Current Diagnosis & Treatment in Infectious Diseases

Section I - Basic Principles

4. General Principles of Antimicrobial Therapy

Walter R. Wilson MD

Anti-infective agents such as inorganic salts, myrrh, and acidic solutions have been used topically for centuries. For several hundred years, European and Arabic physicians noted that the administration of heavy metals such as arsenic, mercury, or bismuth was effective against syphilis and other infections. The modern era of antimicrobial chemotherapy began in the 1930s with the introduction of sulfonamides and gathered momentum in the 1940s with the discovery of penicillin and streptomycin. Currently, antimicrobial agents are among the most widely used classes of drugs. Worldwide expenditures for antimicrobial agents exceed $20 billion annually, and antimicrobial agents represent 20–40% of drugs administered to hospitalized patients. Although the choice of a single agent or a combination of agents should be individualized for each patient, certain general principles of therapy should guide the selection of specific drugs. The following factors are important in determining appropriate antimicrobial therapy for patients with bacterial or fungal infections. The drugs of choice for the treatment of infections are discussed in the chapters on specific infections. Antimicrobial therapies for mycobacterial, fungal, parasitic, and viral infections are discussed in their respective chapters.

ETIOLOGIC AGENT & SUSCEPTIBILITY TESTING

The identification and antimicrobial susceptibility of an etiological agent(s) are the most important factors in determining the choice of antimicrobial therapy. When a microorganism is identified and its susceptibilities are known, specific antimicrobial therapy may be administered. In general, the agent selected should be bactericidal, have a narrow spectrum, be well tolerated, and be cost effective. However, in many instances, empiric therapy must be instituted before such information is known. For empiric therapy, the choice of a single drug or a combination of drugs should be based on the suspected site of infection and knowledge of which microorganisms are likely to cause infection in a specific site. For example, the bacteria that most likely cause community-acquired pneumonia are Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Mycoplasma pneumoniae, or Chlamydia spp.; acute pyelonephritis is usually caused by Escherichia coli or other Enterobacteriaceae, a soft-tissue infection is usually caused by Streptococcus pyogenes or Staphylococcus aureus; and otitis media is usually caused by S pneumoniae, H influenzae, or B catarrhalis..

Most infections may be treated with a single antimicrobial agent. However, in either specific or empiric therapy, it may be necessary to administer a combination of drugs. Synergistic combinations of drugs may be necessary to treat certain infections such as some central nervous system infections or prosthetic valve endocarditis or to treat serious infections caused by enterococci. In other infections, synergistic combinations may be advantageous for the therapy of infections caused by a resistant microorganism or for infections involving a site where antimicrobial penetration is reduced, such as endocarditis, osteomyelitis, or meningitis (Table 4-1). Combination therapy may be necessary for the treatment of polymicrobial infections such as intra-abdominal or pelvic infections. In febrile neutropenic patients or other immunocompromised hosts, combination therapy for empiric or specific treatment may be preferable to single-drug therapy.

Appropriate cultures should be obtained before starting antimicrobial therapy. An exception to this rule is a patient with acute bacterial meningitis. In these patients, blood cultures should be obtained and antimicrobial agents administered, and spinal fluid cultures may be obtained as soon as possible after onset of therapy (see Chapter 7).

A Gram stain of an appropriate specimen is the most useful and cost-effective method for rapid diagnosis. Immunologic methods for antigen detection, polymerase chain reaction, and DNA probes are described in Chapter 6. Antimicrobial susceptibility tests should be performed using disk diffusion, agar dilution, E-testing, or other standard methodology on most bacterial pathogens, and antimicrobial therapy adjusted as necessary according to the results.

Table 4-1. Penetration of antimicrobial agents into the cerebrospinal fluid.

Therapeutic concentration with or without inflammation    Metronidazole
   Rifampin
   Chloramphenicol
   Sulfonamides
   Trimethoprim
Therapeutic concentration with inflammation
   Penicillin
   Ampicillin1
   Ticarcillin1
   Piperacillin1
   Mezlocillin
   Nafcillin
   Oxacillin
   Ceftriaxone
   Ceftizoxime
   Cefotaxime
   Ceftazidime
   Cefepime
   Cefuroxime
   Aztreonam
   Imipenem
   Meropenem
   Fluoroquinolones2
   Vancomycin
   Flucytosine
   Fluconazole
Nontherapeutic concentration with or without inflammation
   Aminoglycosides
   Cefoperazone
   Clindamycin
   First-generation cephalosporins
   Second-generation cephalosporins3
   Ketoconazole
   Itraconazole4
   Amphotericin preparations4
   Macrolides

1Penetration of beta-lactamase inhibitors, sulbactam, clavulanate, and tazobactam may not achieve therapeutic concentrations.
2Fluoroquinolones that achieve therapeutic concentrations are ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin.
3Cefuroxime achieves therapeutic concentrations.
4Achieves therapeutic concentration for treatment of Cryptococcus neoformans.

