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Host Factors Influencing the Response to Antimicrobial Agents
Symposium on Anti-Infective Therapy
Host Factors Influencing the Response to Antimicrobial Agents Richard D. Leff, Pharm.D.,* and Robert]. Roberts, M.D., Ph.D.t
The initial selection of an antibiotic for use in the pediatric patient, whether for acute, chronic, or preventive therapy, is primarily based on knowledge of the suspected or proven infecting pathogen and sensitivity of this organism to the antimicrobial agent. The subsequent decisions focus on determining the appropriate dosage and dosing interval, which is typically accomplished simply on the basis of the patient's weight, surface area, or age. The goal of the antibiotic dosage regimen is to achieve target concentrations of drug in the serum that have demonstrated a favorable clinical response while avoiding drug toxicity. Unfortunately, there are many factors that may influence whether the desired target concentrations of antibiotic in serum and the achievement of the desired clinical response is realized. The purpose of this article is to review host factors that may alter antibiotic disposition and/or clinical response, omitting those obvious causes, such as primary failure of the cardiovascular system or renal system, that have been the subject of numerous articles and reviews. 3 · 17• 18 The host factors have been divided into two general categories for discussion purposes, the noninfectious and infection-related host factors.
NONINFECTIOUS HOST FACTORS Route of Administration Once an antibiotic has been administered by the oral, intramuscular, or intravenous route, the nurse, pharmacist, and physician have often assumed that the patient has received the drug in a reliable and optimal fashion, especially when administration is by the intravenous route. How-
*Assistant Professor, Division of Clinical/Hospital Pharmacy, College of Pharmacy, University of Iowa, Iowa City, Iowa tProfessor, Divisions of Clinical Pharmacology and Neonatology, Departments of Pharmacology and Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
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ever, there are situations in which the method or route of drug administration results in delay in the onset or prolongation of the rate of drug delivery, incomplete drug delivery (bioavailability), or complete omission or loss of the drug dose. Oral Administration. Absorption of drugs from the gastrointestinal tract depends on many host factors, such as intestinal pH, gastric emptying and transit time, available intestinal surface area, gastrointestinal disease, and the presence of food or of other drugs. 33 Several disease states affecting these factors have been associated with altered antibiotic absorption. In cystic fibrosis, the oral absorption of cephalexin has been reported to be reduced. 12 The exact mechanism for the decreased absorption is not known. Celiac disease has shown a variable response with increased absorption of sulfamethoxazole, trimethoprim, and cephalexin, and decreased absorption of pivampicillin. 33• 34 Other penicillin esters (prodrugs) similar to pivampicillin, such as hetacillin or bacampicillin, may conceivably have decreased absorption. It has been suggested that this occurs as a result of an esterase deficiency in the lumen of the intestine necessary for the conversion of the prodrug to the active agent. 34 Other disease states associated with diarrhea (for example, acute bacillary disease) have been reported to have altered absorption of ampicillin and nalidixic acid, 32 which is likely because of a decreased intestinal transit time. Observation of patients with Crohn' s disease revealed a decrease in absorption of lincomycin, sulfamethoxazole, and trimethoprim. 35• 36 This impaired drug absorption may occur as a result of thickening of the bowel wall. As described, the majority of diseases affecting gastrointestinal absorption result in a reduction of the amount of antibiotic absorbed. The influence of food on the gastrointestinal absorption of drugs has been extensively reviewed. 30• 52• 53 As expected, there is a variable response on bioavailability. McCracken et al. have investigated the effect of feeding on bioavailability of selected antibiotics in infants and children. 29 As in adult studies, cephalexin, penicillin V, and penicillin G bioavailabilities (area-under-the-curves) were reduced when administered with food. On the other hand, the absorption of erythromycin ethylsuccinate was enhanced when given with meals. Therefore, the most effective utilization of oral antibiotics depends on knowing which drugs are best absorbed in the presence or in the absence of food (Table 1). Intramuscular Administration. Absorption of drugs from the intramuscular route depends on a number of physical and physiological factors. One well-recognized contributing factor is the status of vascular perfusion at the absorption site. 28 Under the clinical circumstances of shock or heart failure, perfusion of the injection site may be significantly decreased, resulting in prolongation of the rate of absorption. Prolonged or delayed rate of absorption will generally be associated with lower blood levels of drug. Recently, Pfeffer and Van Harken have shown that the administration of differing dosage volumes of aminoglycosides will alter the rate of intramuscular absorption. 39 This is attributed to the administration of various required doses (mg/kg) or drug dilutions (mg/ml) to the patient. This phenomenon may explain, in part, intrapatient and interpatient variation
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Table l.
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Influence of Food and Diet on Gastrointestinal Drug Absorption*
Decreased Bioavailability Ampicillin Cephradine Cephalexin Dicloxacillin Erythromycin Isoniazid Oxacillin Oxytetracycline Penicillin G Penicillin V Pivampicillin Rifampin Sulfisoxazole Tetracycline
Increased Bioavailability Erythromycin stearate Erythromycin ethyl succinate Griseofulvin Hetacillin Nitrofurantoin Unchanged Bioavailability Amoxicillin Erythromycin estolate Metronidazole
*Adapted from Welling, P. G.: Influence of food and drug on gastrointestinal drug absorption: A review. J. Pharmacokinet. Biopharm., 5:291-334, 1977.
