Pharmacokinetics And Pharmacodynamics Of
Antibacterial Agents In Pediatrics: A Practical Approach

Tibisay I. Villalobos, M.D.; Bill Renfro, Pharm. D.; Mobeen H. Rathore, M.D.
Tibisay Villalobos, M.D. is a Fellow in Pediatric Infectious Disease at the University of Florida Health Science Center/Jacksonville.
Bill Renfro, Pharm.D. is the Clinical Pediatric Pharmacologist at University Medical Center.
Mobeen Rathore, M.D. is Associate Professor and Chief of Pediatric Infectious Diseases/Immunology
at the University of Florida Health Science Center/Jacksonville and Nemours Children's Clinic.

In infants and children, the pharmacokinetics and pharmacodynamics of antibacterial agents differ considerably in comparison with adults; consequently, differences exist in therapeutic efficacy and toxicity. The article reviews the basic principles of antimicrobial pharmacology related to clinical application in children. An understanding of these factors can help in the safe and effective prescribing of antimicrobials.

Pharmacokinetics describes the processes by which drugs are absorbed, distributed, metabolized and excreted by the body.

Pharmacokinetics Principles

The pharmacokinetic properties of any given drug are determined by the measurement of such a drug in the plasma, and they are the result of the processes that influence the drug concentration: (Figure 1)

Figure 1. Interrelationship of the absorption, distribution, binding, biotransformation, and excretion of a drug and its concentration at its sites of action.

Absorption and Bioavailability

Absorption is dependent on bioavailability of the drug. Bioavailability is the percentage of the drug administered that reaches the systemic circulation. Oral bioavailability is a reflection of the fraction of an oral dose that reaches the systemic circulation, compared with an equivalent intravenous dose (assumed that IV administered drugs are 100% bioavailable).

Bioavailability of an orally administered drug can be affected mainly by:

• the transformation of the drug in the gastrointestinal lumen;
• metabolism of the drug in the intestinal wall; and
• metabolism by the liver.

This presystemic transformation by the intestine and liver is known as first-pass effect. Some antibiotics must undergo biotransformation to become active drugs (e.g., clindamycin). In addition, many antibiotics have enhanced absorption when administered on an empty stomach (increased acidity produced by food will decrease absorption, for example, for penicillins) while others are better absorbed with meals (e.g., itraconazole, ganciclovir).¹

Drug absorption is altered in the neonate and infant. The gastric pH is neutral at birth but it decreases to 1-3 after birth, increasing again during the first week. Then the pH declines slowly to reach adult values (pH 2-3) by the age of 2-3 years.² As result, acid-labile drugs (e.g., ampicillin) are more efficiently absorbed in the infant than in the adult.

Gastric emptying is also delayed in the neonate and peak concentration of the drug can be unpredictable. On the other hand, in children absorption through the skin is increased since they have a larger surface area relative to body weight than adults. Also, intramuscular absorption is erratic and less reliable in the infant.^2,3

Distribution

Distribution refers to the exchange of drugs among the various body compartments. The distribution of the drug beyond the intravascular space depends on its molecular size, ionization at physiologic pH, water/lipid solubility, and the degree of binding to plasma proteins.²

The apparent volume of distribution of a drug is the term used to relate the concentration of drugs in the body to the amount of drugs in the plasma. It is a theoretic measure that indicates the extent more than the site of distribution.

A small volume of distribution suggests that the drug is retained largely within the vascular compartment; likewise, larger volumes of distribution imply distribution beyond the vascular system and throughout the total body water.

Drug distribution pattern varies throughout life. Those changes are the result, in part, of changes in the protein binding of drugs at different ages, as well as changes in the extracellular fluid volume as a proportion of the total body water.

In term infants the concentration of albumin is lower than in older children or adults, and the concentration is further lowered in premature infants.³ Because of reduced protein binding some antibiotics may attain a concentration of unbound drug in serum higher than expected, which affect levels of ampicillin and nafcillin among others antibiotics.⁴ Competition with bilirubin for albumin binding sites can also result in higher-than-anticipated levels of free bilirubin in the serum and reduced protein binding will result in drugs being distributed more widely through the body and increased apparent volume of distribution of drug.

In the newborn, extracellular fluid makes up approximately 40% of the total body water. This decreases progressively so that at 1 year of age it is only 25% and in adulthood extracellular fluid comprises 20% of the total body water^2,3 (Figure 2).