 

DOSAGE & ROUTE OF ADMINISTRATION

Once the decision is made to initiate antimicrobial therapy, the next choice is between oral and parenteral administration, with the later either intravenous or intramuscular. The oral administration is appropriate for mild to moderately severe infections in patients with a normally functioning gastrointestinal tract. Some antimicrobial agents, such as vancomycin, quinupristin-dalfopristin, and aminoglycosides, are not absorbed after oral administration. They must be administered parenterally. Others, like fluoroquinolones and trimethoprim-sulfamethoxazole, have excellent bioavailability after oral administration and may be administered orally even in patients with serious infections.

The mechanism of bacterial killing by antimicrobial agents affects decisions regarding the amount of drug administered, the frequency, and the route of administration (Table 4-2). There are two major mechanisms of bactericidal activity by antimicrobial agents (Table 4-3). The first is characterized by saturation of the rate of killing by concentrations of antibiotic at or near the minimum inhibitory concentration (MIC) of the microorganism. Accordingly, increasing the concentration of drug in serum does not result in an increased rate or magnitude of bacterial killing. With these drugs, the duration of time of drug concentration in serum or tissue that exceeds the MIC is the major determinant of bacterial killing. This time-dependent killing is observed with beta-lactams, vancomycin, macrolides, and clindamycin. This phenomenon should be considered when selecting optimal dosing of these antimicrobial agents. Failure to do so may result in administration of unnecessarily high or frequent dosages. With this mechanism of killing, the dosage of an antimicrobial agent should be adjusted so that the concentration in serum exceeds the MIC for 40–50% of the dosing interval. However, in bacterial meningitis, infective endocarditis, or other infections in sites with diminished antibiotic penetration, the administration of higher dosages of antimicrobial agents, often at more frequent intervals, may be necessary to ensure an adequate concentration of drug at the site of infection.

The second major mechanism of bactericidal activity is characterized by concentration-dependent killing. The higher the concentration of drug in serum or tissue, the greater the rate and magnitude of killing. This mechanism of killing occurs with aminoglycosides and fluoroquinolones. Additionally, these two drugs and others that inhibit bacterial protein synthesis, such as macrolides, rifampin, and tetracyclines, induce a prolonged post-antibiotic effect on gram-negative bacilli. In contrast, beta-lactams produce minimal or no postantibiotic effect. The phenomenon of concentration-dependent killing supports the concept of single daily dosing for this class of drugs, such as with aminoglycosides and some fluoroquinolones.

Table 4-2. Major mechanism of killing by antimicrobial agents.

Bacterial or fungal cell wall synthesis
   Penicillins
   Cephalosporins
   Vancomycin
   Carbapenems—imipenem, meropenem
   Monobactams
Cell membrane effect
   Azoles-ketoconazole, fluconazole, itraconazole
Inhibit protein synthesis
   Aminoglycosides—30S ribosome
   Tetracyclines—30S ribosome
   Macrolides, clindamycin, chloramphenicol—50S ribosome
   Rifampin—DNA-dependent RNA polymerase
   Fluoroquinolones—DNA gyrase, topoisomerase IV
   Quinupristin-dalfopristin—50S ribosome
   Oxazolidinones-linezolid—blocks initiation complex ribosomal protein synthesis
   Metronidazole—altered DNA
   Flucytosine—inhibit DNA synthesis
Folic acid synthesis
   Trimethoprim-sulfamethoxazole

Table 4-3. Mechanism of bactericidal activity.

Time above MIC
   β-Lactams
   Vancomycin
   Clindamycin
   Macrolides
Concentration dependent
   Aminoglycosides
   Fluoroquinolones
   Metronidazole

Other factors that influence the dosing of antimicrobial agents include the patient's age, renal and hepatic function, and immune status (see next section). Some antimicrobial agents require dosing adjustments in patients with abnormal renal function, and others do not (Table 4-4).

UNDERLYING HOST FACTORS

The underlying conditions of the host, such as history of drug allergy or intolerance, age, renal and hepatic function, and immunosuppression, are major factors which influence the selection of therapy, dosing, efficacy, and safety of antimicrobial agents.

