Gray Syndrome Research Articles

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

Regulatory science needs for neonates: a call for neonatal community collaboration and innovation.

Neonates have long been a vulnerable population to unstudied therapies, starting as early as the late nineteenth century with Mrs. Winslow’s Soothing Syrup, a purported remedy for teething that contained alcohol and morphine sulfate, causing numerous infant deaths (1). In 1959, Gray baby syndrome was first reported in infants receiving large doses of chloramphenicol as a broad spectrum antibacterial agent (2), and in 1983, Mulhall et al. (3) noted the altered pharmacokinetics (PK) of chloramphenicol in neonates and young infants resulting in elevated serum levels and some toxic effects.

Adverse drug reaction and toxicity caused by commonly used antimicrobials in canine practice

An adverse drug reaction (ADR) is a serious concern for practicing veterinarians and other health professionals, and refers to an unintended, undesired and unexpected response to a drug that negatively affects the patient's health. It may be iatrogenic or genetically induced, and may result in death of the affected animal. The ADRs are often complicated and unexpected due to myriad clinical symptoms and multiple mechanisms of drug-host interaction. Toxicity due to commonly used drugs is not uncommon when they are used injudiciously or for a prolonged period. Licosamides, exclusively prescribed against anaerobic pyoderma, often ends with diarrhoea and vomiting in canines. Treatment with Penicillin and ‚-lactam antibiotics induces onset of pemphigious vulgare, drug allergy or hypersensitivity. Chloroamphenicol and aminoglycosides causes Gray's baby syndrome and ototoxicity in puppies, respectively. Aminoglycosides are very often associated with nephrotoxicity, ototoxicity and neuromuscular blockage. Injudicious use of fluroquinones induces the onset of arthropathy in pups at the weight bearing joints. The most effective therapeutic measure in managing ADR is to treat the causative mediators, followed by supportive and symptomatic treatment.

Publishing the evidence for children’s medicines

The right of children to receive medicines that have been scientifically tested for both efficacy and safety is now becoming widely accepted. Tragedies such as the grey baby syndrome in...

The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children.

Altered drug disposition in the developing child occurs as a result of both biochemical and physiological changes. The clearance of many drugs is dependent on their biotransformation in the liver and small bowel and consequently is developmentally determined by a number of factors including both the activity and abundance of enzymes involved in Phase 1 and 2 drug metabolism. Altered drug metabolism can lead to the development of adverse effects in neonates and small infants that are not generally seen in the adult population. For instance, the altered metabolism of sodium valproate in children under 3 years of age is thought to be responsible for a higher incidence of hepatotoxicity, the impaired metabolism of chloramphenicol in neonates has resulted in the grey baby syndrome (cyanosis and respiratory failure) and metabolic acidosis following the use of propofol in the critically ill child may be due to altered drug metabolism. This paper reviews the potential contribution of the ontogeny of a number of drug metabolising enzymes including cytochrome P450 and glucuronoslytransferases to the development of adverse drug reactions in children.

Drug trials in children: problems and the way forward.

The drug-licensing system was introduced with the Medicines Act of 1968, following the thalidomide disaster, with the aim of ensuring that medicines are safe, effective and of high quality. There is increasing concern from the pharmaceutical industry, paediatricians, paediatric pharmacists and the Government that many medicines routinely used in children have not been formally evaluated by this system. Such use is therefore not supported by the assurances that the process brings. A joint report was produced in 1996 by the British Paediatric Association (now the Royal College of Paediatrics and Child Health) and the Association of the British Pharmaceutical Industry. This described in detail the current unsatisfactory situation and made specific recommendations for a way forward [1]. Since then several studies have documented the extent of unlicensed and off-label drug use in critically ill children, paediatric medical and surgical inpatients and neonates [2–4]. These studies all show that unlicensed and off-label drug use is a frequent occurrence for children in hospital with up to 90% of newborn infants in intensive care receiving either unlicensed or off-label treatment. Unlicensed medicines may be those compounded in a hospital pharmacy department or by a ‘specials’ manufacturer due to a lack of licensed alternatives. These medicines may not necessarily undergo the rigorous quality testing procedures that a licensed preparation must, and their quality may be variable. The term off-label refers to the use of a medicine outside the specifications of the product licence [5]. This covers medicines used at a different dosage to that recommended, in different age groups, by a different route or for a different indication. These off-label uses may be based on reliable published data, in which case prescribers can feel confident in using medicines in an off-label manner since this practice would be supported by peer review. In other instances they may rely more on the experience of the paediatrician or pharmacist, or drug information resources such as those of DIAL (Drug Information Advisory Line, Alder Hey Children’s Hospital, Liverpool). They are less likely to be supported by extensive clinical trial information, as would the manufacturer’s recommended uses of a licensed preparation.

