Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 7)

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Distribution To be effective, concentrations of an antibacterial agent must exceed the pathogen's MIC. Serum antibiotic concentrations usually exceed the MIC for susceptible bacteria, but since most infections are extravascular, the antibiotic must also distribute to the site of the infection. Concentrations of most antibacterial agents in interstitial fluid are similar to free-drug concentrations in serum. However, when the infection is located in a "protected" site where penetration is poor, such as cerebrospinal fluid (CSF), the eye, the prostate, or infected cardiac vegetations, high parenteral doses or local administration for prolonged periods may be required for cure. ...

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Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 7) Distribution To be effective, concentrations of an antibacterial agent must exceed the pathogen's MIC. Serum antibiotic concentrations usually exceed the MIC for susceptible bacteria, but since most infections are extravascular, the antibiotic must also distribute to the site of the infection. Concentrations of most antibacterial agents in interstitial fluid are similar to free-drug concentrations in serum. However, when the infection is located in a "protected" site where penetration is poor, such as cerebrospinal fluid (CSF), the eye, the prostate, or infected cardiac vegetations, high parenteral doses or local administration for prolonged periods may be required for cure. In addition, even though an antibacterial agent may penetrate to the site of infection, its activity may be antagonized by factors in the local environment, such as an unfavorable pH or
inactivation by cellular degradation products. For example, since the activity of aminoglycosides is reduced at acidic pH, the acidic environment in many infected tissues may be partly responsible for the relatively poor efficacy of aminoglycoside monotherapy. In addition, the abscess milieu reduces the penetration and local activity of many antibacterial compounds, so that surgical drainage may be required for cure. Most bacteria that cause human infections are located extracellularly. Intracellular pathogens such as Legionella, Chlamydia, Brucella, and Salmonella may persist or cause relapse if the antibacterial agent does not enter the cell. In general, β-lactams, vancomycin, and aminoglycosides penetrate cells poorly, whereas macrolides, ketolides, tetracyclines, metronidazole, chloramphenicol, rifampin, TMP-SMX, and quinolones penetrate cells well. Metabolism and Elimination Like other drugs, antibacterial agents are disposed of by hepatic elimination (metabolism or biliary elimination), by renal excretion of the unchanged or metabolized form, or by a combination of the two processes. For most of the antibacterial drugs, metabolism leads to loss of in vitro activity, although some agents, such as cefotaxime, rifampin, and clarithromycin, have bioactive metabolites that may contribute to their overall efficacy.
The most practical application of information on the mode of excretion of an antibacterial agent is in adjusting dosage when elimination capability is impaired (Table 127-3). Direct, nonidiosyncratic toxicity from antibacterial drugs may result from failure to reduce the dosage given to patients with impaired elimination. For agents that are primarily cleared intact by glomerular filtration, drug clearance is correlated with creatinine clearance, and estimates of the latter can be used to guide dosage. For drugs whose elimination is primarily hepatic, no simple marker is useful for dosage adjustment in patients with liver disease. However, in patients with severe hepatic disease, residual metabolic capability is usually sufficient to preclude accumulation and toxic effects. Table 127-3 Antibacterial Drug Dose Adjustments in Patients with Renal Impairment Antibiotic Major Route of Dosage Excretion Adjustment with Renal Impairment Aminoglycosides Renal Yes Azithromycin Biliary No
Cefazolin Renal Yes Cefepime Renal Yes Ceftazidime Renal Yes Ceftriaxone Renal/biliary Modest reduction in severe renal impairment Ciprofloxacin Renal/biliary Only in severe renal insufficiency Clarithromycin Renal/biliary Only in severe renal insufficiency Daptomycin Renal Yes Erythromycin Biliary Only when given in high IV doses
Levofloxacin Renal Yes Linezolid Metabolism No Metronidazole Biliary No Nafcillin Biliary No Penicillin G Renal Yes (when given in high IV doses) Piperacillin Renal Only with Clcr of
TMP-SMX Renal/biliary Only in severe renal insufficiency Vancomycin Renal Yes Abbreviations: Clcr, creatinine clearance rate; TMP-SMX, trimethoprim- sulfamethoxazole.