CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND ANTIVIRAL AGENTS
Antimicrobial drugs are used to prevent or treat infections caused by pathogenic (disease-producing) microorganisms. The human body and the environment contain many microorganisms, most of which live in a state of balance with the human host and do not cause disease. When the balance is upset and infection occurs, characteristics of the infecting microorganism(s) and the adequacy of host defense mechanisms are major factors in the severity of the infection and the person’s ability to recover. Conditions that impair defense mechanisms increase the incidence and severity of infections and impede recovery. In addition, use of antimicrobial drugs may lead to serious infections caused by drug-resistant microorganisms.
To help prevent infectious diseases and participate effectively in antimicrobial drug therapy, the nurse must be knowledgeable about microorganisms, host responses to microorganisms, and antimicrobial drugs.
Terms and Concepts
Several terms are used to describe these drugs. Anti-infective and antimicrobial include antibacterial, antiviral, and antifungal drugs; antibacterial and antibiotic usually refer only to drugs used in bacterial infections. Most of the drugs in this section are antibacterials. Antiviral and antifungal drugs are discussed in Chapters 39 and 40, respectively. Additional terms for antibacterial drugs include broad spectrum, for those effective against several groups of microorganisms, and narrow spectrum, for those effective against a few groups. The action of an antibacterial drug is usually described as bactericidal (kills the microorganism) or bacteriostatic (inhibits growth of the microorganism). Whether a drug is bactericidal or bacteriostatic often depends on its concentration at the infection site and the susceptibility of the microorganism to the drug. Successful treatment with bacteriostatic antibiotics depends on the ability of the host’s immune system to eliminate the inhibited bacteria and an adequate duration of drug therapy. Stopping an antibiotic prematurely can result in rapid resumption of bacterial growth. Bactericidal drugs are preferred in serious infections, especially in people with impaired immune function.
Actions of antibacterial drugs on bacterial cells
Mechanisms of Action
Most antibiotics act on a specific target in the bacterial cell. Almost any structure unique to bacteria, such as proteins or nucleic acids, can be a target for antibiotics. Specific mechanisms include the following:
1. Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt bacterial cell walls (eg, penicillins, cephalosporins, vancomycin)
2. Inhibition of protein synthesis by bacteria or production of abnormal bacterial proteins (eg, aminoglycosides, clindamycin, erythromycin, tetracyclines). These drugs bind irreversibly to bacterial ribosomes, intracellular structures that synthesize proteins. When antimicrobial drugs are bound to the ribosomes, bacteria cannot synthesize the proteins necessary for cell walls and other structures.
3. Disruption of microbial cell membranes (eg, antifungals)
4. Inhibition of organism reproduction by interfering with nucleic acid synthesis (eg, fluoroquinolones, rifampin, anti–acquired immunodeficiency syndrome antivirals)
5. Inhibition of cell metabolism and growth (eg, sulfonamides, trimethoprim)
INDICATIONS FOR USE
Antimicrobial drugs are used to treat and prevent infections. Because laboratory tests (except Gram’s stain and a rapid test for group A streptococci) to identify causative organisms usually take 24 hours or longer, empiric therapy against the most likely pathogens is often begun. Once organisms are identified, more specific therapy is instituted. Prophylactic therapy is recommended to prevent:
1. Group A streptococcal infections and possibly rheumatic fever, rheumatic heart disease, and glomerulonephritis. Penicillin is commonly used.
2. Bacterial endocarditis in clients with cardiac valvular disease who are having dental, surgical, or other invasive procedures
3. Tuberculosis. Isoniazid is used.
4. Perioperative infections in high-risk clients (eg, those whose resistance to infection is lowered because of age, poor nutrition, disease, or drugs) and for high-risk surgical procedures (eg, cardiac or GI surgery, certain orthopedic procedures, organ transplants)
5. Sexually transmitted diseases (eg, gonorrhea, syphilis, chlamydial infections) after exposure has occurred
6. Recurrent urinary tract infections in premenopausal, sexually active women. A single dose of trimethoprimsulfamethoxazole, cinoxacin, or cephalexin, taken after
sexual intercourse, is often effective.
