Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

1Trimethoprim-sulfamethoxazole (TMP-SMZ) is a mixture of one part trimethoprim plus five parts sulfamethoxazole.

2Quinolones are not recommended for empiric therapy of gonococcal infections acquired in Southeast Asia, Hawaii, and the Pacific Coast of the United States. Azithromycin 2 g is an alternative agent for the treatment of gonococcal urethritis and cervicitis.

3First-generation cephalosporins: Cephalothin, cephapirin, or cefazolin for parenteral administration; cephalexin or cephradine for oral administration. Second-generation cephalosporins: Cefuroxime, cefamandole, cefonicid for parenteral administration; cefaclor, cefuroxime axetil, cefprozil, ceftibuten for oral administration. Third-generation cephalosporins: Cefoperazone, cefotaxime, ceftizoxime, ceftriaxone for parenteral administration; cefixime, cefpodoxime for oral administration.

4Antipseudomonal penicillin: Carbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin.

5Generally, streptomycin and gentamicin are used to treat infections with gram-positive organisms, whereas gentamicin, tobramycin, and amikacin are used to treat infections with gram-negatives.

6See footnote 3 in Table 51–2 for guidelines on the treatment of penicillin-resistant pneumococcal meningitis.

7Parenteral nafcillin, oxacillin; or methicillin; oral dicloxacillin, cloxacillin, or oxacillin.

8There is no regimen that is reliably bactericidal for vancomycin-resistant enterococcus. Regimens that have been reported to be efficacious include single-drug therapy with chloramphenicol, tetracycline, nitrofurantoin (for urinary tract infection); potential regimens for bacteremia include ampicillin + vancomycin and ampicillin + ciprofloxacin + gentamicin.

9Ketoconazole does not penetrate the central nervous system and is unsatisfactory for meningitis.

Table 51–2. Empiric Antimicrobial Therapy Based on Site of Infection.

1See footnote 7, Table 51–1.

2See footnote 3, Table 51–1.

3When meningitis with penicillin-resistant pneumococcus is suspected, empiric therapy with this regimen is recommended.

4Erythromycin, clarithromycin, or azithromycin (an azalide) may be used.

Katzung PHARMACOLOGY, 9e > Section VIII. Chemotherapeutic Drugs > Chapter 51. Clinical Use of Antimicrobial Agents >

Antimicrobial Therapy of Infections with Known Etiology

Interpretation of Culture Results

Properly obtained and processed specimens for culture frequently yield reliable information about the cause of infection. The lack of a confirmatory microbiologic diagnosis may be due to the following:

(1)Sample error, eg, obtaining cultures after antimicrobial agents have been administered.

(2)Noncultivable or slow-growing organisms, (Histoplasma capsulatum, bartonella species), where cultures are often discarded before sufficient growth has occurred for detection.

(3)Requesting bacterial cultures when infection is due to other organisms.

(4)Not recognizing the need for special media or isolation techniques (eg, charcoal yeast extract agar for isolation of legionella species, shell-vial tissue culture system for rapid isolation of CMV).

Even in the setting of a classic infectious disease for which isolation techniques have been established for decades (eg, pneumococcal pneumonia, pulmonary tuberculosis, streptococcal pharyngitis), the sensitivity of the culture technique may be inadequate to identify all cases of the disease.

Guiding Antimicrobial Therapy of Established Infections

Susceptibility Testing

Testing bacterial pathogens in vitro for their susceptibility to antimicrobial agents is extremely valuable in confirming susceptibility, ideally to a narrow-spectrum nontoxic antimicrobial drug. Tests measure the concentration of drug required to inhibit growth of the organism (minimal inhibitory concentration [MIC]) or to kill the organism (minimal bactericidal concentration [MBC]). The results of these tests can then be correlated with known drug concentrations in various body compartments. Only MICs are routinely measured in most infections, whereas in infections in which bactericidal therapy is required for eradication of infection (eg, meningitis, endocarditis, sepsis in the granulocytopenic host), MBC measurements occasionally may be useful.