reported in the literature of the rate of intramuscular drug absorption for the same or different drugs. Intravenous Administration. The administration of antibiotics by the intravenous route has been considered to be the most reliable route of delivery. Recently, some of the factors affecting the rate and completeness of this route of delivery have been identified. 11 · 24 The intravenous fluid flow rate and antibiotic dosing volume as required by the patient are two important considerations that may result in the drug being delivered either faster or slower than desired. As a result, peak drug levels may be sufficiently high to result in an increased risk of dose-dependent toxicity, or unexpectedly low with a reduced likelihood of the antibiotic concentration exceeding the sensitivity of the infecting organism. Pre-Existing Disease Drug disposition (absorption, metabolism, distribution, and excretion) is essentially dependent upon the normal physiologic and biochemical processes operating in the body to maintain homeostasis. Diseases such as those presented below can impose alterations of the normal physiologic and biochemical processes of the body, leading to alterations in drug disposition and/or pharmacologic effect. Endocrine Disorders. Thyroid dysfunction can result in a change in several physiologic events, including intestinal transit time, hepatic microsomal enzyme activity, cardiac output, renal plasma flow, and hepatic blood flow. 49 For those antibiotics metabolized by the liver, a hyperthyroid state can lead to a reduction of the serum drug concentration as a result of increased hepatic metabolism and renal clearance. The hypothyroid state would have the opposite effect. The influence of the thyroid on hepatic drug metabolism has been clearly shown for antipyrine, a drug used as an index of microsomal enzyme function. 10• 49 However, there is an unfortunate void in the literature regarding the effect of thyroid dysfunction on
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the metabolism of antibiotics. It is conceivable that antibiotics that are metabolized, such as chloramphenicol or clindamycin, will be vulnerable to changes in drug disposition based on altered thyroid function. Children with growth hormone deficiency have been shown to have variable antipyrine metabolism. 41 Therefore, it may be necessary to anticipate modification of antibiotic dosage in these children. Hepatic Disease. The influence of liver disease on drug disposition is quite variable. 43 This may be due, in part, to the diversity of hepatic disease etiologies and lack of ability to quantitate the severity of liver parenchymal compromise. To date, only minor alterations in antibiotic disposition have been observed in patients with liver dysfunction with the possible exception of chloramphenicol. The fact that chloramphenicol plasma clearance is closely linked to its being metabolized by the liver makes it difficult for the clinician to maintain the rather narrow therapeutic blood level range in patients with liver disease. A doubling of the half-life of elimination has been observed in some patients with cirrhosis. 2 • 7 As a result, dosage modification based on monitoring of serum levels may be necessary when chloramphenicol is used in patients with hepatic failure. Hepatic metabolism plays a significant role in the disposition of nafcillin, clindamycin, and other antibiotics. Patients with cirrhosis and biliary obstruction have shown a moderate prolongation of half-life for nafcillin (1.4 versus 1.0 hours) and clindamycin (4.4 versus 3.4 hours) when compared with normal. 1· 7 · 27 Similarly, increases in half-lives of isoniazid, rifampin, and trimethoprim have been observed in patients with hepatic dysfunction (acute-chronic liver disease, cirrhosis, and severe decompensated liver damage). 7 Sulfamethoxazole, on the other hand, had no distinguishable alteration in half-life. 7 Penicillins are principally eliminated by the renal route and are not metabolized. Nevertheless, severe liver disease prolongs to a small extent the elimination of carbenicillin and ampicillin when compared with normal.25, 43 However, modification of the dose is not required without concomitant renal impairment. In summary, most antibiotic regimens do not require changes in dosage in patients with hepatic compromise, but some definitely do require drug blood level monitoring. Pulmonary Disease. Antibiotic drug disposition has been shown to be altered in patients with respiratory disease. 9 In newborns with respiratory distress syndrome, inulin and para-aminohippurate clearance is reported to be significantly depressed.l 5 Subsequently, aminoglycosides that are eliminated via renal glomerular filtration have prolonged half-lives in hypoxic newborns irrespective of gestational age. 31 This necessitates close monitoring of serum aminoglycoside levels in neonates with compromised respiratory status. On the other hand, patients with cystic fibrosis have shown an enhanced renal excretion of dicloxacillin and methicillin. The authors recommend an increase in dosage requirements (= 25 per cent for methicillin and 200 per cent for dicloxacillin). 19· 54 Increases in aminoglycoside dosage requirements have also been suggested in this population. 16· 23 Whether
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such increases in dosage improve the clinical outcome without increasing the risk of toxicity needs to be evaluated. 23 Malignancy. Pediatric patients with malignancy have an aminoglycoside half-life comparable to that of the patient with cystic fibrosis (1.24 hours). 6 Individualized drug dosages calculated on the basis of this apparently shortened half-life result in the administration of an increased total dose. Again, the efficacy and toxicity of these aminoglycoside regimens need to be further evaluated. 23 Thermal Injury. Antibiotics may have enhanced elimination in patients with major burns. 46 This has been mainly attributed to an increased glomerular filtration rate, although some investigators have suggested that percutaneous elimination across damaged skin occurs and accounts for the increased elimination. 26 • 46 Regardless of the mechanism, monitoring aminoglycoside blood levels has revealed the necessity to increase dosages of the aminoglycoside antibiotics in the burned patient to maintain target serum drug levels. 47 Other Noninfectious Factors An assortment of other noninfectious host factors has been associated with changes in antibiotic disposition. In the majority of instances, however, the mechanism of such changes is unknown. As an example, the disposition of antibiotics in males versus females has been reviewed. Plasma rifampin levels are higher in the female than the male, and this may support a slight decrease (10 per cent) in dose. 14 A number of other differences in drug disposition have been reported in the female. Chloramphenicol and tetracycline plasma levels are higher; kanamycin and gentamicin plasma half-lives are shorter; procaine penicillin G is absorbed from the intramuscular site slower, achieving lower peak plasma levels; and the bioavailability of cephradine was reduced. 14 In comparisons between the ambulatory and supine patients, amoxicillin serum concentrations were found to be significantly higher in the ambulatory patient. 42 This difference was shown in the ambulatory patient to be secondary to a decrease in renal clearance. The time required to reach a peak concentration was shorter in the ambulatory patient, suggesting an increased absorption rate. Similarly, the absorption rate of cephradine was found to be enhanced in the standing and right recumbent positions. 44 These positions supposedly favor rapid gastric emptying. The significance of nonhepatic metabolism has been recently recognized for the intravenous formulation of chloramphenicol succinate. It appears that the rate of conversion in the blood of the succinate ester by nonspecific esterases to the active chloramphenicol base is quite variable.2o Therefore, lower than expected levels of chloramphenicol free base in blood may be observed despite an apparent appropriate dosage regimen. In contrast, cerebrospinal fluid levels of chloramphenicol free base were observed following intraventricular administration of the succinate ester. 45 The authors concluded that adequate esterase activity for the conversion of the ester to the active constituent is present in cerebrospinal fluid. Nevertheless, recognition of the variability of hydrolysis of the ester moiety has
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prompted recommendation of the use of orally administered chloramphenicol palmitate, which is reported to have equal if not greater bioavailability when compared with intravenously administered chloramphenicol succinate.2l Finally, pharmacologic activity of antimicrobial agents can be related to the amount of unbound drug at the site of infection. The extent of protein binding of a drug largely depends on the molecular characteristics of a drug and concentration of albumin in the blood. 8 Many disease states, such as malnutrition, nephrotic syndrome, or diseases of the liver, may cause a lowering of the serum protein concentration. 4 · 13 · 22 As a result, the amount of free drug may change and the clinician may observe an alteration in pharmacologic activity (efficacy or toxicity). This would be most significant for drugs that are highly protein bound (Table 2).