Rational Use of Antimicrobial Drugs
Antimicrobials are among the most frequently used drugs worldwide. Their success in saving lives and decreasing severity and duration of infectious diseases has encouraged their extensive use. Authorities believe that much antibiotic use involves overuse, misuse, or abuse of the drugs. That is, an antibiotic is not indicated at all or the wrong drug, dose, route, or duration is prescribed. Inappropriate use of antibiotics increases adverse drug effects, infections with drugresistant microorganisms, and health care costs. In addition, it decreases the number of effective drugs for serious or
antibiotic-resistant infections. Guidelines to promote more appropriate use of the drugs include:
1. Avoid the use of broad-spectrum antibacterial drugs to treat trivial or viral infections; use narrow-spectrum agents when likely to be effective.
2. Give antibacterial drugs only when a significant bacterial infection is diagnosed or strongly suspected or when there is an established indication for prophylaxis. These drugs are ineffective and should not be used to treat viral infections.
3. Minimize antimicrobial drug therapy for fever unless other clinical manifestations or laboratory data indicate infection.
4. Use the drugs along with other interventions to decrease microbial proliferation, such as universal precautions, medical isolation techniques, frequent and thorough handwashing, and preoperative skin and bowel cleansing.
5. Follow recommendations of the Centers for Disease Control and Prevention for prevention and treatment of infections, especially those caused by drug-resistant organisms (eg, gonorrhea, penicillin-resistant streptococcal infections, methicillin-resistant staphylococcal infections, vancomycin-resistant enterococcal infections, and MDR-TB).
6. Consult infectious disease physicians, infection control nurses, and infectious disease pharmacists about local patterns of drug-resistant organisms and treatment of complicated infections.
Drug Selection
Once an infection requiring treatment is diagnosed, numerous factors influence the choice of an antimicrobial drug or combination of drugs.
Initial, empiric therapy. Because most laboratory tests to definitively identify causative organisms and to determine susceptibility to antibiotics require 48 to 72 hours, the physician usually prescribes for immediate administration a drug that is likely to be effective. This empiric therapy is based on an informed estimate of the most likely pathogen, given the client’s signs and symptoms and apparent site of infection. A single broad-spectrum antibiotic or a combination of drugs is often chosen.
Culture and susceptibility studies allow the therapist to “match the drug to the bug.” Culture identifies the causative organism; susceptibility tests determine which drugs are likely to be effective against the organism. Culture and susceptibility studies are especially important with suspected gram-negative infections because of the high incidence of drugresistant microorganisms. However, drug-resistant gram-positive organisms are being identified with increasing frequency.
When a specific organism is identified by a laboratory culture, tests can be performed to measure the organism’s susceptibility to particular antibiotics. Laboratory reports indicate whether the organism is susceptible (S) or resistant (R) to the tested drugs. One indication of susceptibility is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that prevents visible growth of microorganisms. Some laboratories report MIC instead of, or in addition to, susceptible (S) or resistant (R). Susceptible organisms have low or moderate MICs that can be attained by giving usual doses of an antimicrobial agent. For the drug to be effective, serum and tissue concentrations should usually exceed the MIC of an organism for a period of time. How much and how long drug concentrations need to exceed the MIC depend on the drug class and the bacterial species. With betalactam agents (eg, penicillins, cephalosporins), the drug concentration usually needs to be maintained above the MIC of the infecting organism for a majority of the dosing interval. With the aminoglycosides (eg, gentamicin, others), the drug concentration does not need to be maintained above the MIC for the entire dosing interval.
Aminoglycosides have a postantibiotic effect, defined as a persistent effect of an antimicrobial on bacterial growth after brief exposure of the organisms to a drug. Some studies demonstrate that large doses of aminoglycosides, given once daily, are as effective as more frequent dosing and may cause less nephrotoxicity. Resistant organisms have high MICs and may require higher concentrations of drug than can be achieved in the body, even with large doses. In some cases the minimum bactericidal concentration (MBC) is reported, indicating no growth of the organism in the presence of a particular antibiotic. The MBC is especially desirable for infected hosts with impaired immune functions.
Clients’ responses to antimicrobial therapy cannot always be correlated with the MIC of an infecting pathogen. Thus, reports of drug susceptibility testing must be applied in the context of the site of infection, the characteristics of the drug, and the clinical status of the client.