Specialized Assay Methods

Beta-Lactamase Assay

For some bacteria (eg, haemophilus species), the susceptibility patterns of strains are similar except for the production of lactamase. In these cases, extensive susceptibility testing may not be required and a direct test for -lactamase utilizing a chromogenic -lactam substrate (nitrocephin disk) may be substituted.

Synergy Studies

These in vitro tests attempt to measure synergistic, additive, indifferent, or antagonistic drug interactions. In general, these tests have not been standardized and have not correlated well with clinical outcome. (See section on combination chemotherapy for details.)

Monitoring Therapeutic Response: Duration of Therapy

The therapeutic response may be monitored microbiologically or clinically. Cultures of specimens

taken from infected sites should eventually become sterile or demonstrate eradication of the pathogen and are useful for documenting recurrence or relapse. Follow-up cultures may also be useful for detecting superinfections or the development of resistance. Clinically, the patient's systemic manifestations of infection (malaise, fever, leukocytosis) should abate and the clinical findings should improve (eg, as shown by clearing of radiographic infiltrates or lessening hypoxemia in pneumonia).

The duration of therapy required for cure depends on the pathogen, the site of infection, and host factors (immunocompromised patients generally require longer courses of treatment). Precise data on duration of therapy exist for some infections (eg, streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, cryptococcal meningitis in non-AIDS patients). In many other situations, duration of therapy is determined empirically. For serious infections, continuing therapy for 7–10 days after the patient has become afebrile is a good rule of thumb. For recurrent infections (eg, sinusitis, urinary tract infections), longer courses of antimicrobial therapy are frequently necessary for eradication.

Clinical Failure of Antimicrobial Therapy

When the patient has an inadequate clinical or microbiologic response to antimicrobial therapy selected by in vitro susceptibility testing, systematic investigation should be undertaken to determine the cause of failure. Errors in susceptibility testing are rare, but the original results should be confirmed by repeat testing. Drug dosing and absorption should be scrutinized and tested directly using serum measurements, pill counting, or directly observed therapy.

The clinical data should be reviewed to determine whether the patient's immune function is adequate and, if not, what can be done to maximize it. For example, are adequate numbers of granulocytes present and are HIV infection, malnutrition, or underlying malignancy present? The presence of abscesses or foreign bodies should also be considered. Lastly, culture and susceptibility testing should be repeated to determine if superinfection has occurred with another organism or if the original pathogen has developed drug resistance.

Antimicrobial Pharmacodynamics

The time course of drug concentration is closely related to the antimicrobial effect at the site of infection and to any toxic effects. Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, and drug synergism, antagonism, and postantibiotic effects. Together with pharmacokinetics, pharmacodynamic information permits the selection of optimal antimicrobial dosage regimens.

Bacteriostatic Versus Bactericidal Activity

Antibacterial agents may be classified as bacteriostatic or bactericidal (Table 51–3). For agents that are primarily bacteriostatic, inhibitory drug concentrations are much lower than bactericidal drug concentrations. In general, cell wall-active agents are bactericidal, and drugs that inhibit protein synthesis are bacteriostatic.

Table 51–3. Bacteriostatic and Bactericidalantibacterial Agents.

Bactericidal agents

Aminoglycosides

Bacitracin

Beta-lactam antibiotics

Isoniazid

Metronidazole

Polymyxins

Pyrazinamide

Quinolones

Quinupristin-dalfopristin

Rifampin

Vancomycin

Bacteriostatic agents

Chloramphenicol

Clindamycin

Ethambutol

Macrolides

Nitrofurantoin

Novobiocin

Oxazolidinones

Sulfonamides

Tetracyclines

Trimethoprim

The classification of antibacterial agents as bactericidal or bacteriostatic has limitations. Some agents that are considered to be bacteriostatic may be bactericidal against selected organisms. On the other hand, enterococci are inhibited but not killed by vancomycin, penicillin, or ampicillin used as single agents.

Bacteriostatic and bactericidal agents are equivalent for the treatment of most infectious diseases in immunocompetent hosts. Bactericidal agents should be selected over bacteriostatic ones in circumstances in which local or systemic host defenses are impaired. Bactericidal agents are required for treatment of endocarditis and other endovascular infections, meningitis, and infections in neutropenic cancer patients.

