Antimicrobials' combinations and failure of therapy

Antimicrobials’ combinations and failure of therapy

Antimicrobials’ combinations

Combinations of antimicrobials are generally used to broaden the spectrum of coverage for empiric therapy, achieve synergistic activity against the infecting organism, and prevent the emergence of resistance. Increasing the coverage of antimicrobial therapy is generally necessary in mixed infections in which multiple organisms are likely to be present, such as intra-abdominal and female pelvic infections in which a variety of aerobic and anaerobic bacteria may produce disease. Another clinical situation in which increased spectrum of activity is desirable is with nosocomial infection.


The achievement of synergistic antimicrobial activity is advantageous for infections caused by gram-negative bacilli in immunosuppressed patients. Traditionally, combinations of aminoglycosides and β-lactams have been used because these drugs together generally act synergistically against a wide variety of bacteria. However, the data supporting superior efficacy of synergistic over nonsynergistic combinations are weak.

Synergistic combinations may produce better results in infections caused by Pseudomonas aeruginosa, as well as in certain infections caused by Enterococcus spp. The use of combinations to prevent the emergence of resistance is widely applied but not often realized. The only circumstance in which this has been clearly effective is in the treatment of tuberculosis


Disadvantages of Combination Therapy

Although there are potentially beneficial effects from combining drugs, there are also potential disadvantages, including increased cost, greater risk of drug toxicity, and superinfection with even more resistant bacteria.

Some combinations of antimicrobials are potentially antagonistic. For example, agents that are capable of inducing β-lactamase production in bacteria (eg, cefoxitin) may antagonize the effects of enzyme-labile drugs such as penicillins or imipenem.

Monitoring therapeutic response

After antimicrobial therapy has been instituted, the patient must be monitored carefully for a therapeutic response. Culture and sensitivity reports from specimens collected must be reviewed. Use of agents with the narrowest spectrum of activity against identified pathogens is recommended.

Patient monitoring should include a variety of parameters, including WBC count, temperature, signs and symptoms of infection, appetite, radiologic studies as appropriate, and determination of antimicrobial concentrations in body fluids.

As the patient improves, the route of antibiotic administration should be reevaluated. Switching to oral therapy is an accepted practice for many infections. Criteria favoring the switch to oral therapy include the following:

✓ Over all clinical improvement ✓ Lack of fever for 8 to 24 hours ✓ Decreased WBC ✓ A functioning gastrointestinal (GI) tract   

Failure of antimicribial therapy

A variety of factors may be responsible for the apparent lack of response to therapy. It is possible that the disease is not infectious or nonbacterial in origin, or there is an undetected pathogen. Other factors include those directly related to drug selection, the host, or the pathogen. Laboratory error in identification and/or susceptibility testing errors are rare.

Failures Caused by Drug Selection

Factors directly related to the drug selection include an inappropriate selection of drug, dosage, or route of administration. Malabsorption of a drug product due to GI disease (eg, short-bowel syndrome) or a drug interaction (eg, complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) may lead to potentially subtherapeutic serum concentrations.

Accelerated drug elimination is also a possible reason for failure and may occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution may result in low serum concentrations, particularly for aminoglycosides.
A common cause of failure of therapy is poor penetration into the site of infection. This is especially true for the so-called privileged sites, such as the CNS, the eye, and the prostate gland.

Failures Caused by Host Factors

Patients who are immunosuppressed (eg, granulocytopenia from chemotherapy and acquired immunodeficiency syndrome) may respond poorly to therapy because their own defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens.

Other host factors are related to the necessity for surgical drainage of abscesses or removal of foreign bodies and/or necrotic tissue. If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.

Failures Caused by Microorganisms

Factors related to the pathogen include the development of drug resistance during therapy. Primary resistance refers to the intrinsic resistance of the pathogens producing the infection. However, acquisition of resistance during treatment has become a major problem as well.

The increase in resistance among pathogenic organisms is believed to be due, in large part, to continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections.



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