Antimicrobial Chemotherapy, 5th Edition
Part 3 - General Principles of Usage of Antimicrobial Agents
Prescribing for Children and the Elderly
Children should not be considered as small adults for the purposes of prescribing. The former practice of scaling down an adult dose on a weight basis may result in either subtherapeutic or toxic concentrations and this is no longer acceptable. This applies to the prescribing of all drugs in childhood, not only antimicrobial agents. Similarly, the risks of adverse reactions increase significantly in elderly patients, especially if liver and kidney function is impaired by age or disease. The evaluation of new drugs in children and elderly people presents particular problems and is extremely important, since the pharmacological handling of the drugs and their unwanted effects may differ considerably in infants, young children, old people, and normal adults.
Age-related epidemiology of infections
When selecting antimicrobial therapy, knowledge of age-related infections is important in the initial management, before laboratory information is available. Many infections, although not entirely peculiar to infancy and childhood, are none the less much more frequently encountered in this age group. For example, respiratory syncytial virus infection of the lung and the classic viral exanthem of varicella are primarily diseases of childhood. Such age-related infections reflect the ready transmission of these agents and the susceptibility of a relatively non-immune population. Certain bacterial infections are also much more common in the very young. Neonatal meningitis is primarily caused by Group B streptococci and Escherichia coli. Meningococcal infection is a disease of early childhood and young adulthood.
Upper respiratory tract infections are extremely common in childhood. Many are caused by viruses, but infection is often complicated by secondary bacterial invasion with Streptococcus pneumoniae or Haemophilus influenzae.
Cystic fibrosis is largely a disease that generally becomes manifest in children, and through careful management many sufferers survive into adult life. A major complication of this disease is recurrent lower respiratory tract
infection in which Staphylococcus aureus and Pseudomonas aeruginosa predominate. Such infections are difficult to control and it is often impossible to eliminate Ps. aeruginosa completely from the sputum.
Pharmacokinetic and pharmacodynamic considerations
In childhood, pharmacokinetic and pharmacodynamic factors often differ markedly from those in the adult (see Table 15.1), hence, dosages may be adjusted according to surface area, which is more closely related than weight to the ability to metabolize drugs. This not only represents variation in the maturity of excretory organs (liver and kidneys) but also reflects differences in body water and fat. In infancy and early childhood the surface area is larger, relative to that of the older child and adult, and so there is a risk of overdosing when using such a system.
To arrive at a safe yet effective concentration of a drug is not without difficulties. In fact, for many drugs the dosage regimens have not been accurately determined for every indication, even in adults. In the case of new antimicrobial agents, until recently pharmacological and toxicological investigations were more commonly carried out in an adult population, so that information in children and particularly in infants and neonates is often extremely limited. To derive the necessary information in childhood requires painstaking and careful observations in sick children, since pharmacokinetic information is not available from healthy children for ethical reasons. Lack of such information may preclude the widespread use of a potentially useful agent in childhood. Recent regulatory changes now actively encourage evaluation in childhood during drug development.
Table 15.1 Pharmacokinetic handling of drugs in childhood (compared with normal adult)
Paediatric prescribing recognizes the fact that growth and development, including organ function and metabolism, change in childhood. This is particularly so for the neonatal period in which chronological age, gestational age, and body weight are all important considerations. Furthermore, owing to physiological differences, information in the preterm or low-birthweight infant cannot necessarily be applied to heavier or full-term infants. Dosages of many drugs, including antimicrobial agents, vary on account of this state of flux of various physiological functions (Table 15.1).
Gastric pH is neutral at birth, but falls to adult levels by age 2-3 years. Gastric emptying is also slower in the first 3 months of life. Acid-labile drugs, such as the oral penicillins, are absorbed more efficiently than in the older child or adult. However, in general, apart from pre-term neonates, intestinal absorption is not a major concern.
Transdermal absorption is markedly increased in infants and was formerly associated with hearing loss after the application of polymyxin, and with methaemoglobinaemia following topical mafenide acetate. Intramuscular absorption can be less reliable but is rarely used.
Protein binding of drugs also varies with age, being lower in the neonate and infant and reflects the lower concentrations of serum albumin relative to adults. Reduced binding can increase the apparent volume of distribution of a drug, with an effect on peak and trough concentrations of certain agents. This is rarely of major therapeutic importance. Variation in renal maturity, differences in the extracellular fluid volume, and the immaturity of various enzyme systems are important determinants of drug disposition and metabolism.
Many drugs, including antimicrobial agents, undergo metabolic biotransformation before their elimination from the body. Such transformation is effected by a variety of enzyme systems, many of which are present in the liver.
In the neonate this organ and its enzymes are still maturing. Acetylation, oxidative, and conjugative phosphorylation are all less efficient in the first few weeks of life, particularly in the pre-term newborn. One example is the inefficient glucuronidation of chloramphenicol in some neonates so that toxic blood and tissue concentrations may develop. This can result in hypotension, cardiovascular collapse, and death if unrecognized. The syndrome has been graphically described as the ‘grey baby’ syndrome.
Other problems of drug toxicity and drug interactions are not peculiar to childhood and are discussed in Chapter 13.
