Pharmacology of Antibiotic Therapy & Drug Resistance
John van den Anker, of the Children’s National Medical Center and the George Washington School of Medicine & Health Sciences, in Washington, D.C. believes that there are now considerable data available to assist in selecting antibiotic therapy which will achieve maximum effectiveness with minimal toxicity and with reduced risk of producing resistant strains of bacteria.
Of all the drugs given to newborn babies, the commonest are antibiotics and these include a wide variety of drugs (Figure 3.1). Antibiotics are administered for suspected sepsis and since there are no absolute criteria for diagnosis of sepsis many treated babies do not have infection. This is a concern due to the risk of developing resistant strains of infection.
Dr. van den Anker discussed that a baby’s development has a large impact on the way drugs are handled. He referred to decreased gastric acidity in the first days of life predisposing a baby at that stage to be able to better absorb orally administered drugs. He showed examples of changes in clearance of amoxicillin (Figure 3.2), ceftazidime (Figure 3.3), and amikacin (Figure 3.4). All showed reduced clearance, related to gestational age, in the newborn with rapid reversion to values for children after a few days or weeks. He also pointed out that disorders such as asphyxia, hypoxia etc could interfere with the metabolism and excretion of drugs. Specifically he showed that hypoxic infants had delayed clearance of drugs (Figure 3.5).
There is clear change in drug clearance early in post-natal life.
Dr. van den Anker then introduced his and other studies of aminoglycosides in the newborn. He prefaced his remarks by saying that in terms of effectiveness, cost and due to the low incidence of induction of bacterial resistance, aminoglycosides are the best treatment for sepsis in newborns.
He described the usual means of monitoring drug kinetics citing the importance of the minimum inhibitory concentration and “area under the curve”. This has been the practice in monitoring the use of aminoglycosides to ensure effectiveness and to reduce the potential for ototoxicity and nephrotoxicity. This approach has now undergone dramatic change based on scientific studies of drug monitoring and toxicity.
In introducing the topic he cited a study in which therapy of newborns with penicillin and tobramycin was compared to amoxicillin and ceftazidime. (Figures 3.6 and 3.7). . In that study, infants in one NICU were treated for sepsis with either a combination of amoxicillin and ceftazidime or penicillin and tobramycin (an aminoglycoside). In the second phase (cross over) the drugs used in the units were reversed. Drug resistance was then studied after completion of the course. Anal and respiratory swabs were taken weekly. In the figures each open circle represents resistance to the antibiotic used. There were three resistant isolates (out of 2519 tested) in the penicillin/tobramycin group and 41 (out of 1914 tested) in the amoxicillin/ceftazidime group. The conclusion was that an antibiotic regimen avoiding the use of amoxicillin and ceftazidime restricts the development of resistance. Both treatments were effective however the development of bacterial resistance was much higher in the amoxicillin/ceftazidime group.
Dr. van den Anker then cited a metanalysis of 24 reports of trials in children which suggested that once daily dosing of aminoglycosides was as effective as more frequent administration (Figures 3.8, 3.9, 3.10 and 3.11).
This then lead to studies of:
Dosage: It is now recommended that a dose of 4-5 mg/kilo is the appropriate dose.
Frequency of administration: It is now recommended that aminoglycosides should be given once per 24 hours in full term newborns and less frequently in prematures.
The question of toxicity following therapy in newborns was then addressed. A study of 625 children was carried out (Figures 3.12 and 3.13). Multiple factors were examined to determine whether they influenced the development of ototoxicity (Figure 3.14). There appeared to be no relation between the development of ototoxicity and use of tobramycin. Therefore there was no evidence that aminoglycoside therapy was toxic and no evidence that monitoring drug levels was necessary during the first days of life. Monitoring of drug levels is indicated if the neonate is extremely ill, severely asphyxiated, has been exposed antenatally or postnatally to NSAIDs and if started on ECMO. (Figures 3.15 and 3.16)
Accordingly it was recommended that full term newborn infants with suspected sepsis should receive aminoglycosides empirically at a dose of 4-5 mg /kilo/ once daily and that monitoring of drug levels is unnecessary. Premature infants should receive treatment every 36 hours, with the smallest infants being treated every 48 hours. If treatment with aminoglycosides cannot be discontinued after 48-72 hours because of the underlying disease monitoring of drug levels will be necessary to optimize the treatment outcome.