Chloramphenicol

Chloramphenicol

Is Pediatric Labeling Really Necessary?

Labeling refers to the label on the drug container and all printed materials, including the package insert, that accompanies the product. Labeling of a drug indicates that there is substantial evidence from adequate and well controlled clinical trials for the safe and effective use of that drug. Labeling provides important information on clinical pharmacology, indications and usage, contraindications, precautions, adverse effects, dosage, and administration. Unfortunately for children, most drug labeling contains the precautionary disclaimer, because safety and efficacy in children have not been established. The availability of safe and effective drugs has been directly responsible for the improvement in health over the past 50 years. Children essentially have been excluded from the benefit of the many therapeutic advances that have marked pharmaceutic drug development. The failure to include children in clinical trials during drug development leads to delay in implementing potentially effective treatment. Most US food and Drug Administration-approved drugs lack approval for use in all children or are restricted to certain pediatric age groups, primarily older children.1 Only a few of the new drugs released in this country each year are approved for use in children. This lack of information on the safe and effective use of drugs in the most vulnerable patients, infants and neonates, is of greatest concern. Only five of the 80 most frequently used drugs have been approved for use in this population. Another problem is that most drugs are not available in suitable pediatric dosage forms. They are not available in appropriate dosage sizes, lack liquid formulation, and taste peculiar to the child, making compliance difficult. Pharmacies extemporaneously prepare many drugs in liquid dosage forms for use in children. These dosage forms are not sufficiently tested to determine stability, efficacy, or expiration dating. For solid dosage forms, parents often must divide adult tablets …

Clindamycin, Metronidazole, and Chloramphenicol

Clindamycin, metronidazole, and chloramphenicol are three antimicrobial agents useful in the treatment of anaerobic infections. Clindamycin is effective in the treatment of most infections involving anaerobes and gram-positive cocci, but emerging resistance has become a problem in some clinical settings. Metronidazole is effective in the treatment of infections involving gram-negative anaerobes, but it is unreliable in the treatment of gram-positive anaerobic infections and is ineffective in treating aerobic infections. Additionally, metronidazole is often the drug of choice in treating infections in which Bacteroides fragilis is a serious concern. Chloramphenicol is effective in the treatment of a wide variety of bacterial infections, including serious anaerobic infections, but is rarely used in Western countries because of concerns about toxicity, including aplastic anemia and gray baby syndrome.

Membrane action of chloramphenicol measured by protozoan motility inhibition.

The mechanism of the grey baby syndrome produced by chloramphenicol overdose is poorly understood. The present study assessed the membrane toxicity of this agent by means of its depressant effect on excitable tissues. The inhibition by drugs of protozoan motility was used as a toxicity endpoint, measured by the swimming speed of Tetrahymena pyriformis using an image analysis system. The n-octanol/water partition coefficient at pH 7.4, 37 degrees C was determined as a measure of the hydrophobicity of the drugs. Chloramphenicol dose-dependently depressed the motility of the test organism with an IC50 value (the concentration reducing the mean swimming speed to 50% of control) of 2.95 +/- 0.25 mM, in contrast to a significantly weaker effect of its succinate salt with an IC50 of 28.2 +/- 1.93 mM. Thiamphenicol, a drug with similar properties to chloramphenicol, produced little effect on protozoan motility. Several other antibiotics either in free or salt forms were also ineffective. A series of agents known to possess membrane stabilising action also tested for comparison showed that chloramphenicol possesses the ability to reduce protozoan motility. Measurement of the n-octanol/water partition coefficient revealed a value for chloramphenicol of 11.9 +/- 0.66. This property was correlated with protozoan immobilising potency among a series of heterogeneous compounds, suggesting that the mechanism involved a hydrophobic interaction with the excitable membrane. These results show that chloramphenicol has a depressant effect on protozoan motility comparable to agents with known toxicity effects on cell membranes. This suggests that chloramphenicol has the potential to cause membrane-mediated toxic effects, a mode of action that may underlie its acute toxicity to excitable tissues.