INFECTION-RELATED HOST FACTORS Neutropenia
Antibiotic therapy is particularly critical when the infectious process overwhelms the natural defense mechanisms of the host. This is commonly seen in neutropenic patients who have or develop bacteremia. One of the strongest prognosticators of the antimicrobial response in patients with neutropenia is the rise in the granulocyte count when the initial granulocyte count is less than 500 cells per f,Ll of blood. A small rise above the initial granulocyte count of greater than 100 cells per f,Ll of blood has been shown to significantly improve the clinical outcome in cancer patients receiving combination antibiotic therapy to treat their bacteremia. 48 Purulent Material
The formation of pus at the infection site has been shown to play a significant role in determining the activity of antibiotics. A marked reduction in the activity of gentamicin, colistin, and polymyxin B following the
Table 2. DRUG
Antibiotics Highly Protein Bound* PER CENT BOUND
Cefazolin Clindamycin Cloxacillin Die!oxacillin Doxycycline Nafcillin Oxacillin Penicillin V
86 94 94 94 85 87 93
80
*Adapted from Craig, W. A., and Welling, P. G.: Protein binding of antimicrobials: Clinical pharamcokinetic and therapeutic implications. Clin. Pharmacokinet., 2:252-268, 1977.
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incubation of antibiotics with pus has been reported. 5 The reduced activity was attributed to a drug-binding interaction with purulent material. Carbenicillin activity in these same studies was unaffected. A related factor is the influence of pH at the site of infection. The pH at these sites is usually low and will result in the loss of activity of the aminoglycosides, macrolides, and lincomycin. 51 This data reaffirms the need to drain abscesses to improve the clinical response. Inflammation Inflammation is an important factor that influences the distribution of antimicrobial agents. Successful delivery of an antibiotic to an infection site depends on the respective characteristics of the drug and the inflammatory process separating the two compartments (for example, blood-brain or blood-bronchial barrier). 37. 40 A favorable clinical response is most likely when the antibiotic at the infection site exceeds the minimal inhibitory concentration of the pathogen. Increased penetration of ampicillin, amoxicillin, and cephalexin into bronchial secretions during the inflamed state has been reported. 37 Similarly, extensive literature supports the effect of inflammation on cerebrospinal fluid levels of antibiotics (Table 3). During the noninflamed state, penetration is reduced and the resulting levels may be potentially lower than the minimal inhibitory concentration of the pathogen. Fever The influence of body temperature on antibiotic disposition has been observed. Serum concentrations of gentamicin were lowered by an average of 40 per cent, with no observable change in serum half-life or renal clearance. 38 A subsequent report cites a similar reduction in peak serum concentrations, but it was associated with a shortening of serum half-life. 50 Regardless of the mechanism by which fever results in a reduction in the serum concentration of gentamicin, close monitoring of the aminoglycosides is necessary to ensure that an adequate concentration is achieved for optimal effect.
Table 3.
Antibiotic Penetration into Cerebrospinal Fluid: Effect of I riflammation* CEREBROSPINAL FLUID LEVEL (AS PER CENT PLASMA LEVEL)
Drug
Inflamed
Noninflamed
Ampicillin Chloramphenicol Methicillin Nafcillin Penicillin G
10-20 20-50 10-30 15-30 30-40
0-5 20-50 5-15 0-5 0-20
*Adapted from Richards, M. L., et al.: Antimicrobial penetration into cerebrospinal fluid. Drug Intell. Clin. Pharm., 15:341-368, 1981.
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SUMMARY When the desired clinical response to an antibiotic therapeutic regimen is not achieved, despite appropriate antibiotic selection and organism sensitivity, the clinician must be aware that several host factors exist that may influence the outcome. Examples of the influence of host-related factors on drug disposition have been briefly reviewed in this article. It should be noted, however, that further investigation is needed to determine whether these factors truly exert a significant influence on the outcome of antibiotic utilization.
REFERENCES 1. Avant, G. R., Schenker, S., and Alford, R. H.: The effect of cirrhosis on the disposition and elimination of clindamycin. Am. J. Dig. Dis., 20:223-230, 1975. 2. Azollini, F., Gazzaniga, A., Lodola, E., eta!.: Elimination of chloramphenicol and thiamphenicol in subjects with cirrhosis of the liver. Int. J. Clin. Pharmacol., 6:130-134, 1972. 3. Bennett, W. M., Muther, R. S., Parker, R. A., et a!.: Drug therapy in renal failure: Dosing guidelines for adults. Part 1: Antimicrobial agents, analgesics. Ann. Intern. Med., 93:62-89, 1980. 4. Blaschke, T. F.: Protein binding and kinetics of drugs in liver disease. Clin. Pharmacokinet., 2:32--44, 1977. 5. Bryant, R. E., and Hammond, D.: Interaction of purulent material with antibiotics used to treat Pseudomonas infections. Antimicrob. Agents Chemother., 6:702-707, 1974. 6. Cleary, T. G., Pickering, L. K., Karmer, W. G., eta!.: Amikacin pharmacokinetics in pediatric patients with malignancy. Antimicrob. Agents Chemother., 16:82!}-832, 1979. 7. Closson, R. G.: Terminal half-lives of drugs studied in patients with hepatic disease. Am. J. Hosp. Pharm., 34:520-524, 1974. 8. Craig, W. A., and Welling, P. G.: Protein binding of antimicrobials: Clinical pharmacokinetic and therapeutic implications. Clin. Pharmacokinet., 2:252-268, 1977. 9. du Souich, P., McLean, A. J., Lalka, D., eta!.: Pulmonary disease and drug kinetics. Clin. Pharmacokinet., 3:257-266, 1978. 10. Eichelbaum, M.: Drug Metabolism in thyroid disease. Clin. Pharmacokinet., 1:339-350, 1976. ll. Gould, T., and Roberts, R. J.: Therapeutic problems arising from the use of the intravenous route for drug administration. J. Pediatr., 95:465-471, 1979. 12. Guggenbichler, J.P., and Kiene!, G.: Bioavailability of oral antibiotics in cystic fibrosis. Monogr. Paediat., 10:34-40, 1979. 13. Gugler, R., and Azarnoff, D. L.: Drug protein binding and the nephrotic syndrome. Clin. Pharmacokinet., 1:25--35, 1976. 14. Guidicelli, J. F., and Tillement, J. P.: Influence of sex on drug kinetics in man. Clin. Pharmacokinet., 2:157-166, 1977. 15. Guignard, J. P., Torrado, A., Mazouni, S. M., eta!.: Renal function in respiratory distress syndrome. J. Pediatr., 88:845-850, 1976. 16. Hendeles, L., Stillwell, P., and Mangos, J.: Gentamicin dosage requirements for cystic fibrosis (abstract). Drug Intell. Clin. Pharm., 15:479, 1981. 17. Jackson, E. A., and McLeod, D. C.: Pharmacokinetics and dosing of antimicrobial agents in renal impairment. Part l. Am. J. Hosp. Pharm., 31:36-52, 1974. 18. Jackson, E. A., and McLeod, D. C.: Pharmacokinetics and dosing of antimicrobial agents in renal impairment. Part 2. Am. J. Hosp. Pharm., 31:137-147, 1974. 19. Jusko, W. J., Mosovich, L. L., Gerbracht, L. M., eta!.: Enhanced renal excretion of die!oxacillin in patients with cystic fibrosis. Pediatrics, 56:1038-1044, 1975. 20. Kauffman, R. E., Miceli, J. N., Strebel, L., eta!.: Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children. J. Pediatr., 98:315--320, 1980.