Since the volume of distribution of a drug is measured as a function of its concentration in the extracellular (particularly intravascular) compartment, these changes will result in a relatively higher volume of water soluble drugs in children than in the adult. For example, the volume of distribution of sulfisoxazole in the neonate is twice than in the adult.²

Conversely, as the percentage of body water decreases with age there is a corresponding increase in body fat. This will affect the volume of distribution of lipophilic compounds, which will also be greater in term infants than in premature infants.⁴

Metabolism

Many drugs need to be transformed into different compounds in order to be eliminated more efficiently from the body. The liver is by far the most important organ for drug metabolism. There are two types of chemical reactions responsible for the metabolism of drugs:

• Phase 1 Reactions involve structural alteration of the drug molecule. These reactions are frequently catalyzed by the cytochrome P450 enzyme system.
• Phase 2 Reactions consist of configuration with another, often more water soluble moiety which is easily excreted by the urine.

Both groups of metabolic reactions may be immature at birth. Oxidation processes are certainly reduced; they develop relatively rapidly and are normal by six to twelve months of life. The glucuronidation process (Phase 2 metabolism) is also impaired and may not approach adult values until approximately three to six months of life.^2-4 Antibiotics excreted through the liver should be used with caution in the newborn and according to specific indications and guidelines. Examples of agents include ceftriaxone and rifampin.

Excretion

Renal excretion is responsible for the elimination of drug metabolites as well as many parent compounds. Excretion by the kidneys is dependent mainly on two processes: glomerular filtration and tubular secretion.

Glomerular filtration rate (GFR) is reduced in the newborn and it rises to adult values (100ml/min/1.73ml) around three months of age. After three months of age, the GFR may exceed adult values. For example, aminoglycosides are eliminated by glomerular filtration at a known fraction of excretion. In this case, changes and dosage adjustment can be made for renal dysfunction based on the knowledge of the fraction excreted renally (e.g. for gentamicin it is 0.98).¹

Active tubular secretion is also low at birth and takes longer to reach adult values. This is important for antibiotics like penicillins and cephalosporins. They need to be administered at longer intervals in the neonate to assure adequate elimination without potentially toxic levels.

Pharmacokinetic Parameters

There are mathematical models that explain the pharmacokinetic principles that govern the input and elimination processes determining the final drug concentration. These parameters are clinically useful in designing safe and effective dosage regimens.

Elimination Process

• The first-order or linear pharmacokinetic principles refer to the elimination process independent of drug concentration: the concentration of the drug in plasma decreases by a fixed percentage per unit of time. Most antibiotics exhibit first-order or linear elimination.
• The zero-order or non-linear pharmacokinetics refers to a capacity-limited elimination process: the amount of drug that is eliminated per unit of time is constant. This type of pharmacokinetic model applies to systems that require carrier or enzymatic process for drug elimination.

Half-life and Elimination Rate Constant

A drug half-life is the time it takes for the plasma concentration to fall by one half; the elimination rate constant is the slope of the line formed when the natural logarithm of drug concentration versus time is plotted (Figure 3). These two parameters are important to remember when estimating the time to total drug elimination. Most drugs will be eliminated in approximately five half-lives. The steady-state is the condition reached when the same amount of drug that enters a given compartment per unit of time is eliminated at the same rate from that compartment. Most therapeutic drug concentration refers to this state.

Area Under the Concentration Time Curve (AUC)

The AUC is the measure of total exposure of drug to the circulation over time. The serum antibiotic concentration and the period of time the antibiotic concentration is above the Minimum Inhibitory Concentration (MIC) are considered to be pharmacokinetic properties of antimicrobials. The product of these two factors is represented by the area under the serum concentration-time curve (AUC). Bacterial killing is therefore a function of the AUC.⁵

Clearance

Clearance refers to the time it takes for a drug to be eliminated from the blood. It is the sum of all routes of elimination and is affected by changes in the function of the organs involved in the elimination or distribution of a drug.

Loading Dose

The purpose of a loading dose is to achieve therapeutic concentration as quickly as possible. Some drugs have a long half-life and it will take a long time to achieve steady state concentration (remember it takes five half-lives). In some clinical situations, a rapid therapeutic effect is desired and a loading dose is recommended (e.g., pediatric patients with altered renal function or larger volumes of distribution).

Multiple Dosing

Most antibiotics are administered using this method. Doses given at regular intervals may result in accumulation of the drug in the body. The steady state is achieved when the amount of drug delivered to the systemic circulation is equal to the amount of drug excreted over that dosing interval.