Drug toxicity and surveillance in children.

The use of medicines in children is an area of increasing after this syndrome was noted, pharmacokinetic studiesinterest [1]. Many medicines are being used outside the showed that newborn infants had impaired metabolismterms of their product licence [2] thereby increasing of chloramphenicol and that a reduction of the dosagethe risk of drug toxicity. Clinicians need to ensure not from 100 mgkg−1daily to 50 mg kg−1daily preventedonly that toxicity is kept to a minimum but also that the development of this syndrome [12].children arenot denied theuse ofappropriate medicines.This can only be achieved by the scientific study of drugtoxicity in children and is ideally carried out byprospective studies of drug surveillance. This involvesspecifically monitoring for drug toxicity, either in Toxicity in youngchildrenrelation to particular drugs [3,4] or selected patientgroups [5,6].Drug use in children may be accompanied Althoughtheseinitialstudies described clinicalproblemsby problems not seen in adults, or cause adverse drug in newborn infants, and the preterm infant in particular,reactions that are more frequent than in adults. An problems with other drugs have highlighted theexampleofthisismetoclopramide whichcausesdystonia enhanced toxicity of some medicines in children.in teenagers and Parkinsonism in the elderly [7]. Hepatotoxicity in association with the anticonvulsantsodium valproate was initially reported in 1979 [13].Subsequently more than 100 patients died, the majorityof whom were children. A retrospective review [14] of37 patients who died in the USA, showed that thoseAntibiotictoxicity inneonates patients at greatest risk fell into one of three categories:(i) age under 3 years; (ii) receiving other anticonvuls-Infectionshavealwaysbeena majorprobleminneonates ants as well as valproate; (iii) developmental delay.with significant mortality and morbidity. The introduc- Subsequent changes in prescribing habits resulted in ation of antibiotic therapy resulted in major clinical dramatic reduction in the number of deaths due toadvances [8]. However, antibiotic therapy also pro- sodium valproate [15]. The mechanism of valproateduced particular clinical problems. Silverman et al. hepatotoxicity is not fully understood but is thought toreported considerably higher mortality in neonates relate to abnormal metabolism [16]. Other anticonvul-receiving a combination of penicillin and sulphisoxazole sants result in enzyme induction and, therefore, enhancethan those receiving oxytetracycline [9]. There was a certain metabolic pathways resulting in the formationsignificantly higher incidence of kernicterus, both clini- of toxic intermediate metabolites. These pathways maycally(opisthotonos,spasticity,seizures, oculogyricmove- be more prominent in children under the age of 3 yearsments) and pathologically (yellow staining of the brain) and it is important to realise that drug metabolism inin the children who died following penicillin and the children differs from that of adults.sulphonamide. Subsequently, others have shown that The other drug causing hepatotoxicity specifically insulphonamides are highly protein bound and displace children was aspirin. The use of salicylates in childrenbilirubin from albumin [10]. As the preterm infant is with a mild viral infection resulted in a greater risk ofusually jaundiced, the sulphonamide displaced bilirubin developing Reye’s syndrome—a life threatening illnessfrom albumin and this is thought to increase the associated with drowsiness, coma, hypoglycaemia, seiz-incidence of kernicterus. ures and liver failure. Epidemiological work confirmedNewborninfants receivingchloramphenicoldeveloped the association between salicylate ingestion and theabdominaldistension,vomiting, cyanosis,cardiovascular development of Reye’s syndrome [17], although thecollapse, irregular respiration and subsequent death possible association had been postulated 15 years[11]. This was termed the grey baby syndrome. Shortly previously [18]. Starko et al. [17] studied children

Adverse Drug Reactions in Neonates

Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates.