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21. Kauffman, R. E., Thirumoorthi, M. C., Buckley, J. A., et al.: Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children. J. Pediatr., 99:963--967, 1981. 22. Krishnaswamy, K.: Drug metabolism and pharmacokinetics in malnutrition. Clin. Pharmacokinet., 3:21~240, 1978. 23. Leff, R. D., and Roberts, R. J.: Aminoglycoside dosage in pediatric patients: Considerations regarding pharmacokinetic-based dose adjustment in patients requiring high versus low dose therapy. Dev. Pharmacol. Ther., 3:242-250, 1981. 24. Leff, R. D., and Roberts, R. J.: Methods for intravenous drug administration in the pediatric patient. J. Pediatr., 98:631--635, 1981. 25. Lewis, G. P., and Jusko, W. J.: Pharmacokinetics of ampicillin in cirrhosis. Clin. Pharmacol. Ther., 18:475-484, 1975. 26. Loirat, P., Rohan, J., Baillet, A., et al.: Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N. Engl. J. Med., 17:915-919, 1978. 27. Marshall, J.P., Salt, W. B., Elam, R. 0., et al.: Disposition ofnafcillin in patients with cirrhosis and extrahepatic biliary obstruction. Gastroenterology, 73:1388--1392, 1977. 28. Mayer, S. E., Melman, K. L., and Gilman, A. G.: Introduction: The dynamics of drug absorption, distribution, and elimination. In Gilman, A. G., Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics. 6th ed. New York, MacMillan Publishing Co., Inc., 1980. 29. McCracken, G. H., Ginsburg, C. M., Clahsen, J. C., et al.: Pharmacologic evaluation of orally administered antibiotics in infants and children: Effect of feeding on bioavailability. Pediatrics, 62:738--743, 1978. 30. Melander, A.: Influence of food on the bioavailability of drugs. Clin. Pharmacokinet., 3:337-351, 1978. 31. Myers, M. G., Roberts, R. J., and Mirhij, N.J.: Effects of gestational age, birth weight, and hypoxemia on pharmacokinetics of amikacin in serum of infants. Antimicrob. Agents Chemother., 11:1027-1032, 1977. 32. Nelson, J. D., Shelton, S., Kusmiesz, H. T., et al.: Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis. Clin. Pharmacol. Ther., 13:879-886, 1972. 33. Parsons, R. L.: Drug absorption in gastrointestinal disease with particular reference to malabsorption syndromes. Clin. Pharmacokinet., 2:45-50, 1977. 34. Parsons, R. L., Hossack, G. A., and Paddock, G. M.: The absorption of antibiotics in adult patients with coeliac disease. J. Antimicrob. Chemother., 1:39-50, 1975. 35. Parsons, R. L., and Paddock, G. M.: Absorption of two antibacterial drugs, cephalexin and co-trimoxazole, in malabsorption syndromes. J. Antimicrob. Chemother., 1(Suppl.):5~7, 1975. 36. Parson, R. L., Paddock, G. M., Hossack, G. A., et al.: Antibiotic absorption in Crohn's disease. In Williams and Geddes (eds.): Chemotherapy, Vol. 4. Pharmacology of Antibiotics New York, Plenum Press, 1976, p. 219-229. 37. Pennington, J. E.: Penetration of antibiotics into respiratory secretions. Rev. Infect. Dis., 3:67-73, 1981. 38. Pennington, J. E., Dale, D. C., Reynolds, H. Y., et al.: Gentamicin sulfate: Lower levels of blood during fever. J. Infect. Dis., 132:270-275, 1975. 39. Pfeffer, M., and Van Harken, D. R.: Effect of dosing volume on intramuscular absorption rate of aminoglycosides. J. Pharm. Sci., 70:449-452, 1981. 40. Richards, M. L., Prince, R. A., Kenaley, K. A., et al.: Antimicrobial penetration into cerebrospinal fluid. Drug Intell. Clin. Pharm., 15:341-368, 1981. 41. Rifkind, A. B., Saenger, P., Levine, L. S., et al.: Effects of growth hormone on antipyrine kinetics in children. Clin. Pharmacol. Ther., 30:127-132, 1981. 42. Roberts, M. S., and Denton, M. J.: Effect of posture and sleep on pharmacokinetics. Eur. J. Clin. Pharmacol., 18:175-183, 1980. 43. Roberts, R. K., Desmond, P. V., and Schenker, S.: Drug prescribing in hepatobiliary disease. Drugs, 17:198--212, 1979. 44. Rommel, A. J., Vukovich, R. A., Knill, J. R., et al.: Posture-induced alterations in oral cephradine absorption kinetics (abstract). Clin. Pharmacol. Ther., 23:127, 1978. 45. Salmon, J. H.: Intraventricular chloramphenicol. Child's Brain, 4:114-119, 1978.
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46. Sawchuk, R. J., and Rector, T. S.: Drug kinetics in burn patients. Clin. Pharmacokinet., 5:548--556, 1980. 47. Sawchuk, R. J., and Zaske, D. E.: Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: Gentamicin in burn patients. J. Pharmacokinet. Biopharm., 4:183-195, 1976. 48. Schimpf£, S. C.: Therapy of infection in patients with granulocytopenia. Med. Clin. North Am., 61:1101-1117, 1977. 49. Shenfield, G. M.: Influence of thyroid dysfunction on drug pharmacokinetics. Clin. Pharmacokinet., 6:275-297, 1981. 50. Siber, G. R., Echeverria, P., Smith, A. L., et al.: Pharmacokinetics of gentamicin in children and adults. J. Infect. Dis., 132:637-651, 1975. 51. Strausbaugh, L. J., and Sande, M. A.: Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits. J. Infect. Dis., 137:251-260, 1978. 52. Welling, P. G.: Influence of food and diet on gastrointestinal drug absorption: A review. J. Pharmacokinet. Biopharm., 5:291-334, 1977. 53. Welling, P. G.: How food and fluid affect drug absorption. Postgrad. Med., 62:73-82, 1977. 54. Yaffe, S. J., Gerbacht, L. M., Mosovich, L. L., et al.: Pharmacokinetics of methicillin in patients with cystic fibrosis. J. Infect. Dis., 135:828--831, 1977. University of Iowa College of MediCine Iowa City, Iowa 52242 (Dr. Roberts)
Host Factors Influencing the Response to Antimicrobial Agents Richard D. Leff, Pharm.D.,* and Robert]. Roberts, M.D., Ph.D.t
The initial selection of an antibiotic for use in the pediatric patient, whether for acute, chronic, or preventive therapy, is primarily based on knowledge of the suspected or proven infecting pathogen and sensitivity of this organism to the antimicrobial agent. The subsequent decisions focus on determining the appropriate dosage and dosing interval, which is typically accomplished simply on the basis of the patient's weight, surface area, or age. The goal of the antibiotic dosage regimen is to achieve target concentrations of drug in the serum that have demonstrated a favorable clinical response while avoiding drug toxicity. Unfortunately, there are many factors that may influence whether the desired target concentrations of antibiotic in serum and the achievement of the desired clinical response is realized. The purpose of this article is to review host factors that may alter antibiotic disposition and/or clinical response, omitting those obvious causes, such as primary failure of the cardiovascular system or renal system, that have been the subject of numerous articles and reviews. 3 · 17• 18 The host factors have been divided into two general categories for discussion purposes, the noninfectious and infection-related host factors.