How to Monitor Antibiotics in Plasma

In order to obtain useful and reliable information about drug concentrations, the sampling must consider the following factors:

• Route and method of administration: Intravenous antimicrobials are usually administered intravenously over 15-60 minutes. Prolonged infusions and sampling ports distant from the patient may decrease peak antibiotic concentrations. Samples should not be collected from the same site the drug is infused (Figure 4).
• Timing: Sample collection should be performed after distribution of the drug into the vascular system is completed (e.g., one hour for aminoglycosides). The timing of the test sample must be as close to steady state as possible. In most clinical settings, this is performed after three to five half-lives have passed from starting antibiotic therapy. Peak and trough concentrations preferably should be obtained after the same dose, not before and after the same dose as is often done, until desired level is reached and no more changes in dose or interval are expected. Once the steady state has been reached, obtaining peak and trough levels with the same dose is reliable since all peak and troughs will be the same.

Many factors can affect the response of a patient to a given dose. Some patients respond well with subtherapeutic levels or do not manifest any adverse affects with toxic antibiotic concentrations. Alterations in protein concentration, malabsorption, alterations of volume of distribution (e.g., edema), and renal or hepatic dysfunction affect the pharmacokinetic of the antibiotic. When the patient is receiving multiple drugs, the possibility of drug-interaction is likely. Also, errors in dosage, method of administration or sampling may occur and mislead the interpretation of the results. The patient's condition and clinical response must also be considered when evaluating antibiotic therapy before making a decision based only on pharmacokinetic models. For example, children with cystic fibrosis have altered drug pharmacokinetics due to increased volume of distribution, decreased plasma protein concentration and enhanced renal and non-renal elimination of drugs requiring higher doses of beta-lactam antibiotics, aminogly-cosides and quinolones.^6,7

Antimicrobial Agents

The antimicrobial agents of value in treatment of infectious diseases in infants and children may be classified into five groups:

• B-lactams, including the penicillins, the cephalosporins, and the carbacephems;
• The glycopeptides (vancomycin);
• Aminoglycosides;
• The macrolides, including erythromycin, clarithromycin and azithromycin; and
• Miscellaneous antibacterials, including sulfonamides, clindamycin and tetracyclines.

Beta-lactams

Penicillin G, penicillin V, procaine penicillin, and benzathine penicillin, are excreted through the kidneys. Plasma concentrations are higher in neonates due to immaturity of glomerular filtration and tubular secretion. Dosage is higher in infants and young children compared to older children due to a higher percentage of total body water.³

Penicillinase-Resistant Penicillins include nafcillin, oxacillin, cloxacillin, dicloxacillin, and methicillin. Nafcillin and oxacillin have significant hepatic clearance when compared with natural penicillins (60% and 49%; respectively). Methicillin is cleared predominantly by the kidneys and the renal clearance correlates with postnatal age.³

Aminopenicillins, such as ampicillin, amoxicillin, ampicillin-sulbactam, and amoxicillin clavulanate, have predominant renal clearance. Amoxicillin has higher absorption and bioavailability than ampicillin.¹¹ The absorption of ampicillin is decreased when administered with food. Higher plasma concentration and prolonged half-life of ampicillin are seen in neonates during the first week of life. The use of amoxicillin with the beta-lactamase inhibitor clavulanate enhances the antibacterial activity of amoxicillin. The initial formulation of amoxicillin/clavulanate comprised a 4:1 ratio and was most often given every eight hours. The new formulation containing 7:1 ratio of amoxicillin to clavulanate is designed for every 12-hour dosing. The pharmacokinetics of this new formulation is very similar and the AUC for amoxicillin remains above the minimal inhibitory concentrations for most important pediatric pathogens⁸.

Extended spectrum penicillins, such as carbenicillin, mezlocillin, piperacillin, piperacillin-tazobactam, ticarcillin, and ticarcillin-clavulanate have minimal CSF penetration (<10% of plasma concentration), and almost no oral bioavailability. Elimination is primarily by renal excretion. Changes in body-water distributions affect dose requirements.

Carbapenems, such as imipenem-cilastatin, meropenem and the investigational biapenem, are parenteral agents belonging to this group. Their pharmacokinetic properties are similar to other typical parenteral beta-lactams with low protein binding and renal excretion.¹² Meropenem lacks the toxicity of seizure potentiation associated with imipenem.¹³ These agents are a reasonable choice for empiric monotherapy in infants and children with serious infections.