Bactericidal agents can be divided into two groups: agents that exhibit concentration-dependent killing (eg, aminoglycosides and quinolones) and agents that exhibit time-dependent killing (eg, -lactams and vancomycin). For drugs whose killing action is concentration-dependent, the rate and extent of killing increase with increasing drug concentrations. Concentration-dependent killing is one of the pharmacodynamic factors responsible for the efficacy of once-daily dosing of aminoglycosides.

For drugs whose killing action is time-dependent, bactericidal activity continues as long as serum concentrations are greater than the MBC. Drug concentrations of time-dependent killing agents that

lack a postantibiotic effect should be maintained above the MIC for the entire interval between doses.

Postantibiotic Effect

Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent is known as the postantibiotic effect (PAE). The PAE can be expressed mathematically as follows:

where T is the time required for the viable count in the test (in vitro) culture to increase tenfold above the count observed immediately before drug removal and C is the time required for the count in an untreated culture to increase tenfold above the count observed immediately after completion of the same procedure used on the test culture. The PAE reflects the time required for bacteria to return to logarithmic growth.

Proposed mechanisms include (1) recovery after reversible nonlethal damage to cell structures; (2) persistence of the drug at a binding site or within the periplasmic space; and (3) the need to synthesize new enzymes before growth can resume. Most antimicrobials possess significant in vitro PAEs ( 1.5 hours) against susceptible gram-positive cocci (Table 51–4). Antimicrobials with significant PAEs against susceptible gram-negative bacilli are limited to carbapenems and agents that inhibit protein or DNA synthesis.

Table 51–4. Antibacterial Agents with In Vitro Postantibiotic Effects 1.5 Hours.

Against gram-positive cocci

Aminoglycosides

Carbapenems

Cephalosporins

Chloramphenicol

Clindamycin

Macrolides

Oxazolidinones

Penicillins

Quinolones

Quinupristin-dalfopristin

Rifampin

Sulfonamides

Tetracyclines

Trimethoprim

Vancomycin

Against gram-negative bacilli

Aminoglycosides

Carbapenems

Chloramphenicol

Quinolones

Rifampin

Tetracyclines

In vivo PAEs are usually much longer than in vitro PAEs. This is thought to be due to postantibiotic leukocyte enhancement (PALE) and exposure of bacteria to subinhibitory antibiotic concentrations. The efficacy of once-daily dosing regimens is in part due to the PAE. Aminoglycosides and quinolones possess concentration-dependent PAEs; thus, high doses of aminoglycosides given once daily result in enhanced bactericidal activity and extended PAEs. This combination of pharmacodynamic effects allows aminoglycoside serum concentrations that are below the MICs of target organisms to remain effective for extended periods of time.

Pharmacokinetic Considerations

Route of Administration

Many antimicrobial agents have similar pharmacokinetic properties when given orally or parenterally (ie, tetracyclines, trimethoprim-sulfamethoxazole, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, and fluconazole). In most cases, oral therapy with these drugs is equally effective, less costly, and results in fewer complications than parenteral therapy.

The intravenous route is preferred in the following situations: (1) for critically ill patients; (2) for patients with bacterial meningitis or endocarditis; (3) for patients with nausea, vomiting, gastrectomy, or diseases that may impair oral absorption; and (4) when giving antimicrobials that are poorly absorbed following oral administration.

Conditions That Alter Antimicrobial Pharmacokinetics

Various diseases and physiologic states alter the pharmacokinetics of antimicrobial agents. Impairment of renal or hepatic function may result in decreased elimination. Table 51–5 lists drugs that require dosage reduction in patients with renal or hepatic insufficiency. Failure to reduce antimicrobial agent dosage in such patients may cause toxic side effects. Conversely, patients with burns, cystic fibrosis, or trauma may have increased dosage requirements for selected agents. The pharmacokinetics of antimicrobials are also altered in the elderly, in neonates, and in pregnancy.

Table 51–5. Antimicrobial Agents That Require Dosage Adjustment or Are Contraindicated in Patients with Renal or Hepatic Impairment.