NONINFECTIOUS HOST FACTORS Route of Administration Once an antibiotic has been administered by the oral, intramuscular, or intravenous route, the nurse, pharmacist, and physician have often assumed that the patient has received the drug in a reliable and optimal fashion, especially when administration is by the intravenous route. How-
*Assistant Professor, Division of Clinical/Hospital Pharmacy, College of Pharmacy, University of Iowa, Iowa City, Iowa tProfessor, Divisions of Clinical Pharmacology and Neonatology, Departments of Pharmacology and Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
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ever, there are situations in which the method or route of drug administration results in delay in the onset or prolongation of the rate of drug delivery, incomplete drug delivery (bioavailability), or complete omission or loss of the drug dose. Oral Administration. Absorption of drugs from the gastrointestinal tract depends on many host factors, such as intestinal pH, gastric emptying and transit time, available intestinal surface area, gastrointestinal disease, and the presence of food or of other drugs. 33 Several disease states affecting these factors have been associated with altered antibiotic absorption. In cystic fibrosis, the oral absorption of cephalexin has been reported to be reduced. 12 The exact mechanism for the decreased absorption is not known. Celiac disease has shown a variable response with increased absorption of sulfamethoxazole, trimethoprim, and cephalexin, and decreased absorption of pivampicillin. 33• 34 Other penicillin esters (prodrugs) similar to pivampicillin, such as hetacillin or bacampicillin, may conceivably have decreased absorption. It has been suggested that this occurs as a result of an esterase deficiency in the lumen of the intestine necessary for the conversion of the prodrug to the active agent. 34 Other disease states associated with diarrhea (for example, acute bacillary disease) have been reported to have altered absorption of ampicillin and nalidixic acid, 32 which is likely because of a decreased intestinal transit time. Observation of patients with Crohn' s disease revealed a decrease in absorption of lincomycin, sulfamethoxazole, and trimethoprim. 35• 36 This impaired drug absorption may occur as a result of thickening of the bowel wall. As described, the majority of diseases affecting gastrointestinal absorption result in a reduction of the amount of antibiotic absorbed. The influence of food on the gastrointestinal absorption of drugs has been extensively reviewed. 30• 52• 53 As expected, there is a variable response on bioavailability. McCracken et al. have investigated the effect of feeding on bioavailability of selected antibiotics in infants and children. 29 As in adult studies, cephalexin, penicillin V, and penicillin G bioavailabilities (area-under-the-curves) were reduced when administered with food. On the other hand, the absorption of erythromycin ethylsuccinate was enhanced when given with meals. Therefore, the most effective utilization of oral antibiotics depends on knowing which drugs are best absorbed in the presence or in the absence of food (Table 1). Intramuscular Administration. Absorption of drugs from the intramuscular route depends on a number of physical and physiological factors. One well-recognized contributing factor is the status of vascular perfusion at the absorption site. 28 Under the clinical circumstances of shock or heart failure, perfusion of the injection site may be significantly decreased, resulting in prolongation of the rate of absorption. Prolonged or delayed rate of absorption will generally be associated with lower blood levels of drug. Recently, Pfeffer and Van Harken have shown that the administration of differing dosage volumes of aminoglycosides will alter the rate of intramuscular absorption. 39 This is attributed to the administration of various required doses (mg/kg) or drug dilutions (mg/ml) to the patient. This phenomenon may explain, in part, intrapatient and interpatient variation
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Table l.
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Influence of Food and Diet on Gastrointestinal Drug Absorption*
Decreased Bioavailability Ampicillin Cephradine Cephalexin Dicloxacillin Erythromycin Isoniazid Oxacillin Oxytetracycline Penicillin G Penicillin V Pivampicillin Rifampin Sulfisoxazole Tetracycline
Increased Bioavailability Erythromycin stearate Erythromycin ethyl succinate Griseofulvin Hetacillin Nitrofurantoin Unchanged Bioavailability Amoxicillin Erythromycin estolate Metronidazole
*Adapted from Welling, P. G.: Influence of food and drug on gastrointestinal drug absorption: A review. J. Pharmacokinet. Biopharm., 5:291-334, 1977.