Drug Allergy, Adverse Events, & Drug Interactions

The first factor to be considered in the choice of therapy is a history of adverse drug reactions or allergy (Table 4-5). Failure to do so may result in serious or fatal consequences. Additionally, one should review carefully other medications administered concomitantly. Numerous drug interactions with antimicrobial agents have been reported. These may result in decreased absorption of orally administered antimicrobial agents or may result in or potentiate serious drug toxicity resulting from the concomitant drug, the antimicrobial agent, or both. The potential drug interactions are so numerous and newly described interactions are reported so frequently that it is difficult, if not impossible, for the practicing physician to be aware of all of these interactions. Computer software programs are available to identify potential drug interactions. It is important for the patient and the care team, which includes the physician, nursing staff, and pharmacist, to provide accurate and complete information regarding a history of drug allergy, intolerance, or concomitant medications before antimicrobial agents are prescribed.

Table 4-4. Antimicrobial agents that do not require dosage adjustments in patients with renal failure.

Cephalosporins
   Cefoperazone
   Ceftriaxone
Macrolides
   Erythromycin
   Clarithromycin
   Azithromycin
Teracyclines
   Doxycycline
   Minocycline
Fluoroquinolones
   Trovafloxacin
   Grepafloxacin
Others
   Clindamycin
   Metronidazole
   Chloramphenicol
   Rifampin

Age

Patient age, especially at the extremes of lifespan, is a major factor that influences appropriate antimicrobial therapy. Elderly patients may have a normal serum creatinine, but creatinine clearance decreases with age. Antimicrobial agents that are renally excreted may require reduction in dosages in elderly patients, including those with a normal serum creatinine. Failure to recognize this factor may result in accumulation of toxic concentrations of antimicrobial agents in serum that may produce serious consequences, including central nervous system manifestations such as seizures or coma, nephrotoxicity, hepatotoxicity, or ototoxicity. Similarly, renal function is diminished in neonates. Dosages of antimicrobial agents that are excreted by the kidneys should be altered.

Hepatic function is underdeveloped in neonates. Chloramphenicol is metabolized in the liver. High serum concentrations of unconjugated chloramphenicol may occur in neonates, resulting in severe toxicity, such as shock and cardiovascular collapse (gray-baby syndrome). Chloramphenicol should not be administered to neonates. Sulfonamides compete with bilirubin for binding sites on serum albumin and, when administered to neonates, increase the concentrations of unbound bilirubin in serum, which may result in kernicterus. Consequently, sulfa drugs should not be administered to neonates.

Tetracyclines readily pass the placental barrier and bind to bone and teeth of neonates and children; therefore, the use of tetracyclines should be avoided in this age group. Fluoroquinolones cause arthropathy and cartilage damage in puppies and have not yet been approved for use in children. Fluoroquinolone use should be avoided, if possible, in children who are <15 years of age.

Table 4-5. Toxicities of antimicrobial agents.

Antimicrobial Agent(s)

More Common

Less Common

Penicillins and cephalosporins

Hypersensitivity; gastrointestinal; diarrhea; disulfiram with Methyltetrathiazole side chain (cefamandole, cefoperazone, cefotetan)

Bone marrow suppression; nephrotoxicity; hypoprothrombinemia with methyltetrathiazole side chain; hepatotoxocity with β-lactamase inhibitors

Carbapenems and monobactams

Nausea, metallic taste with imipenem; seizures with imipenem

Hypersensitivity with aztreonam

Fluoroquinolones

Gastrointestinal; phototoxicity with lomefloxacin, sparfloxacin

Hypersensitivity; cartilage damage (young patients); central nervous system; QT interval prolongation—sparfloxacin; Achilles tendon rupture; hepatic-trovafloxacin

Macrolides

Gastrointestinal; thrombophlebitis—erythromycin

Hypersensitivity; transient hearing loss—erythromycin

Trimethoprim-sulfamethoxazole

Hypersensitivity

Gastrointestinal; Stevens-Johnson syndrome

Aminoglycosides
Vancomycin

Nephrotoxicity
Red man syndrome—histamine mediated

CN1-VII; neuromuscular blockade
CN1-VIII; neuromuscular blockade

Clindamycin

Diarrhea

Hypersensitivity, gastrointestinal—nausea, vomiting

Metronidazole

Gastrointestinal—nausea, vomiting, metallic taste

 

Tetracyclines

Phototoxicity; impaired bone growth and teeth discoloration in pediatric patients; skin, mucous membranes
Discoloration with prolonged minocycline use

Gastrointestinal; hypersensitivity; hepatitis; dizziness with minocycline; lupus phenomena; pseudotumor cerebri

Rifampin

Orange secretions

Hypersensitivity; hepatic, bone marrow suppression

Quinupristin-dalfopristin

Muscle pain

Hypersensitivity; hepatitis

Oxazolidinones; linezolid

Gastrointestinal, headache

Bone marrow suppression; hypersensitivity

Chloramphenicol

Bone marrow suppression

Aplastic anemia; gray baby syndrome; neurotoxicity; gastrointestinal; hypersensitivity