Knowledge of antibiotic resistance patterns in the community and agency. Because these patterns change, continuing efforts must be made. Pseudomonas aeruginosa is resistant to many antibiotics. Those strains resistant to gentamicin may be susceptible to amikacin, ceftazidime, imipenem, or aztreonam. Some gramnegative organisms have become increasingly resistant to aminoglycosides, third-generation cephalosporins, and aztreonam, but may be susceptible to imipenem.
Knowledge of the organisms most likely to infect particular body tissues. For example, urinary tract infections are often caused by E. coli, and a drug effective against this organism is indicated.
A drug’s ability to penetrate infected tissues. Several antimicrobials are effective in urinary tract infections because they are excreted in the urine. However, the choice of an effective antimicrobial drug may be limited in infections of the brain, eyes, gallbladder, or prostate gland because many drugs are unable to reach therapeutic concentrations in these tissues.
A drug’s toxicity and the risk-to-benefit ratio. In general, the least toxic drug should always be used. However, for serious infections, more toxic drugs may be necessary.
Drug costs. If an older, less expensive drug meets the criteria for rational drug selection and is likely to be effective in a given infection, it should be used as opposed to a more expensive agent. For hospitals and nursing homes, personnel costs in relation to preparation and administration should be considered as well as purchasing costs.
Antibiotic Combination Therapy
Antimicrobial drugs are often used in combination. Indications for combination therapy may include:
• Infections caused by multiple microorganisms (eg, abdominal and pelvic infections)
• Nosocomial infections, which may be caused by many different organisms
• Serious infections in which a combination is synergistic (eg, an aminoglycoside and an antipseudomonal penicillin for pseudomonal infections)
• Likely emergence of drug-resistant organisms if a single drug is used (eg, tuberculosis). Although drug combinations to prevent resistance are widely used, the only clearly effective use is for treatment of tuberculosis.
• Fever or other signs of infection in clients whose immune systems are suppressed. Combinations of antibacterial plus antiviral and/or antifungal drugs may be needed.
Dosage
Dosage (amount and frequency of administration) should be individualized according to characteristics of the causative organism, the chosen drug, and the client’s size and condition (eg, type and severity of infection, ability to use and excrete the chosen drug). For example, dosage may need to be increased for more resistant organisms such as Pseudomonas and for infections in which antibiotics have difficulty penetrating to the site of infection (eg, meningitis). Dosage often must be reduced if the client has renal impairment or other disorders that delay drug elimination.
Route of Administration
Most antimicrobial drugs are given orally or IV for systemic infections. The route of administration depends on the client’s condition (eg, location and severity of the infection, ability to take oral drugs) and the available drug dosage forms. In serious infections, the IV route is preferred for most drugs.
Duration of Therapy
Duration of therapy varies from a single dose to years, depending on the reason for use. For most acute infections, the average duration is approximately 7 to 10 days or until the recipient has been afebrile and asymptomatic for 48 to 72 hours.
Beta-Lactam Antibacterials
Beta-lactam antibacterials derive their name from the betalactam ring that is part of their chemical structure. An intact beta-lactam ring is essential for antibacterial activity. Several gram-positive and gram-negative bacteria produce betalactamase enzymes that disrupt the beta-lactam ring and inactivate the drugs. This is a major mechanism by which microorganisms acquire resistance to beta-lactam antibiotics.
Penicillinase and cephalosporinase are beta-lactamase enzymes that act on penicillins and cephalosporins, respectively. Despite the common element of a beta-lactam ring, characteristics of beta-lactam antibiotics differ widely because of variations in their chemical structures. The drugs may differ in antimicrobial spectrum of activity, routes of administration, susceptibility to beta-lactamase enzymes, and adverse effects. Beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams.
Beta-lactam antibacterial drugs inhibit synthesis of bacterial cell walls by binding to proteins (penicillin-binding proteins) in bacterial cell membranes. This binding produces a defective cell wall that allows intracellular contents to leak out, destroying the microorganism. In sub-bactericidal concentrations, the drugs may inhibit growth, decrease viability, and alter the shape and structure of organisms. The latter characteristic may help to explain the development of mutant strains of microorganisms exposed to the drugs. Betalactam antibiotics are most effective when bacterial cells are dividing.
