for clinical resolution to be achieved.
Assuming the antimicrobial possesses an appropriate spectrum of activity to curtail the growth of an infectious organism, what additional factors relevant to the ability of a drug to influence the outcome of an infection must be considered? Three specific features of the antimicrobial certainly can contribute to therapeutic efficacy.
Bactericidal compounds are preferred for patients with bacterial endocarditis or gram-negative bacillary meningitis. Bactericidal agents are also indicated when life-threatening infections develop in granulocytopenic hosts.
When a b-lactim antibiotic is prescribed, it is best to maintain blood and tissue concentrations above the minimal inhibitory concentration (MIC) for the organism causing infection throughout the entire dosing interval. Lower doses or longer dosing intervals, sometimes used to save money, raise the risk for treatment failure. Alternatively, aminoglycoside antibiotics exhibit concentration-dependent killing of organisms and are probably best administered once a day.
Drug-drug interaction has the potential to diminish antimicrobial efficacy. The ingestion of food impairs the bioavailability of azithromycin, and milk products diminish the absorption of the tetracyclines. The coadministration of antacids, iron, didanosine, and multivitamins that contain zinc decreases absorption of the tetracyclines and fluoroquinolones. In addition, the bioavailability of fluoroquinolones is impaired by ingestion of sucralfate.
Table 80-1 lists some considerations that the clinician might ponder when a patient appears not to be responding to antibiotic treatment of acute maxillary sinusitis, exacerbation of chronic bronchitis, or community-acquired pneumonia.
Table 80-1. Failure to respond to antibiotic therapy
When a patient is persistently febrile (longer than 96 hours) after antibiotic treatment has been initiated to manage pyelonephritis, concerns should focus on a drug-resistant uropathogen, obstructive uropathy, intrarenal or perinephric abscess, an adverse drug reaction, diabetes mellitus compromising the host, or xanthogranulomatous pyelonephritis. (R.A.G.)
Bartlett JG, et al. Community-acquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998;26:811–838.
Reviews why patients fail to respond to the antibiotic treatment of community-acquired pneumonia and provides an assessment of a nonresponding patient.
Borrego F, Gleckman R. Preventing antibiotic treatment failure. Contemp Intern Med 1996;8:9–15.
An approach for evaluating patients whose infection fails to respond to antibiotics.
Cunha BA. Differentiating pneumonitis and pneumonia in your SLE patient. J Crit Illness 1997;12:779–783.
In a patient with systemic lupus erythematosus, pneumonitis, as a complication of the systemic disorder, can resemble infectious pneumonia.
Cunha BA, Ortega AM. Antibiotic failure. Med Clin North Am 1995;79:663–671.
A review of the causes of antibiotic failure.
Feinsilver SH, Fein AM, Niederman MS. Nonresolving, slowly resolving, and recurrent pneumonia. In: Niederman MS, Sarois GA, Glassroth J, eds. Respiratory infections: a scientific basis for management. Philadelphia: WB Saunders, 1994:277–290.
Outlines the diagnostic and therapeutic approach for the patient with pneumonia in whom the infection is not resolving.
Genovese MC. Fever, rash, and arthritis in a woman with silicone gel breast implants. West J Med 1997;167:149–158.
Difficulty of differentiating a connective tissue disease (systemic inflammatory illness) from an infectious or neoplastic process.
Melby MJ, et al. Acute adrenal insufficiency mimicking septic shock: a case report. Pharmacotherapy 1988;8:69–71.
Acute adrenal insufficiency can resemble septic shock.
Mulligan MJ, Cobbs CG. Bacteriostatic versus bactericidal activity. Infect Dis Clin North Am 1989;3:389–398.
Outlines those conditions in which bactericidal activity appears necessary for successful antibiotic treatment.
Schattner A. Quinidine hypersensitivity simulating sepsis. Am J Med 1998;104: 488–490.
Adverse drug reaction can resemble an infectious disease.
Wallace JM. Mimics of infectious pneumonia in persons infected with human immunodeficiency virus. In: Niederman MS, Saros GA, Glassroth J, eds. Respiratory infections: a scientific basis for management. Philadelphia: WB Saunders, 1994:217–223.
Malignant and infiltrative disorders in the HIV-infected patient that resemble infectious pneumonia.