reported in the literature of the rate of intramuscular drug absorption for the same or different drugs. Intravenous Administration. The administration of antibiotics by the intravenous route has been considered to be the most reliable route of delivery. Recently, some of the factors affecting the rate and completeness of this route of delivery have been identified. 11 · 24 The intravenous fluid flow rate and antibiotic dosing volume as required by the patient are two important considerations that may result in the drug being delivered either faster or slower than desired. As a result, peak drug levels may be sufficiently high to result in an increased risk of dose-dependent toxicity, or unexpectedly low with a reduced likelihood of the antibiotic concentration exceeding the sensitivity of the infecting organism. Pre-Existing Disease Drug disposition (absorption, metabolism, distribution, and excretion) is essentially dependent upon the normal physiologic and biochemical processes operating in the body to maintain homeostasis. Diseases such as those presented below can impose alterations of the normal physiologic and biochemical processes of the body, leading to alterations in drug disposition and/or pharmacologic effect. Endocrine Disorders. Thyroid dysfunction can result in a change in several physiologic events, including intestinal transit time, hepatic microsomal enzyme activity, cardiac output, renal plasma flow, and hepatic blood flow. 49 For those antibiotics metabolized by the liver, a hyperthyroid state can lead to a reduction of the serum drug concentration as a result of increased hepatic metabolism and renal clearance. The hypothyroid state would have the opposite effect. The influence of the thyroid on hepatic drug metabolism has been clearly shown for antipyrine, a drug used as an index of microsomal enzyme function. 10• 49 However, there is an unfortunate void in the literature regarding the effect of thyroid dysfunction on
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the metabolism of antibiotics. It is conceivable that antibiotics that are metabolized, such as chloramphenicol or clindamycin, will be vulnerable to changes in drug disposition based on altered thyroid function. Children with growth hormone deficiency have been shown to have variable antipyrine metabolism. 41 Therefore, it may be necessary to anticipate modification of antibiotic dosage in these children. Hepatic Disease. The influence of liver disease on drug disposition is quite variable. 43 This may be due, in part, to the diversity of hepatic disease etiologies and lack of ability to quantitate the severity of liver parenchymal compromise. To date, only minor alterations in antibiotic disposition have been observed in patients with liver dysfunction with the possible exception of chloramphenicol. The fact that chloramphenicol plasma clearance is closely linked to its being metabolized by the liver makes it difficult for the clinician to maintain the rather narrow therapeutic blood level range in patients with liver disease. A doubling of the half-life of elimination has been observed in some patients with cirrhosis. 2 • 7 As a result, dosage modification based on monitoring of serum levels may be necessary when chloramphenicol is used in patients with hepatic failure. Hepatic metabolism plays a significant role in the disposition of nafcillin, clindamycin, and other antibiotics. Patients with cirrhosis and biliary obstruction have shown a moderate prolongation of half-life for nafcillin (1.4 versus 1.0 hours) and clindamycin (4.4 versus 3.4 hours) when compared with normal. 1· 7 · 27 Similarly, increases in half-lives of isoniazid, rifampin, and trimethoprim have been observed in patients with hepatic dysfunction (acute-chronic liver disease, cirrhosis, and severe decompensated liver damage). 7 Sulfamethoxazole, on the other hand, had no distinguishable alteration in half-life. 7 Penicillins are principally eliminated by the renal route and are not metabolized. Nevertheless, severe liver disease prolongs to a small extent the elimination of carbenicillin and ampicillin when compared with normal.25, 43 However, modification of the dose is not required without concomitant renal impairment. In summary, most antibiotic regimens do not require changes in dosage in patients with hepatic compromise, but some definitely do require drug blood level monitoring. Pulmonary Disease. Antibiotic drug disposition has been shown to be altered in patients with respiratory disease. 9 In newborns with respiratory distress syndrome, inulin and para-aminohippurate clearance is reported to be significantly depressed.l 5 Subsequently, aminoglycosides that are eliminated via renal glomerular filtration have prolonged half-lives in hypoxic newborns irrespective of gestational age. 31 This necessitates close monitoring of serum aminoglycoside levels in neonates with compromised respiratory status. On the other hand, patients with cystic fibrosis have shown an enhanced renal excretion of dicloxacillin and methicillin. The authors recommend an increase in dosage requirements (= 25 per cent for methicillin and 200 per cent for dicloxacillin). 19· 54 Increases in aminoglycoside dosage requirements have also been suggested in this population. 16· 23 Whether
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such increases in dosage improve the clinical outcome without increasing the risk of toxicity needs to be evaluated. 23 Malignancy. Pediatric patients with malignancy have an aminoglycoside half-life comparable to that of the patient with cystic fibrosis (1.24 hours). 6 Individualized drug dosages calculated on the basis of this apparently shortened half-life result in the administration of an increased total dose. Again, the efficacy and toxicity of these aminoglycoside regimens need to be further evaluated. 23 Thermal Injury. Antibiotics may have enhanced elimination in patients with major burns. 46 This has been mainly attributed to an increased glomerular filtration rate, although some investigators have suggested that percutaneous elimination across damaged skin occurs and accounts for the increased elimination. 26 • 46 Regardless of the mechanism, monitoring aminoglycoside blood levels has revealed the necessity to increase dosages of the aminoglycoside antibiotics in the burned patient to maintain target serum drug levels. 47 Other Noninfectious Factors An assortment of other noninfectious host factors has been associated with changes in antibiotic disposition. In the majority of instances, however, the mechanism of such changes is unknown. As an example, the disposition of antibiotics in males versus females has been reviewed. Plasma rifampin levels are higher in the female than the male, and this may support a slight decrease (10 per cent) in dose. 14 A number of other differences in drug disposition have been reported in the female. Chloramphenicol and tetracycline plasma levels are higher; kanamycin and gentamicin plasma half-lives are shorter; procaine penicillin G is absorbed from the intramuscular site slower, achieving lower peak plasma levels; and the bioavailability of cephradine was reduced. 14 In comparisons between the ambulatory and supine patients, amoxicillin serum concentrations were found to be significantly higher in the ambulatory patient. 42 This difference was shown in the ambulatory patient to be secondary to a decrease in renal clearance. The time required to reach a peak concentration was shorter in the ambulatory patient, suggesting an increased absorption rate. Similarly, the absorption rate of cephradine was found to be enhanced in the standing and right recumbent positions. 44 These positions supposedly favor rapid gastric emptying. The significance of nonhepatic metabolism has been recently recognized for the intravenous formulation of chloramphenicol succinate. It appears that the rate of conversion in the blood of the succinate ester by nonspecific esterases to the active chloramphenicol base is quite variable.2o Therefore, lower than expected levels of chloramphenicol free base in blood may be observed despite an apparent appropriate dosage regimen. In contrast, cerebrospinal fluid levels of chloramphenicol free base were observed following intraventricular administration of the succinate ester. 45 The authors concluded that adequate esterase activity for the conversion of the ester to the active constituent is present in cerebrospinal fluid. Nevertheless, recognition of the variability of hydrolysis of the ester moiety has
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prompted recommendation of the use of orally administered chloramphenicol palmitate, which is reported to have equal if not greater bioavailability when compared with intravenously administered chloramphenicol succinate.2l Finally, pharmacologic activity of antimicrobial agents can be related to the amount of unbound drug at the site of infection. The extent of protein binding of a drug largely depends on the molecular characteristics of a drug and concentration of albumin in the blood. 8 Many disease states, such as malnutrition, nephrotic syndrome, or diseases of the liver, may cause a lowering of the serum protein concentration. 4 · 13 · 22 As a result, the amount of free drug may change and the clinician may observe an alteration in pharmacologic activity (efficacy or toxicity). This would be most significant for drugs that are highly protein bound (Table 2).