The penicillins are effective, safe, and widely used antimicrobial agents. The group includes natural extracts from the Penicillium mold and several semisynthetic derivatives.
When penicillin G, the prototype, was introduced, it was effective against streptococci, staphylococci, gonococci, meningococci, Treponema pallidum, and other organisms. It had to be given parenterally because it was destroyed by gastric acid, and injections were painful. With extensive use, strains of drug-resistant staphylococci appeared. Later penicillins were developed to increase gastric acid stability, betalactamase stability, and antimicrobial spectrum of activity, especially against gram-negative microorganisms. Semisynthetic derivatives are formed by adding side chains to the penicillin nucleus.
After absorption, penicillins are widely distributed and achieve therapeutic concentrations in most body fluids, including joint, pleural, and pericardial fluids and bile. Therapeutic levels are not usually obtained in intraocular and cerebrospinal fluids (CSF) unless inflammation is present because normal cell membranes act as barriers to drug penetration.
Penicillins are rapidly excreted by the kidneys and produce high drug concentrations in the urine (an exception is nafcillin, which is excreted by the liver). The most serious, and potentially fatal, adverse effect of the penicillins is hypersensitivity. Seizures, interstitial nephritis, and nephropathy may also occur.
Indications for Use
Clinical indications for use of penicillins include bacterial infections caused by susceptible microorganisms. As a class, penicillins usually are more effective in infections caused by gram-positive bacteria than those caused by gram-negative bacteria. However, their clinical uses vary significantly according to the subgroup or individual drug and microbial patterns of resistance. The drugs are often useful in skin/ soft tissue, respiratory, gastrointestinal, and genitourinary infections. However, the incidence of resistance among streptococci, staphylococci, and other microorganisms continues to grow.
Contraindications to Use
Contraindications include hypersensitivity or allergic reactions to any penicillin preparation. An allergic reaction to one penicillin means the client is allergic to all members of the penicillin class. The potential for cross-allergenicity with cephalosporins and carbapenems exists, so other alternatives should be selected in pencillin-allergic clients when possible.
Penicillinase-Resistant (Antistaphylococcal)Penicillins
This group includes four drugs (cloxacillin, dicloxacillin, nafcillin, and oxacillin) that are effective in some infections caused by staphylococci resistant to penicillin G. An older member of this group, methicillin, is no longer marketed for clinical use. However, susceptibility of bacteria to the antistaphylococcal penicillins is determined by exposing the bacteria to methicillin (methicillin-susceptible or -resistant) or oxacillin (oxacillinsusceptible or -resistant) in bacteriology laboratories. These drugs are formulated to resist the penicillinases that inactivate other penicillins. They are recommended for use in known or suspected staphylococcal infections, except for methicillin-resistant Staphylococcus aureus (MRSA) infections. Although called “methicillin-resistant,” these staphylococcal microorganisms are also resistant to other antistaphylococcal penicillins.
Aminopenicillins
Ampicillin is a broad-spectrum, semisynthetic penicillin that is bactericidal for several types of gram-positive and gramnegative bacteria. It has been effective against enterococci, Proteus mirabilis, Salmonella, Shigella, and Escherichia coli, but resistant forms of these organisms are increasing. It is ineffective against penicillinase-producing staphylococci and gonococci. Ampicillin is excreted mainly by the kidneys; thus, it is useful in urinary tract infections (UTI). Because some is excreted in bile, it is useful in biliary tract infections not caused by biliary obstruction. It is used in the treatment of bronchitis, sinusitis, and otitis media.
Extended-Spectrum (Antipseudomonal) Penicillins
The drugs in this group (carbenicillin, ticarcillin, mezlocillin, and piperacillin) have a broad spectrum of antimicrobial activity, especially against gram-negative organisms such as Pseudomonas and Proteus species and E. coli. For pseudomonal infections, one of these drugs is usually given concomitantly with an aminoglycoside or a fluoroquinolone. Carbenicillin is available as an oral formulation for UTI or prostatitis caused by susceptible pathogens. The other drugs are usually given by intermittent IV infusion, although most can be given IM.