Cephalosporins (summarized in Table 1) are available as parenteral and oral products. Parenteral formulations can be administered either intravenously or intramuscularly. Oral formulations have excellent bioavailability except for cefuroxime and cefpodoxime for which estrification is required to enhance GI absorption.⁹ Only third generation cephalosporins penetrate well enough through the blood brain barrier to achieve sufficient levels in the cerebrospinal fluid (CSF) to treat CNS infections. Glomerular filtration and tubular secretion are the primary modes of excretion. Cefoperazone and ceftriaxone have dual excretion via the kidneys and the biliary tract.¹⁰

Loracarbef is the first carbacephem used in the clinical setting. It is well absorbed and it is excreted in the urine unchanged. Absorption is enhanced on an empty stomach. The pharmacokinetic profile in children is comparable with that in the adult.¹¹

Vancomycin

Vancomycin is approximately 55% bound to serum proteins and diffuses well into most body tissues with adequate concentrations achieved in pericardial pleural, ascitic and synovial fluids. It does not diffuse well into CSF, especially in the absence of inflamed meninges. Adequate CSF concentrations can be achieved for meningitis when higher dosages (15 mg/kg/every 6 hrs) are administered. Vancomycin is not metabolized significantly and is excreted by glomerular filtration.

In preterm and term infants different dosing schedules have been proposed taking into account post-conceptual age, plasma creatinine levels and vancomycin half life.¹⁴ Also, the presence of malignancy in infants and children may increase vancomycin clearance, resulting in larger dose requirements.¹⁵

Renal function should be monitored and serum peak and trough levels determined after fifth half life or the third to fifth dose. There is considerable variability among patient receiving the same dose.¹⁴

Aminoglycosides

There are eight aminoglycosides approved for use in the United States: Streptomycin, Kanamycin, Amikacin, Tobramycin, Gentamicin, Netilmicin, Neomycin, and Paromomycin.

Among their common properties are high polarity, water solubility and antibacterial activity that is pH dependent with increased activity at higher pH. They do not penetrate the blood-brain barrier in absence of meningeal inflammation, but with inflammation approximately 20 to 25 percent of the serum concentration in achieved in the CSF. Aminoglycosides are not metabolized and are excreted unchanged by the kidneys. In neonates there are data defining the relationship of postconceptual age to pharmacokinetic variability which provide the basis for current dosage schedules.^16,17 Serum levels should be determined after three to five doses have been administered and thereafter to document adequacy of level or to make adjustments appropriately.

The pharmacokinetics after intramuscular administration is almost identical to intravenous infusion.¹⁷ Moreover, compared with parenteral administration, aerosol administration of aminoglycosides results in higher concentration in bronchial
secretion and less toxicity. This is important in children with cystic fibrosis who usually require higher doses of parenteral antibiotics due to changes in the volume of distribution.¹⁸

Because aminoglycosides demonstrate concentration-dependent antibacterial activity, higher peak serum concentrations result in extensive and rapid killing. Aminoglycosides also demonstrate a postantibiotic effect against susceptible bacteria that lasts longer with higher peak serum concentration. These facts have prompted the use of once-daily dose schedule in adults with at least the same efficacy as the traditional twice or thrice daily regime. Fewer data exist in children but results suggest the once-daily aminoglycoside dosing may be effective.^19,20

Macrolides

The macrolide group includes erythromycin, clarithromycin and azithromycin. They differ in their pharmacokinetic properties. Clarithromycin and azithomycin are gastric acid-stable and well absorbed from the gastrointestinal tract. Erythromycin is acid-labile and absorption varies with the oral preparation used. Macrolides undergo liver metabolism by the microsomal P450 system. Most of the metabolites are inactive, except for 14-hydroxyclarithromycin a metabolite that acts additively with clarithromycin.⁵ Newer macrolides are extensively distributed to body tissues (except CSF) where concentrations are well above those in serum. High concentration of azithromycin persists in tissues for several days. Their long serum half life allows the once-daily dosing schedule for azithromycin and twice-daily for clarithyomycin.

Clindamycin

Clindamycin has a rapid oral absorption and distribution to most tissues and body fluids. High concentration is achieved in bone due to the active transport into macrophages and polymorphonuclear leukocytes. Penetration into CSF is limited. Clindamycin undergoes hepatic metabolism to active and inactive metabolites. It is excreted primarily in the biliary system.

Trimethoprim -- Sulfamethoxazole (TMP-SMZ)

The optimal synergistic activity of the two compounds occurs after administration of a fixed 1:5 ratio of TMP to SMZ. Both agents are absorbed rapidly and penetrate most body fluids. Both are metabolized in the liver to inactive metabolites and the primary route of elimination is by the kidneys.

Tetracyclines

The oral absorption approaches 100% with doxycycline and minocycline. Dairy products, antacids, calcium and iron supplements reduce absorption and should be avoided. All agents penetrate many tissues and fluids (including bone, teeth and breast milk). Highest concentrations are achieved in the bile. Because tetracyclines form complexes with calcium orthophosphate that may cause bone growth depression and staining of teeth, they are not recommended for use in children under 9 years of age. Minocycline is metabolized by the liver and the other tetracyclines are excreted unchanged in the urine. Forty 40% of doxycycline is excreted by the bile.