INFECTION-RELATED HOST FACTORS Neutropenia
Antibiotic therapy is particularly critical when the infectious process overwhelms the natural defense mechanisms of the host. This is commonly seen in neutropenic patients who have or develop bacteremia. One of the strongest prognosticators of the antimicrobial response in patients with neutropenia is the rise in the granulocyte count when the initial granulocyte count is less than 500 cells per f,Ll of blood. A small rise above the initial granulocyte count of greater than 100 cells per f,Ll of blood has been shown to significantly improve the clinical outcome in cancer patients receiving combination antibiotic therapy to treat their bacteremia. 48 Purulent Material
The formation of pus at the infection site has been shown to play a significant role in determining the activity of antibiotics. A marked reduction in the activity of gentamicin, colistin, and polymyxin B following the
Table 2. DRUG
Antibiotics Highly Protein Bound* PER CENT BOUND
Cefazolin Clindamycin Cloxacillin Die!oxacillin Doxycycline Nafcillin Oxacillin Penicillin V
86 94 94 94 85 87 93
80
*Adapted from Craig, W. A., and Welling, P. G.: Protein binding of antimicrobials: Clinical pharamcokinetic and therapeutic implications. Clin. Pharmacokinet., 2:252-268, 1977.
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incubation of antibiotics with pus has been reported. 5 The reduced activity was attributed to a drug-binding interaction with purulent material. Carbenicillin activity in these same studies was unaffected. A related factor is the influence of pH at the site of infection. The pH at these sites is usually low and will result in the loss of activity of the aminoglycosides, macrolides, and lincomycin. 51 This data reaffirms the need to drain abscesses to improve the clinical response. Inflammation Inflammation is an important factor that influences the distribution of antimicrobial agents. Successful delivery of an antibiotic to an infection site depends on the respective characteristics of the drug and the inflammatory process separating the two compartments (for example, blood-brain or blood-bronchial barrier). 37. 40 A favorable clinical response is most likely when the antibiotic at the infection site exceeds the minimal inhibitory concentration of the pathogen. Increased penetration of ampicillin, amoxicillin, and cephalexin into bronchial secretions during the inflamed state has been reported. 37 Similarly, extensive literature supports the effect of inflammation on cerebrospinal fluid levels of antibiotics (Table 3). During the noninflamed state, penetration is reduced and the resulting levels may be potentially lower than the minimal inhibitory concentration of the pathogen. Fever The influence of body temperature on antibiotic disposition has been observed. Serum concentrations of gentamicin were lowered by an average of 40 per cent, with no observable change in serum half-life or renal clearance. 38 A subsequent report cites a similar reduction in peak serum concentrations, but it was associated with a shortening of serum half-life. 50 Regardless of the mechanism by which fever results in a reduction in the serum concentration of gentamicin, close monitoring of the aminoglycosides is necessary to ensure that an adequate concentration is achieved for optimal effect.
Table 3.
Antibiotic Penetration into Cerebrospinal Fluid: Effect of I riflammation* CEREBROSPINAL FLUID LEVEL (AS PER CENT PLASMA LEVEL)
Drug
Inflamed
Noninflamed
Ampicillin Chloramphenicol Methicillin Nafcillin Penicillin G
10-20 20-50 10-30 15-30 30-40
0-5 20-50 5-15 0-5 0-20
*Adapted from Richards, M. L., et al.: Antimicrobial penetration into cerebrospinal fluid. Drug Intell. Clin. Pharm., 15:341-368, 1981.
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SUMMARY When the desired clinical response to an antibiotic therapeutic regimen is not achieved, despite appropriate antibiotic selection and organism sensitivity, the clinician must be aware that several host factors exist that may influence the outcome. Examples of the influence of host-related factors on drug disposition have been briefly reviewed in this article. It should be noted, however, that further investigation is needed to determine whether these factors truly exert a significant influence on the outcome of antibiotic utilization.
REFERENCES 1. Avant, G. R., Schenker, S., and Alford, R. H.: The effect of cirrhosis on the disposition and elimination of clindamycin. Am. J. Dig. Dis., 20:223-230, 1975. 2. Azollini, F., Gazzaniga, A., Lodola, E., eta!.: Elimination of chloramphenicol and thiamphenicol in subjects with cirrhosis of the liver. Int. J. Clin. Pharmacol., 6:130-134, 1972. 3. Bennett, W. M., Muther, R. S., Parker, R. A., et a!.: Drug therapy in renal failure: Dosing guidelines for adults. Part 1: Antimicrobial agents, analgesics. Ann. Intern. Med., 93:62-89, 1980. 4. Blaschke, T. F.: Protein binding and kinetics of drugs in liver disease. Clin. Pharmacokinet., 2:32--44, 1977. 5. Bryant, R. E., and Hammond, D.: Interaction of purulent material with antibiotics used to treat Pseudomonas infections. Antimicrob. Agents Chemother., 6:702-707, 1974. 6. Cleary, T. G., Pickering, L. K., Karmer, W. G., eta!.: Amikacin pharmacokinetics in pediatric patients with malignancy. Antimicrob. Agents Chemother., 16:82!}-832, 1979. 7. Closson, R. G.: Terminal half-lives of drugs studied in patients with hepatic disease. Am. J. Hosp. Pharm., 34:520-524, 1974. 8. Craig, W. A., and Welling, P. G.: Protein binding of antimicrobials: Clinical pharmacokinetic and therapeutic implications. Clin. Pharmacokinet., 2:252-268, 1977. 9. du Souich, P., McLean, A. J., Lalka, D., eta!.: Pulmonary disease and drug kinetics. Clin. Pharmacokinet., 3:257-266, 1978. 10. Eichelbaum, M.: Drug Metabolism in thyroid disease. Clin. Pharmacokinet., 1:339-350, 1976. ll. Gould, T., and Roberts, R. J.: Therapeutic problems arising from the use of the intravenous route for drug administration. J. Pediatr., 95:465-471, 1979. 12. Guggenbichler, J.P., and Kiene!, G.: Bioavailability of oral antibiotics in cystic fibrosis. Monogr. Paediat., 10:34-40, 1979. 13. Gugler, R., and Azarnoff, D. L.: Drug protein binding and the nephrotic syndrome. Clin. Pharmacokinet., 1:25--35, 1976. 14. Guidicelli, J. F., and Tillement, J. P.: Influence of sex on drug kinetics in man. Clin. Pharmacokinet., 2:157-166, 1977. 15. Guignard, J. P., Torrado, A., Mazouni, S. M., eta!.: Renal function in respiratory distress syndrome. J. Pediatr., 88:845-850, 1976. 16. Hendeles, L., Stillwell, P., and Mangos, J.: Gentamicin dosage requirements for cystic fibrosis (abstract). Drug Intell. Clin. Pharm., 15:479, 1981. 17. Jackson, E. A., and McLeod, D. C.: Pharmacokinetics and dosing of antimicrobial agents in renal impairment. Part l. Am. J. Hosp. Pharm., 31:36-52, 1974. 18. Jackson, E. A., and McLeod, D. C.: Pharmacokinetics and dosing of antimicrobial agents in renal impairment. Part 2. Am. J. Hosp. Pharm., 31:137-147, 1974. 19. Jusko, W. J., Mosovich, L. L., Gerbracht, L. M., eta!.: Enhanced renal excretion of die!oxacillin in patients with cystic fibrosis. Pediatrics, 56:1038-1044, 1975. 20. Kauffman, R. E., Miceli, J. N., Strebel, L., eta!.: Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children. J. Pediatr., 98:315--320, 1980.