Cephalosporins are a widely used group of drugs that are derived from a fungus. Although technically cefoxitin and cefotetan (cephamycins derived from a different fungus) and loracarbef (a carbacephem) are not cephalosporins, they are categorized with the cephalosporins because of their similarities to the group. Cephalosporins are broad-spectrum agents with activity against both gram-positive and gram-negative bacteria. Compared with penicillins, they are in general less active against gram-positive organisms but more active against gram-negative ones. Once absorbed, cephalosporins are widely distributed into most body fluids and tissues, with maximum concentrations in the liver and kidneys. Many cephalosporins do not reach therapeutic levels in CSF; exceptions are cefuroxime, a secondgeneration drug, and the third-generation agents. These drugs reach therapeutic levels when meninges are inflamed. Most cephalosporins are excreted through the kidneys. Exceptions include cefoperazone, which is excreted in bile, and ceftriaxone, which undergoes dual elimination via the biliary tract and kidneys. Cefotaxime is primarily metabolized in the liver to an active metabolite, desacetylcefotaxime, which is eliminated by the kidneys.
Clinical indications for the use of cephalosporins include surgical prophylaxis and treatment of infections of the respiratory tract, skin and soft tissues, bones and joints, urinary tract, brain and spinal cord, and bloodstream (septicemia). In most infections with streptococci and staphylococci, penicillins are more effective and less expensive. In infections caused by methicillin-resistant S. aureus, cephalosporins are not clinically effective even if in vitro testing indicates susceptibility. Infections caused by Neiserria gonorrhoeae, once susceptible to penicillin, are now preferentially treated with a third-generation cephalosporin such as ceftriaxone.
Cefepime is indicated for use in severe infections of the lower respiratory and urinary tracts, skin and soft tissue, female reproductive tract, and infebrile neutropenic clients. It may be used as monotherapy for all infections caused by susceptible organisms except P. aeruginosa; a combination of drugs should be used for serious pseudomonal infections.
A major contraindication to the use of a cephalosporin is a previous severe anaphylactic reaction to a penicillin. Because cephalosporins are chemically similar to penicillins, there is a risk of cross-sensitivity. However, incidence of cross-sensitivity is low, especially in clients who have had delayed reactions (eg, skin rash) to penicillins. Another contraindication is cephalosporin allergy. Immediate allergic reactions with anaphylaxis, bronchospasm, and urticaria occur less often than delayed reactions with skin rash, drug fever, and eosinophilia.
Carbapenems are broad-spectrum, bactericidal, beta-lactam antimicrobials. Like other beta-lactam drugs, they inhibit synthesis of bacterial cell walls by binding with penicillinbinding proteins. The group consists of three drugs.
Imipenem/cilastatin (Primaxin) is given parenterally and distributed in most body fluids. Imipenem is rapidly broken down by an enzyme (dehydropeptidase) in renal tubules and therefore reaches only low concentrations in urine. Cilastatin was synthesized to inhibit the enzyme and reduce potential renal toxicity of the antibacterial agent. Recommended doses indicate the amount of imipenem; the solution contains an equivalent amount of cilastatin.
The drug is effective in infections caused by a wide range of bacteria, including penicillinase-producing staphylococci, E. coli, Proteus species, Enterobacter–Klebsiella–Serratia species, P. aeruginosa, and Enterococcus faecalis. Its main indication for use is treatment of infections caused by organisms resistant to other drugs. Adverse effects are similar to those of other beta-lactam antibiotics, including the risk of crosssensitivity in clients with penicillin hypersensitivity. Central nervous system toxicity, including seizures, has been reported. Seizures are more likely in clients with a seizure disorder or when recommended doses are exceeded; however, they have occurred in other clients as well. To prepare the solution for IM injection, lidocaine, a local anesthetic, is added to decrease pain. This solution is contraindicated in people allergic to this type of local anesthetic or who have severe shock or heart block.
Meropenem (Merrem) has a broad spectrum of antibacterial activity and may be used as a single drug for empiric therapy before causative microorganisms are identified. It is effective against penicillin-susceptible staphylococci and S. pneumoniae, most gram-negative aerobes (eg, E. coli, H. influenzae, Klebsiella pneumoniae, P. aeruginosa), and some anaerobes, including B. fragilis. It is indicated for use in intra-abdominal infections and bacterial meningitis caused by susceptible organisms. Compared with imipenem, meropenem costs more and seems to offer no clinical advantages. Adverse effects are similar to those of imipenem.