In the neonate and especially the pre-term newborn, renal function is less efficient than in the older child since glomerular and tubular functions continue to mature. The creatinine clearance rate in the neonate is approximately one-third that in the older child. However, most infants achieve an adult glomerular filtration rate between 6 and 12 months of age. Hence, drugs excreted by the kidneys may require dose modification if toxicity is to be avoided.
Kidney function is not the only consideration. The volume of distribution of antibiotics is important in determining the dose that is necessary to achieve a therapeutic concentration at the site of infection. Agents that are essentially confined to the extracellular fluid, such as the aminoglycosides, are affected by the proportionally larger extracellular fluid volume in the pre-term and full term neonate compared with the older child and the adult. The extracellular fluid volume is approximately one-third of the body weight in the newborn.
To consider a specific example, the guidelines for prescribing the aminoglycoside gentamicin vary according to body weight, and also the chronological age, against which the drug's half-life varies inversely. This takes into consideration the immaturity of renal function, the different clearance rates, and the differing volumes of distribution. Thus the mean half-life of gentamicin in neonates less than a week old is about 4-5 h, whereas for infants older than 1 month the half-life decreases to 2-5 h. In order to ensure safe, yet therapeutic, drug concentrations in pre-term and term newborns, dosage of gentamicin are: premature neonate <1000 g 3.5 mg/kg every 24 h; term newborn <7 days postnatal 2.5 mg/kg every 12 h; term newborn >7 days postnatal and >2000 g 2.5 mg/kg every 8 h.
Drugs, including antibiotics, are frequently prescribed to pregnant women—although since the thalidomide disaster there has been a far more critical approach to prescribing in pregnancy. Antimicrobial agents are most commonly prescribed in pregnancy for maternal urinary and respiratory tract infections. They may also be prescribed to treat intrauterine infections such as amnionitis.
Pregnancy frequently alters the pharmacokinetic handling of drugs, including anti-infective agents. Plasma concentrations of ampicillin are 50% of those observed in the non-pregnant state, as a result of increased plasma clearance. The same applies to many cephalosporins.
Placental passage of antimicrobial agents
The placenta is not only an important defence against fetal infection, but also largely determines the concentration of a drug in fetal tissues. The transplacental passage of drugs may be by simple diffusion, or by an active transport system. As in other membrane situations, molecular weight, protein binding, ionizability, lipid solubility, and blood flow are all important considerations. In addition, the placenta is able to metabolize drugs through oxidation, conjugation, reduction, and hydrolysis. Drugs of low molecular weight (<1 kDa) tend to cross readily.
Antimicrobial agents that achieve good concentrations in fetal tissues include ampicillin, penicillin G, sulphonamides, metronidazole, and nitrofurantoin. The aminoglycosides cross moderately well and have occasionally been associated with fetal ototoxicity. The cephalosporins and clindamycin cross less readily, and erythromycin is particularly poor in this respect.
The general caution restricting all unnecessary prescribing in pregnancy, in particular during the first 3 months when organogenesis is maximal, also applies to antimicrobial drugs. For example, the antifolate properties of trimethoprim and the sulphonamides carry a theoretical risk of inducing fetal abnormalities. However, of more importance is the complication of hyperbilirubinaemia that can result should sulphonamides be prescribed in the latter few weeks of pregnancy or during the neonatal period. Displacement of protein-bound bilirubin by sulphonamide may result in toxic concentrations of bilirubin in the basal ganglia of the brain with the resultant risk of kernicterus.
Excretion of antimicrobial agents into breast milk
In common with other drugs, antimicrobial agents can enter human breast milk and therefore may potentially affect the suckling infant.
The secretory process may either be active or passive and the final concentration is determined by factors such as molecular weight, lipid or water solubility, the degree of protein binding and, of course, maternal serum concentrations. Breast milk has a neutral pH, which will affect the ionization of drugs.
Few antimicrobial drugs pass readily into breast milk to achieve concentrations similar to those in maternal blood. However, isoniazid and some sulphonamides do so. Tetracyclines achieve moderate concentrations and could possibly cause discoloration of primary dentition and enamel hypoplasia and hence its contra-indication in early childhood. Erythromycin is found in concentrations approximately half those present in maternal blood. Metronidazole achieves concentrations comparable with maternal serum levels. The penicillins and cephalosporins are generally poorly excreted into human breast milk.
In general, such concentrations are more of theoretical than of practical significance. There have been occasional reports of dapsone and nalidixic acid associated drug toxicity in children with glucose-6-phosphate dehydrogenase deficiency. Disturbance of the bowel flora has been reported with ampicillin; use of clindamycin has resulted in bloody diarrhoea. Under most circumstances, the short-term administration of antimicrobial agents to lactating mothers need not interfere with breast feeding.
