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.
Enhanced Antibacterial Action
In specific infections, a combination of antibiotics can have greater antibacterial action than a single agent. This is true of the combined use of penicillin plus an aminoglycoside in the treatment of enterococcal endocarditis. Penicillin acts to weaken the bacterial cell wall; the aminoglycoside acts to suppress protein synthesis. The combination has enhanced antibacterial action because, by weakening the cell wall, penicillin facilitates penetration of the aminoglycoside to its intracellular site of action.
Disadvantages of Antibiotic Combinations
Use of multiple antibiotics has several drawbacks, including (1) increased risk for toxic and allergic reactions, (2) possible antagonism of antimicrobial effects, (3) increased risk for superinfection, (4) selection of drug-resistant bacteria, and (5) increased cost. Accordingly, antimicrobial combinations should be employed only when clearly indicated.
Prophylactic Use of Antimicrobial Drugs
Estimates indicate that between 30% and 50% of the antibiotics used in the United States are administered for prophylaxis. That is, these agents are given to prevent an infection rather than to treat an established infection. Much of this prophylactic use is uncalled for. However, in certain situations, antimicrobial prophylaxis is both appropriate and effective. Whenever prophylaxis is proposed, the benefits must be weighed against the risks for toxicity, allergic reactions, superinfection, and selection of drug-resistant organisms. Generally approved indications for prophylaxis are discussed next.
Surgery
Prophylactic use of antibiotics can decrease the incidence of infection in certain kinds of surgery. Procedures in which prophylactic efficacy has been documented include cardiac surgery, peripheral vascular surgery, orthopedic surgery, and surgery on the gastrointestinal (GI) tract (stomach, duodenum, colon, rectum, and appendix). Prophylaxis is also beneficial for women undergoing a hysterectomy or an emergency cesarean section. In contaminated surgery (operations performed on perforated abdominal organs, compound fractures, or lacerations from animal bites), the risk for infection is nearly 100%. Hence, for these operations, use of antibiotics is considered treatment, not prophylaxis. When antibiotics are given for prophylaxis, they should be given before the surgery. If the procedure is unusually long, dosing again during surgery may be indicated. As a rule, postoperative antibiotics are unnecessary. For most operations, a first-generation cephalosporin (e.g., cefazolin) will suffice.
Bacterial Endocarditis
Individuals with congenital or valvular heart disease and those with prosthetic heart valves are unusually susceptible to bacterial endocarditis. For these people, endocarditis can develop after certain dental and medical procedures that dislodge bacteria into the bloodstream. Thus before undergoing such procedures, these patients may need prophylactic antimicrobial medication. However, according to guidelines released by the American Heart Association, antibiotic prophylaxis is less necessary than previously believed and hence should be done much less often than in the past.
Neutropenia
Severe neutropenia puts individuals at high risk for infection. There is some evidence that the incidence of bacterial infection may be reduced through antibiotic prophylaxis. However, prophylaxis may increase the risk for infection with fungi: by killing normal flora, whose presence helps suppress fungal growth, antibiotics can encourage fungal invasion.
Other Indications for Antimicrobial Prophylaxis
For young women with recurrent urinary tract infection, prophylaxis with trimethoprim/sulfamethoxazole may be helpful. Oseltamivir (an antiviral agent) may be employed for prophylaxis against influenza. For individuals who have had severe rheumatic endocarditis, lifelong prophylaxis may be needed. Antimicrobial prophylaxis is indicated after exposure to organisms responsible for sexually transmitted diseases (e.g., syphilis, gonorrhea).
Misuses of Antimicrobial Drugs
Misuse of antibiotics is common. According to the CDC, about 50% of antibiotic prescriptions are either inappropriate or entirely unnecessary. Ways that we misuse antibiotics are discussed next.
Attempted Treatment of Viral Infection
Most viral infections—including mumps, chickenpox, and the common cold—do not respond to currently available drugs. Hence, when drug therapy of these disorders is attempted, patients are exposed to all the risks of drugs but have no chance of receiving benefits.
Acute upper respiratory tract infections, including the common cold, are a particular concern. When these infections are treated with antibiotics, only 1 patient out of 4000 is likely to benefit. However, the risks remain high: 1 in 4 patients will get diarrhea, 1 in 50 will get a rash, and 1 in 1000 will need to visit an emergency department, usually because of a severe allergic reaction.
Treatment of Fever of Unknown Origin
Although fever can be a sign of infection, it can also signify other diseases, including hepatitis, arthritis, and cancer. Unless the cause of a fever is a proven infection, antibiotics should not be employed. If the fever is not due to an infection, antibiotics would not only be inappropriate, they would also expose the patient to unnecessary toxicity and delay correct diagnosis of the fever’s cause. If the fever is caused by infection, antibiotics could hamper later attempts to identify the infecting organism.
The only situation in which fever, by itself, constitutes a legitimate indication for antibiotic use is when fever occurs in the severely immunocompromised host. Because fever may indicate infection, and because infection can be lethal to the immunocompromised patient, these patients should be given antibiotics when fever occurs—even if fever is the only indication that an infection may be present.
Improper Dosage
Like all other medications, antibiotics must be used in the right dosage. If the dosage is too low, the patient will be exposed to a risk for adverse effects without benefit of antibacterial effects. If the dosage is too high, the risks for superinfection and adverse effects become unnecessarily high.
Treatment in the Absence of Adequate Bacteriologic Information
As stressed earlier, proper antimicrobial therapy requires information on the identity and drug sensitivity of the infecting organism. Except in life-threatening situations, therapy should not be undertaken in the absence of bacteriologic information. This important guideline is often ignored.
Omission of Surgical Drainage
Antibiotics may have limited efficacy in the presence of foreign material, necrotic tissue, or exudate. Hence, when appropriate, surgical drainage and cleansing should be performed to promote antimicrobial effects.
Monitoring Antimicrobial Therapy
Antimicrobial therapy is assessed by monitoring clinical responses and laboratory results. The frequency of monitoring is directly proportional to the severity of infection. Important clinical indicators of success are reduction of fever and resolution of signs and symptoms related to the affected organ system (e.g., improvement of breath sounds in patients with pneumonia).
Various laboratory tests are used to monitor treatment. Serum drug levels may be monitored for two reasons: to ensure that levels are sufficient for antimicrobial effects and to avoid toxicity from excessive levels. Success of therapy is indicated by the disappearance of infectious organisms from posttreatment cultures. Cultures may become sterile within hours of the onset of treatment (as may happen with urinary tract infections), or they may not become sterile for weeks (as may happen with tuberculosis).