Ertapenem (Invanz) also has a broad spectrum of antibacterial activity, although more limited than imipenem and meropenem. It is approved for complicated intra-abdominal, skin and skin structure, acute pelvic, and urinary tract infections. It can be used to treat community-acquired pneumonia caused by penicillin-susceptible S. pneumoniae. Unlike imipenem and meropenem, ertapenem does not have in vitro activity against Pseudomonas aeruginosa and Acinetobacter baumannii.
Ertapenem shares the adverse effect profile of the other carbapenems. Lidocaine is also used in preparation of the solution for IM injection, and the same cautions should be used as with imipenem.
Aztreonam (Azactam) is active against gram-negative bacteria, including Enterobacteriaceae and P. aeruginosa, and many strains that are resistant to multiple antibiotics. Activity against gram-negative bacteria is similar to that of the aminoglycosides, but the drug does not cause kidney damage or hearing loss. Aztreonam is stable in the presence of beta-lactamase enzymes. Because gram-positive and anaerobic bacteria are resistant to aztreonam, the drug’s ability to preserve normal gram-positive and anaerobic flora may be an advantage over
most other antimicrobial agents.
Indications for use include infections of the urinary tract, lower respiratory tract, skin and skin structures, as well as intra-abdominal and gynecologic infections and septicemia. Adverse effects are similar to those for penicillin, including possible hypersensitivity reactions.
Drug Selection
Choice of a beta-lactam antibacterial depends on the organism causing the infection, severity of the infection, and other factors. With penicillins, penicillin G or amoxicillin is the drug of choice in many infections; an antipseudomonal penicillin is indicated in most Pseudomonas infections; and an antistaphylococcal penicillin is indicated in staphylococcal infections. Antistaphylococcal drugs of choice are nafcillin for IV use and dicloxacillin for oral use.
With cephalosporins, first-generation drugs are often used for surgical prophylaxis, especially with prosthetic implants, because gram-positive organisms such as staphylococci cause most post-implant infections. They may also be used alone for treatment of infections caused by susceptible organisms in body sites where drug penetration and host defenses are adequate.
Cefazolin (Kefzol) is a frequently used parenteral agent. It reaches a higher serum concentration, is more protein bound, and has a slower rate of elimination than other firstgeneration drugs. These factors prolong serum half-life, so cefazolin can be given less frequently. Cefazolin may also be administered IM.
Second-generation cephalosporins are also often used for surgical prophylaxis, especially for gynecologic and colorectal surgery. They are also used for treatment of intraabdominal infections such as pelvic inflammatory disease, diverticulitis, penetrating wounds of the abdomen, and other infections caused by organisms inhabiting pelvic and colorectal areas.
Third-generation cephalosporins are recommended for serious infections caused by susceptible organisms that are resistant to first- and second-generation cephalosporins. They are often used in the treatment of infections caused by E. coli, Proteus, Klebsiella, and Serratia species, and other Enterobacteriaceae, especially when the infections occur in body sites not readily reached by other drugs (eg, CSF, bone) and in clients with immunosuppression. Although effective against many Pseudomonas strains, these drugs should not be used alone in treating pseudomonal infections because drug resistance develops.
Fourth-generation drugs are most useful in serious gramnegative infections, especially infections caused by organisms resistant to third-generation drugs. Cefepime has the same indications for use as ceftazidime, a third-generation drug.
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome and inhibits the peptidyl transferase step of protein synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most gram-positive bacteria are inhibited at concentrations of 1-10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2-5 mcg/mL. H influenzae, N meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal.
Empiric Antimicrobial Therapy
Antimicrobial agents are frequently used before the pathogen responsible for a particular illness or the susceptibility to a particular antimicrobial agent is known. This use of antimicrobial agents is called empiric (or presumptive) therapy and is based on experience with a particular clinical entity. The usual justification for empiric therapy is the hope that early intervention will improve the outcome; in the best cases, this has been established by placebo-controlled, double-blind prospective clinical trials. For example, treatment of febrile episodes ieutropenic cancer patients with empiric antimicrobial therapy has been demonstrated to have impressive morbidity and mortality benefits even though the specific bacterial agent responsible for fever is determined for only a minority of such episodes. Finally, there are many clinical entities, such as certain episodes of community-acquired pneumonia, in which it is difficult to identify a specific pathogen. In such cases, a clinical response to empiric therapy may be an important clue to the likely pathogen.