Pharmacodynamics

Pharmacodynamics is the relationship between serum concentration and the antimicrobial effect at the site of infection. The time course of antimicrobial activity is a reflection of the interrelationship between pharmacokinetics and pharmacodynamics.⁹ Antimicrobial agents can be divided into different groups, based on antimicrobial pharmacodynamic characteristics.

The first group is agents characterized by concentration-dependent killing over a wide range of concentration. The higher the drug concentration, the greater the rate and extent of killing (e.g., the aminoglycosides and fluroquinolones). The second group is characterized by time-dependent bactericidal activity that has little relationship to the magnitude of drug concentration, as long as the concentration are above a minimally effective level. Saturation of the killing rate occurs at low multiples of the minimum inhibitory concentration (MIC). Concentration above these values do not kill the organisms any faster or more extensively. This is a common characteristic of B-lactams, vancomycin and clindamycin.²² These properties suggest that maintaining B-lactam concentration at or above the MIC of the infecting organism should optimize antibacterial effect. Likewise, it would appear that maximizing the peak concentration of an aminoglycoside or a fluoroquinolone would maximize it antibacterial effect.^21,22 The post-antibiotic effect (PAE) is another important pharmacodynamic phenomenon, which is the persistent suppression of bacterial growth after antibiotic concentrations have fallen below the MIC for the infecting bacteria.^4,21 The PAE is typically seen in vitro with inhibitors of protein and nucleic acid synthesis (amino-glycosides, fluoroquinolones, tetracycline, clindamycin, rifampim). Also, during the PAE, organisms may be more susceptible than untreated bacteria to the antibacterial action of phagocytes, a phenomenon called post antibiotic leukocyte effect (PALE).

An example of clinical application of the pharmacodynamics of antibacterial agents in pediatrics occurs with the therapy of otitis media. With the increasing number of resistant isolates causing otitis media in children it is necessary to predict the efficacy of the antibiotics commonly used to treat middle ear infections. It has been observed that 80-85% efficacy is achieved with commonly prescribed oral antimicrobials when the time above the MIC is reached for 40-50% of the dosing interval. Not all dosage regimes currently approved for treatment of otitis media provide concentration above the MIC₉₀ goal for common pathogens for at least 40% of the dosing interval. This is especially true for the eradication of penicillin intermediately sensitive and penicillin-resistant Streptococcus pneumoniae. Therefore, higher doses of B-lactams (e.g., amoxicillin) are needed to achieve and maintain the MIC in the middle ear fluid.²³

Summary

The pharmacokinetics and pharmacodynamics of antimicrobial agents vary among children and they are also affected by factors such as prematurity, underlying disease, drug interaction, tissue distribution and oral absorption. Knowledge of these factors allows a more rational use of antibiotics in pediatrics.

REFERENCES

1. Stowe CD, Farrar HC. Pharmacokinetics of Antimicrobial agents. In: Long SS, Pickering LK and Prober Cg (eds). Principles and Practice of Pediatric Infectious Diseases. New York. Churchill Livingston 1997:1599-1604.
2. Routledge PA. Pharmacokinetics in children. J Antimicrob chemother. 1994; 34 (suppl A) : 19-24.
3. Edwards MS. Antibacterial therapy in pregnancy and neonates. Clin Perinatol. 1997; 24 (1) : 251-66.
4. Lindsay CA, Bosso JA. Fundamentals of pharmocokinetics, antiinfective pharmacodynamics and therapeutic drug monitoring. In: Feigin RD and Cherry JD (eds): Textbook of Pediatric Infectious Diseases. 4^th edition, Philadelphia, PA, WB Saunders, 1997: 2604-2613.
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18. Ramsey BW, Donkin HL, Eisenber JD., et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993; 328 : 1740-1746.
19. Hayani KC, Hatzopoulos FK; Frank AL, Thummala MR, Hantsch MJ; Schatz BM, John EG, Vidyasaqar D. Pharmacokinetics of once daily dosing of gentamicin in neonates. J Pediatr. 1997; 131: 76-80.
20. Elhanan K, Siplovich L, Raz R. Gentamicin once-daily versus twice-daily in children. J Antimicrob Chemother. 1995; 35: 327-332.
21. Levison ME. Pharmacodynamics of antimicrobial agents. Bactericidal and post-antibiotic effects. Infect Dis Clin North Am. 1995; 9: 483-95.
22. Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998; 26: 1-12.
23. Craig WA, Andes D. Pharmacokinetic and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996; 15: 944-8.

Jacksonville Medicine / August, 1998

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