Safety Assurance in Antimicrobial Therapy

AbstractThe toxicity of penicillins and cephalosporins per se is low but they cause hypersensitivity reactions in some patients. These antibiotics also disturb the ecological balance of the normal flora and lead to antibiotic associated colitis or other systemic superinfections in immunocompromised hosts. Aminoglycosides are oto‐ and nephrotoxic, erythromycin estolate causes sometimes liver function abnormalities, and clindamycin in particular causes pseudomembranous colitis. Chloramphenicol has been associated with aplastic anemia and gray baby syndrome, and tetracycline with discoloration of the teeth of infants.To avoid adverse effects and to assure the safety of antimicrobial therapy, one should avoid unnecessary antibiotic administration, and make the duration of antibiotic therapy as short as possible. Blood levels of chloramphenicol or aminoglycosides have to be monitored in cases with lowered renal function and in prolonged therapy.

Acidosis as a presenting feature of chloramphenicol toxicity

Metabolic acidosis has previously been described in the gray baby syndrome, but has not been documented as a presenting feature. Four seriously ill children (bronchiolitis, hypoaldosteronism, dysautonomia, Reye syndrome), ages 4 months to 11 years, received chloramphenicol (CAP) intravenously. After initial stabilization, unexplained metabolic acidosis occurred 40 to 81 hours after beginning CAP. Serum CAP concentrations were 84, 62, 80, and 30 micrograms/ml, respectively, when acidosis was recognized. Hypotension, hypothermia, and abdominal distension occurred a mean of 23 hours after the onset of acidosis. Acidosis resolved and signs of the gray baby syndrome cleared with the decrease in serum CAP concentrations. Metabolic acidosis should be considered an early sign of CAP toxicity, and CAP should be used in reduced doses in severely ill patients, especially those with liver dysfunction.

Acute myocardial effects of chloramphenicol in newborn pigs: a possible insight into the gray baby syndrome.

Mechanical function and mitochondrial respiration were observed in newborn pig hearts in the presence of chloramphenicol. Isolated perfused hearts exposed to chloramphenicol (25, 50, or 100 micrograms/ml) demonstrated acute reductions in pressure development and cardiac output accompanied by elevated left atrial filling pressure. The effects of chloramphenicol and chloramphenicol succinate (25, 50, 100, or 200 micrograms/ml) on oxidative activity of isolated mitochondria were also investigated. With unesterified chloramphenicol, inhibition of state 3 respiration was most apparent when glutamate and palmitylcarnitine were supplied as substrates. Inhibition of mitochondrial oxidation of succinate or glutamate was only detectable at 200 micrograms/ml. Inhibition of alpha-ketoglutarate oxidation was not seen at any concentration of antibiotic studied. Chloramphenicol succinate most strongly inhibited state 3 oxidation of succinate and alpha-ketoglutarate and had relatively mild effects on oxidation of glutamate and palmitylcarnitine. Succinate oxidation by submitochondrial particles was unaffected by chloramphenicol succinate, a result suggesting interference with succinate transport.

ACIDOSIS IS A PRESENTING FEATURE OF CHLORAMPHENICOL TOXICITY

Chloramphenicol (CAP) is an inhibitor of mitochondrial protein synthesis and impairs energy production through interference with oxidative phosphorylation. Metabolic acidosis associated with lactic acidemia has not been described as a presenting feature of CAP toxicity. Three critically ill children 6 mos to 11 y/o (congenital hypoaldosteronism, brain stem dysfunction, Reye's syndrome) received CAP (75-100 mg/kg/d) and had normal pH and stable cardiovascular, renal and pulmonary function for 48 hrs. Each developed profound acidosis (arterial pH 7.13-7.22) 60-108 hrs after beginning CAP. Initial CAP conc. were 61, 80, and 30 mcg/ml and subsequent levels decreased; CAP was 30 mcg/ml in the child with Reye's syndrome, a condition with recognized mitochondrial dysfunction. SGPT conc. were 386, 2,620, and 145 IU/1 when acidosis was recognized. Serum lactate was 6.6 and 8.8 mM in 2 patients prior to CAP and increased to 11.1 and 17.1 mM. Mean anion gap increased from 16.8 to 32.3 mM in the 3 patients. Hypotension followed acidosis by 6-19 hrs and was severe in one and mild in 2. Other signs of gray baby syndrome were absent. CAP was stopped in each patient and resolution of acidosis and hypotension paralleled the fall of serum CAP. 1) Unexplained metabolic acidosis is an early sign of CAP toxicity; 2) pre-existing lactic acidemia, hepatic dysfunction, and/or mitochondrial dysfunction may predispose to CAP toxicity; 3) toxicity may occur with CAP levels in a therapeutic range in Reye's syndrome.

