Basic Principles of Antimicrobial Therapy

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It is imperative that antibiotics not be discontinued prematurely. Accordingly, patients should be instructed to take their medication for the entire prescribed course, even though symptoms may subside before the full course has been completed. Early discontinuation is a common cause of recurrent infection, and the organisms responsible for relapse are likely to be more drug resistant than those present when treatment began.

Therapy With Antibiotic Combinations

Therapy with a combination of antimicrobial agents is indicated only in specific situations. Under these well-defined conditions, use of multiple drugs may be lifesaving. However, it should be stressed that, although antibiotic combinations do have a valuable therapeutic role, routine use of two or more antibiotics should be discouraged. When an infection is caused by a single, identified microbe, treatment with just one drug is usually most appropriate.

Antimicrobial Effects of Antibiotic Combinations

When two antibiotics are used together, the result may be additive, potentiative, or, in certain cases, antagonistic. An additive response is one in which the antimicrobial effect of the combination is equal to the sum of the effects of the two drugs alone. A potentiative interaction (also called a synergistic interaction) is one in which the effect of the combination is greater than the sum of the effects of the individual agents. A classic example of potentiation is produced by trimethoprim plus sulfamethoxazole, drugs that inhibit sequential steps in the synthesis of tetrahydrofolic acid (see Chapter 73).

In certain cases, a combination of two antibiotics may be less effective than one of the agents by itself, indicating antagonism between the drugs. Antagonism is most likely when a bacteriostatic agent (e.g., tetracycline) is combined with a bactericidal drug (e.g., penicillin). Antagonism occurs because bactericidal drugs are usually effective only against organisms that are actively growing. Hence, when bacterial growth has been suppressed by a bacteriostatic drug, the effects of a bactericidal agent can be reduced. If host defenses are intact, antagonism between two antibiotics may have little significance. However, if host defenses are compromised, the consequences can be dire.

Indications for Antibiotic Combinations

Initial Therapy of Severe Infection

The most common indication for using multiple antibiotics is initial therapy of severe infection of unknown etiology, especially in the neutropenic host. Until the infecting organism has been identified, wide antimicrobial coverage is appropriate. Just how broad the coverage should be depends on the clinician’s skill in narrowing the field of potential pathogens. After the identity of the infecting microbe is known, drug selection can be adjusted accordingly. As discussed earlier, samples for culture should be obtained before drug therapy starts.

Mixed Infections

An infection may be caused by more than one microbe. Multiple infectious organisms are common in brain abscesses, pelvic infections, and infections resulting from perforation of abdominal organs. When the infectious microbes differ from one another in drug susceptibility, treatment with more than one antibiotic is required.

Preventing Resistance

Although use of multiple antibiotics is usually associated with promoting drug resistance, there is one infectious disease—tuberculosis—in which drug combinations are employed for the specific purpose of suppressing the emergence of resistant bacteria. Why tuberculosis differs from other infections in this regard is discussed in Chapter 75.

Decreased Toxicity

In some situations, an antibiotic combination can reduce toxicity to the host. For example, by combining flucytosine with amphotericin B in the treatment of fungal meningitis, the dosage of amphotericin B can be reduced, thereby decreasing the risk for amphotericin-induced damage to the kidneys.

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