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21. Kauffman, R. E., Thirumoorthi, M. C., Buckley, J. A., et al.: Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children. J. Pediatr., 99:963--967, 1981. 22. Krishnaswamy, K.: Drug metabolism and pharmacokinetics in malnutrition. Clin. Pharmacokinet., 3:21~240, 1978. 23. Leff, R. D., and Roberts, R. J.: Aminoglycoside dosage in pediatric patients: Considerations regarding pharmacokinetic-based dose adjustment in patients requiring high versus low dose therapy. Dev. Pharmacol. Ther., 3:242-250, 1981. 24. Leff, R. D., and Roberts, R. J.: Methods for intravenous drug administration in the pediatric patient. J. Pediatr., 98:631--635, 1981. 25. Lewis, G. P., and Jusko, W. J.: Pharmacokinetics of ampicillin in cirrhosis. Clin. Pharmacol. Ther., 18:475-484, 1975. 26. Loirat, P., Rohan, J., Baillet, A., et al.: Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N. Engl. J. Med., 17:915-919, 1978. 27. Marshall, J.P., Salt, W. B., Elam, R. 0., et al.: Disposition ofnafcillin in patients with cirrhosis and extrahepatic biliary obstruction. Gastroenterology, 73:1388--1392, 1977. 28. Mayer, S. E., Melman, K. L., and Gilman, A. G.: Introduction: The dynamics of drug absorption, distribution, and elimination. In Gilman, A. G., Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics. 6th ed. New York, MacMillan Publishing Co., Inc., 1980. 29. McCracken, G. H., Ginsburg, C. M., Clahsen, J. C., et al.: Pharmacologic evaluation of orally administered antibiotics in infants and children: Effect of feeding on bioavailability. Pediatrics, 62:738--743, 1978. 30. Melander, A.: Influence of food on the bioavailability of drugs. Clin. Pharmacokinet., 3:337-351, 1978. 31. Myers, M. G., Roberts, R. J., and Mirhij, N.J.: Effects of gestational age, birth weight, and hypoxemia on pharmacokinetics of amikacin in serum of infants. Antimicrob. Agents Chemother., 11:1027-1032, 1977. 32. Nelson, J. D., Shelton, S., Kusmiesz, H. T., et al.: Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis. Clin. Pharmacol. Ther., 13:879-886, 1972. 33. Parsons, R. L.: Drug absorption in gastrointestinal disease with particular reference to malabsorption syndromes. Clin. Pharmacokinet., 2:45-50, 1977. 34. Parsons, R. L., Hossack, G. A., and Paddock, G. M.: The absorption of antibiotics in adult patients with coeliac disease. J. Antimicrob. Chemother., 1:39-50, 1975. 35. Parsons, R. L., and Paddock, G. M.: Absorption of two antibacterial drugs, cephalexin and co-trimoxazole, in malabsorption syndromes. J. Antimicrob. Chemother., 1(Suppl.):5~7, 1975. 36. Parson, R. L., Paddock, G. M., Hossack, G. A., et al.: Antibiotic absorption in Crohn's disease. In Williams and Geddes (eds.): Chemotherapy, Vol. 4. Pharmacology of Antibiotics New York, Plenum Press, 1976, p. 219-229. 37. Pennington, J. E.: Penetration of antibiotics into respiratory secretions. Rev. Infect. Dis., 3:67-73, 1981. 38. Pennington, J. E., Dale, D. C., Reynolds, H. Y., et al.: Gentamicin sulfate: Lower levels of blood during fever. J. Infect. Dis., 132:270-275, 1975. 39. Pfeffer, M., and Van Harken, D. R.: Effect of dosing volume on intramuscular absorption rate of aminoglycosides. J. Pharm. Sci., 70:449-452, 1981. 40. Richards, M. L., Prince, R. A., Kenaley, K. A., et al.: Antimicrobial penetration into cerebrospinal fluid. Drug Intell. Clin. Pharm., 15:341-368, 1981. 41. Rifkind, A. B., Saenger, P., Levine, L. S., et al.: Effects of growth hormone on antipyrine kinetics in children. Clin. Pharmacol. Ther., 30:127-132, 1981. 42. Roberts, M. S., and Denton, M. J.: Effect of posture and sleep on pharmacokinetics. Eur. J. Clin. Pharmacol., 18:175-183, 1980. 43. Roberts, R. K., Desmond, P. V., and Schenker, S.: Drug prescribing in hepatobiliary disease. Drugs, 17:198--212, 1979. 44. Rommel, A. J., Vukovich, R. A., Knill, J. R., et al.: Posture-induced alterations in oral cephradine absorption kinetics (abstract). Clin. Pharmacol. Ther., 23:127, 1978. 45. Salmon, J. H.: Intraventricular chloramphenicol. Child's Brain, 4:114-119, 1978.
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46. Sawchuk, R. J., and Rector, T. S.: Drug kinetics in burn patients. Clin. Pharmacokinet., 5:548--556, 1980. 47. Sawchuk, R. J., and Zaske, D. E.: Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: Gentamicin in burn patients. J. Pharmacokinet. Biopharm., 4:183-195, 1976. 48. Schimpf£, S. C.: Therapy of infection in patients with granulocytopenia. Med. Clin. North Am., 61:1101-1117, 1977. 49. Shenfield, G. M.: Influence of thyroid dysfunction on drug pharmacokinetics. Clin. Pharmacokinet., 6:275-297, 1981. 50. Siber, G. R., Echeverria, P., Smith, A. L., et al.: Pharmacokinetics of gentamicin in children and adults. J. Infect. Dis., 132:637-651, 1975. 51. Strausbaugh, L. J., and Sande, M. A.: Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits. J. Infect. Dis., 137:251-260, 1978. 52. Welling, P. G.: Influence of food and diet on gastrointestinal drug absorption: A review. J. Pharmacokinet. Biopharm., 5:291-334, 1977. 53. Welling, P. G.: How food and fluid affect drug absorption. Postgrad. Med., 62:73-82, 1977. 54. Yaffe, S. J., Gerbacht, L. M., Mosovich, L. L., et al.: Pharmacokinetics of methicillin in patients with cystic fibrosis. J. Infect. Dis., 135:828--831, 1977. University of Iowa College of MediCine Iowa City, Iowa 52242 (Dr. Roberts)