Amphotericin compounds; amphotericin B; deoxycholate

Infusion-fever, nausea, vomiting, headache, hypotension, hypertension, flushing, myalgias, nephrotoxicity

Hepatic; anemia; neurotoxicity

   Lipid complex;

Hypokalemia, hypomagnesemia

Infusion related; nephrotoxicity, anemia

   Cholesterol sulfate

Infusion related; hypokalemia, hypomagnesemia

Nephrotoxicity, anemia

   Liposomal

Hypokalemia, hypomagnesemia

Nephrotoxicity; infusion-related anemia

Flucytosine

Gastrointestinal

Bone marrow suppression; hepatotoxicity; hypersensitivity

Azole
   Ketoconazole

Gastrointestinal; hypersensitivity; gynecomastia; decreased libido; impotence

Hepatotoxicity; decreased synthesis of cortisol; hypertension with prolonged use; alopecia

   Fluconazole

Headache; hypersensitivity

Gastrointestinal; hepatotoxicity; alopecia

   Itraconazole

Headache; dizziness; hypersensitivity

Gastrointestinal; hepatotoxicity; gynecomastia; impotence; hypertension with prolonged use

1CN, cranial nerve.

 

Other Underlying Conditions

Patients with peripheral vascular disease or shock may not adequately absorb drugs administered intramuscularly. Sulfonamides, nitrofurantoin, or chloramphenicol may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides may cause hemolysis in patients with hemoglobinopathies, such as hemoglobin Zurich or hemoglobin H.

Antimicrobial agents must be chosen carefully for administration to pregnant or nursing mothers. Virtually all antimicrobial agents cross the placental barrier to some degree. Macrolides and beta-lactam drugs with the possible exception of ticarcillin, which may cause teratogenic effects in rodents, may be administered safely to pregnant females. Tetracycline use should be avoided in pregnant women as mentioned above. In addition, the administration of tetracycline intravenously has been associated with acute fatty necrosis of the liver in pregnant women. Streptomycin may cause vestibular or ototoxic damage to the fetus.

Most antimicrobial agents administered to women may be detected in the breast milk of nursing mothers, although their concentrations in breast milk are usually low. Sulfonamide and fluoroquinolone use should be avoided, if possible, in nursing mothers. Tetracyclines may be administered to nursing mothers. Tetracyclines are excreted in breast milk, but tetracycline forms an insoluble chelate with calcium in breast milk, which is not absorbed by the nursing child.

The underlying renal and hepatic function must be considered in the choice of antimicrobial agent. The effect of impaired renal function in elderly patients is described above. Tetracyclines (except doxycycline and possibly minocycline) should not be administered to patients with impaired renal function, because the elevated concentrations in serum that result may produce worsening of uremia because of their anti-anabolic effect. Additionally, the elevated serum concentration of tetracycline may result in hepatotoxicity. Antimicrobial agents which are metabolized or excreted primarily by the liver include rifampin, macrolides, clindamycin, metronidazole, some beta-lactams (eg, ceftriaxone and cefoperazone), nitrofurantoin, and some fluoroquinolones (eg, trovafloxacin). The dosages of these drugs do not require adjustment in patients with renal dysfunction but should be reduced in patients with hepatic failure, and some (eg, trovafloxacin and tetracycline) should be avoided or used with extreme caution.

The immunocompromised condition of the patient is a major factor that influences the selection of antimicrobial agents. Combinations of agents may be preferable, at least as initial therapy (see Chapters 23, 24, and 25 on AIDS, febrile neutropenic patients, and organ transplant recipients, respectively).

MONITORING THE RESPONSE TO ANTIMICROBIAL THERAPY

The most important factor in determining the response of patients to antimicrobial therapy is the clinical assessment. Measurement of concentrations in serum may help guide subsequent dosage adjustment in patients who are receiving vancomycin or an aminoglycoside or other agents in the presence of impairment of renal or hepatic functions. The major value in measuring concentrations in serum is to avoid toxicity from excessively high concentrations. After the onset of antimicrobial therapy, repeating cultures such as from blood, urine, or spinal fluid may be useful in selected patients. The determination of serum bactericidal titers is of minimal if any value in assessing the efficacy of therapy, and this test should not be performed routinely.

REFERENCES

Wilhelm MP (editor): Symposium on antimicrobial agents. Mayo Clin Proc 1997;73:994.

Wilhelm MP (editor): Symposium on antimicrobial agents. Mayo Clin Proc 1998;74:78.

Wilhelm MP (editor): Symposium on antimicrobial agents. Mayo Clin Proc 1999;75:86.

Wilhelm MP (editor): Symposium on antimicrobial agents. Mayo Clin Proc 2000;76: In press.