Frequently, the signs and symptoms of infection diminish as a result of empiric therapy, and microbiologic test results become available that establish a specific microbiologic diagnosis. At the time that the pathogenic organism responsible for the illness is identified, empiric therapy is optimally modified to definitive therapy, which is typically narrower in coverage and is given for an appropriate duration based on the results of clinical trials or experience when clinical trial data is not available.
Initiation of empiric therapy should follow a specific and systematic approach.
Formulate a Clinical Diagnosis of Microbial Infection
Using all available data, the clinician should determine that there is anatomic evidence of infection (eg, pneumonia, cellulitis, sinusitis).
Obtain Specimens for Laboratory Examination
Examination of stained specimens by microscopy or simple examination of an uncentrifuged sample of urine for white blood cells and bacteria may provide important etiologic clues in a very short time. Cultures of selected anatomic sites (blood, sputum, urine, cerebrospinal fluid, and stool) and nonculture methods (antigen testing, polymerase chain reaction, and serology) may also confirm specific etiologic agents.
Formulate a Microbiologic Diagnosis
The history, physical examination, and immediately available laboratory results (eg, Gram stain of urine or sputum) may provide highly specific information. For example, in a young man with urethritis and a Gram-stained smear from the urethral meatus demonstrating intracellular gram-negative diplococci, the most likely pathogen is Neisseria gonorrhoeae. In the latter instance, however, the clinician should be aware that a significant number of patients with gonococcal urethritis have uninformative Gram stains for the organism and that a significant number of patients with gonococcal urethritis harbor concurrent chlamydial infection that is not demonstrated on the Gram-stained smear.
Determine the Necessity for Empiric Therapy
Whether or not to initiate empiric therapy is an important clinical decision based partly on experience and partly on data from clinical trials. Empiric therapy is indicated when there is a significant risk of serious morbidity if therapy is withheld until a specific pathogen is detected by the clinical laboratory. In other settings, empiric therapy may be indicated for public health reasons rather than for demonstrated superior outcome of therapy in a specific patient. For example, urethritis in a young sexually active man usually requires treatment for N gonorrhoeae and Chlamydia trachomatis despite the absence of microbiologic confirmation at the time of diagnosis. Because the risk of noncompliance with follow-up visits in this patient population may lead to further transmission of these sexually transmitted pathogens, empiric therapy is warranted.
Selection of empiric therapy may be based on the microbiologic diagnosis or a clinical diagnosis without available microbiologic clues. If no microbiologic information is available, the antimicrobial spectrum of the agent or agents chosen must necessarily be broader, taking into account the most likely pathogens responsible for the patient’s illness.
Selection from among several drugs depends on host factors that include the following: (1) concomitant disease states (eg, AIDS, neutropenia due to the use of cytotoxic chemotherapy; severe chronic liver or kidney disease) or the use of immunosuppressive medications; (2) prior adverse drug effects; (3) impaired elimination or detoxification of the drug (may be genetically predetermined but more frequently is associated with impaired renal or hepatic function due to underlying disease); (4) age of the patient; (5) pregnancy status; and (6) epidemiologic exposure (eg, exposure to a sick family member or pet, recent hospitalization, recent travel, occupational exposure, or new sexual partner).
Pharmacologic factors include (1) the kinetics of absorption, distribution, and elimination; (2) the ability of the drug to be delivered to the site of infection; (3) the potential toxicity of an agent; and (4) pharmacokinetic or pharmacodynamic interactions with other drugs.
Knowledge of the susceptibility of an organism to a specific agent in a hospital or community setting is important in the selection of empiric therapy. Pharmacokinetic differences among agents with similar antimicrobial spectrums may be exploited to reduce the frequency of dosing (eg, ceftriaxone may be conveniently given once every 24 hours). Finally, increasing consideration is being given to the cost of antimicrobial therapy, especially when multiple agents with comparable efficacy and toxicity are available for a specific infection. Changing from intravenous to oral antibiotics for prolonged administration can be particularly cost-effective.