Serum level monitoring of antibacterial drugs. A review.

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations. Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring. Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the 'grey baby syndrome' and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients. Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function. The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.

Chloramphenicol toxicity in neonates: its incidence and prevention.

The incidence of dose related chloramphenicol toxicity was determined in 64 neonates from 12 hospitals. Ten of the 64 exhibited symptoms attributed clinically to chloramphenicol toxicity. Nine received the dose prescribed and one an overdose. Symptoms of the grey baby syndrome were observed in five of the 10 babies; four babies suffered reversible haematological reactions; and one baby was described as very grey. Peak serum chloramphenicol concentrations in these 10 babies ranged from 28 to 180 mg/l and trough concentrations from 19 to 47 mg/l. Serum chloramphenicol concentrations above the therapeutic range (15-25 mg/l) were observed in a further 27 neonates (two had received a 10-fold overdose), none of whom showed signs of toxicity. Serious toxicity was associated with either prescription of dosages greater than that recommended or overdosage of chloramphenicol. High concentrations in young neonates may be avoided by prescribing and giving the recommended dose and then careful monitoring; concentrations should be maintained between 15 and 25 mg/l. No babies with concentrations within this range showed clinical signs of toxicity.

EFFICACY OF CHLORAMPHENICOL IN THE TREATMENT OF NEONATAL AND INFANTILE MENINGITIS: A STUDY OF 70 CASES

The efficacy of chloramphenicol in the treatment of 21 neonates and 9 infants with proven meningitis and 37 neonates and 3 infants with suspected meningitis was evaluated from mortality and morbidity data, and by assay of the drug in serum and cerebrospinal fluid. Minimum inhibitory concentrations (MICs) were established for ten isolates. 25% of neonates and 50% of infants had subtherapeutic concentrations of chloramphenicol in serum or cerebrospinal fluid. Dosage was less than that currently recommended in over half of these subjects. Mild toxicity (reversible thrombocytopenia) was observed in only 1 of 20 babies being treated at the recommended dose. Toxic reactions, including the grey-baby syndrome, occurred in 10 babies receiving higher doses. In 4 cases, doses up to ten times that prescribed had been given, and death of 1 baby was attributable in part to chloramphenicol toxicity. 5 of 21 neonates and 1 of 9 infants with bacteriologically proven meningitis died, an overall mortality of 20%. Those infected with gram-negative bacteria had a higher mortality than those infected with gram-positive bacteria (p<0·05). 21% of the survivors had neurological sequelae. Therapeutic concentrations of chloramphenicol will be achieved in serum and cerebrospinal fluid with daily doses of 25 mg/kg in preterm and term infants during the first week of life and 37·5-50 mg/kg for older term babies. The drug should be assayed at 48-hour intervals, to maintain concentrations in the therapeutic, non-toxic range. Dosage should be increased when the peak serum concentration falls below 20 mg/l and decreased when the trough serum concentration exceeds 15 mg/l or the peak concentration exceeds 30 mg/l.

Chloramphenicol

Chloramphenicol was introduced into medical practice in 1949. At therapeutic concentrations of 10 to 20 micrograms drug per ml, the drug inhibits bacterial ribosomal and, to a lesser extent, mammalian mitochondrial protein synthesis but concentrations above 60 micrograms drug per ml induce progressive reduction of oxygen-dependent cellular metabolism. Some adverse reactions (e.g. bone marrow suppression and the "gray baby syndrome") reflect these effects. The pathogenesis of chloramphenicol-induced aplastic anemia remains unclear. Chloramphenicol is most bioavailable after oral administration and has a remarkable ability to diffuse into body fluids and tissues. However, there are wide interindividual variations in its metabolism and elimination, particularly in newborns. Chloramphenicol is indicated for invasive ampicillin-resistant H. influenzae infections; for patients allergic to penicillin with pneumococcal, meningococcal or H. influenzae meningitis; in patients under 8 years of age with Rocky Mountain spotted fever; and for the treatment of brain abscess and other severe anaerobic infections (excluding endocarditis) due to B. fragilis. Other indications include selected patients with Salmonella meningitis or carditis, rickettsioses and intraocular infections. Unravelling the pathogenesis of chloramphenicol-induced aplastic anemia is critical to more widespread application of this remarkable antimicrobial.