Compliance in children
Of particular importance in paediatric prescribing is the acceptability of the medication to the patient. Injections are understandably unpopular with children and their anxious parents; oral preparations are preferred whenever possible provided their use does not compromise the likely success of therapy. In some cases antibiotics that are otherwise poorly absorbed when given by the oral route are available as esters or salts that exhibit greatly improved oral absorption, as for example with erythromycin. The need to make preparations palatable with syrup and flavourings is important if compliance is to be observed. Children generally find tablet and capsule preparations difficult to swallow—hence the popularity of flavoured syrup suspensions. A word of caution is necessary, since some preparations contain high concentrations of sucrose, which may encourage dental caries. This applies essentially to children on long-term preparations, which for the most part will be drugs other than antimicrobial agents.
In addition to palatability, compliance is increased by making the prescribing instructions clear and least disruptive to the normal daily routine. Unnecessary disturbance of sleep patterns is a sure way to reduce compliance.
An important aspect of all prescribing, particularly with paediatric formulations, which may be attractively coloured and sweet tasting, is the need to warn parents that any residual medication should be discarded.
Drugs should not be stored in anticipation of using them for a future infection. It is important to emphasize that accidental self-poisoning in childhood may occasionally be life threatening.
Prescribing for the elderly
As with most therapeutic agents, use of antibiotics is greatest in old age. This reflects the increased susceptibility to microbial disease as a result of degenerative, neoplastic, and metabolic disorders. Furthermore, the host response to infection is often impaired owing to involution or the immunosuppressive effects of disease or drugs. The inflammatory response is often dampened and this may lead to more serious infective states, which can have a profound effect on major organ function and thus modify response to antimicrobial therapy.
Infection is an important cause of morbidity and mortality in elderly people. The classic infections of childhood have little impact in old age, whereas infections of the respiratory tract, urinary tract, and skin structures become more common as one grows older. For example, the lower respiratory tract, often compromised by life-long exposure to cigarette smoke and atmospheric pollution, is an important target for infections that require medical consultation, hospital admission, and the administration of antibiotics.
Urinary tract infections increase substantially beyond the age of 50. In men this is largely related to benign or malignant enlargement of the prostate; in women it may have various causes, including sphincter disturbance, uterine prolapse, pelvic neoplasms, and poor hygiene compounded by periods of immobility.
Intra-abdominal infection may complicate gall bladder disease, diverticulosis, and malignancy of the bowel; metabolic disorders, notably diabetes mellitus, predispose to infection of the urinary tract and septicaemia, as well as infected ischaemic or neuropathic ulcers of the feet.
Pharmacokinetic and pharmacodynamic changes in elderly people
Elderly people are the least homogeneous population in relation to drug prescribing, which must take account of the involution of many physiological systems.
Gastric acid output often falls, with a rise in gastric pH; reduced blood flow to the gut and liver may lower first-pass extraction leading to increased oral bioavailability. Changes in lean body mass and body water may lower the apparent volume of distribution. Of greatest significance are changes in the functional integrity of the kidneys and liver, which can substantially alter drug disposition and elimination; superimposed disease can further aggravate the natural decline in function.
These changes may have the advantage of allowing higher concentrations of drug to be achieved, but the risk of toxicity may also increase. Loss of glomerular function is a normal concomitant of advancing years and may not be clinically apparent. For this reason all drugs should be used with caution in old people, especially those compounds for which the route of excretion is primarily renal. Use of aminoglycosides in elderly patients requires careful attention to dosage and monitoring of serum concentrations to ensure therapeutic, yet non-toxic, levels that may further impair renal, auditory, or vestibular function.
Unwanted effects of drugs are more common in elderly people. It is estimated that 10% of hospital admissions in the UK are caused solely, or in part, by adverse drug reactions. Some of these will be due to antimicrobial drugs. While some are idiosyncratic, others are related to dose or dose duration. This partly follows from the increased frequency of drug prescribing in this group, as well as the impaired efficiency of the excretory organs. However, certain drug reactions cannot be explained by such considerations as, for example, the increased frequency and severity of serious adverse reactions to co-trimoxazole seen in the elderly. Here rashes, including the Stevens-Johnson syndrome with extensive skin and mucous membrane ulceration, and major blood dyscrasias are more common in old people. The effect is almost certainly related to the sulphonamide component of this drug.
Old people are often prescribed multiple drugs, and such polypharmacy raises important issues of drug interactions that may affect pharmacological activity, as well as increasing the risks of side effects. Examples include the chelation of tetracyclines by antacids and the effect of H2-antagonists on the absorption of drugs such as the quinolones that are affected by alterations in pH. Likewise, the co-administration of theophyllines and quinolones, such as ciprofloxacin, or macrolides, such as erythromycin, can result in toxic concentrations of the former leading to agitation, confusion, and even seizures.
Poor compliance with medication may be the result of cognitive or visual impairment. Compliance with complex polypharmaceutical regimens can be assisted by daily ‘dosette’ containers and supported by written instructions for the patient or carer. Much can be done to mitigate the present high rate of adverse effects of medication.
The principles of antimicrobial prescribing are common to all age groups, but greater attention to issues of drug distribution, excretion, and potential for adverse reactions is necessary in patients at the extremes of age. The burden of infection falls most heavily on the very young and the very old, and antibiotic prescribing is correspondingly more common in these age groups. In the treatment of infection in children and old people it is essential, therefore, to choose the safest and most effective agent, and to use it in appropriate dosage for the shortest time necessary.