Pharmacokinetics and clinical studies with cefadroxil in paediatrics

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1 Journal of Antimicrobial Chemotherapy (9), Suppl. B, 5-9 Pharmacokinetics and clinical studies with cefadroxil in paediatrics A. Windorfer and P. Bauer Department of Paediatrics, Technical University, Munich, West Germany The results of pharmacokinetic studies with cefadroxil in serum and saliva of infants and children after single doses of 5 mg/kg body weight are presented. The kinetic parameters largely correspond with those found in adults. Two hours after drug administration mean salivary concentrations of - and - mg/ were found in the two age groups studied. These values are above the minimal inhibitory concentrations for Staphylococcus aureus, Streptococcus pneumoniae and Str. pyogenes. Because of the longer elimination half-life of cefadroxil in comparison to those of other oral cephalosporins, we investigated the therapeutic efficacy and tolerability of a twice-daily dosage regimen in children. Cephalexin and cefaclor were used for comparison. Similar results were obtained for both agents when comparing cefadroxil with cefaclor in respiratory and urinary-tract infections in children. Both substances were administered in doses of 5 mg/kg daily, cefadroxil being given bid and cefaclor tid. Clinical success, as indicated by the time period which elapsed until body temperature returned to normal, as well as the bacteriological efficacy determined by the rate of bacterial eradication, were about the same for cefadroxil and cefaclor with the dosage regimens used. Phannakokinetische und klinische Untersuchungen fiber in der Padiatrie Es werden phannakokinetische Untersuchungen von in Serum und Speichel bei Sauglingen und Kleinkindern nach einmaliger Gabe von 5 mg/kg Korpergewicht prasentiert. Die kinetischen Parameter stimmen weitgehend mit denen u herein, die bei erwachsenen Patienten ermittelt wurden. Die Speichelkonzentrationen lagen Stunden nach Applikation im Durchschnitt bei, bzw., mg/ und damit fiber der MHK gegen Staphylococcus aureus, Streptococcus pneumoniae und Streptococcus pyogenes. Aufgrund der langeren Eliminationshalbwertszeit im Vergleich zu anderen Oralcephalosporinen lages nahe, auch im Kindesalter die Wirksamkeit und Vertraglichkeit von bei zweimal-taglicher Gabe zu testen. Als Vergleichssubstanzen wurden Cephalexin und gewahlt. Es zeigte sich, dafi bei Infektionen der oberen Luftwege 5 mg pro kg Korpergewicht in Einzeldosen ebenso wirksam sind wie mg Cephalexin pro kg Korpergewicht in 4 Einzeldosen. Ahnliche Ergebnisse zeigte auch der Vergleich von und bei Atemwegs- und Harnwegsinfektionen im Kindesalter. Hier wurden beide Substanzen in der gleichen Tagesdosis von 5 mg/kg Korpergewicht eingesetzt, wobei wieder x taglich, jedoch x taglich verabreicht wurde. Sowohl der klinische Erfolg, ablesbar an dem Zeitraum bis zur Entfieberung, als auch die bakteriologische Wirksamkeit, ablesbar an der Rate der Keimelimination, waren fur beide Substanzen etwa gleich //B5 + 7 $./ 5 9 The British Society for Antimicrobial Chemotherapy

2 A. Windorfer and P. Bauer Introduction is active against Gram-positive and Gram-negative organisms, including penicillin-sensitive and resistant strains of staphylococci, Streptococcus pyogenes, pneumococci, Escherichia coli, Proteus mirabilis and, to a limited extent, Haemophilus influenzae. Although this spectrum of antibacterial activity is similar to that of other oral cephalosporins, cefadroxil has some advantages in the treatment of infections in children, particularly because of its favourable pharmacokinetic properties. Methods We performed three different studies. In the first we investigated the serum and salivary concentrations of cefadroxil after the first oral administration of 5 mg/kg to children ( infants and young children) who required antibiotic treatment. Seven blood samples were obtained from each child over a period of h through an existing intravenous infusion. At, and h samples of saliva were collected in capillary pipettes. Briefly, 5 ml samples were used for determining the drug concentrations by a method developed in our laboratory using high-pressure liquid chromatography (HPLC) on a C- column, as published earlier (Windorfer, Alterthum & Bauer, 9). The samples were mixed with 5 ml trichloracetic acid; after vigorous shaking and centrifugation ml of the supernatant were injected into the HPLC apparatus (Kontron). The mobile phase was acetonitrile/water/acetic acid 5/5/, the flow rate was ml/min and the detection wavelength 5 nm. Two treatment studies were performed in children, - years of age, hospitalized with respiratory or urinary-tract infections. The patients were assigned treatment with cefadroxil monohydrate or cefaclor alternately. No other antibacterial medication was given. Complete blood counts and blood chemistry examinations as well as complete urinalysis were performed before treatment was started and were repeated at the end of the medication period. Nose and throat swabs were taken from patients with respiratorytract infections. Urine samples were obtained by the clean-catch midstream technique. Susceptibility was determined by the method of Kirby-Bauer with /ig cefadroxil or cefaclor discs. If the inhibition zone was 4 mm or less the organism was considered resistant and the patient withdrawn from the study. The dosage regimen for the cefadroxil group was 5 mg/kg per day in two divided doses every h and for cefaclor 5 mg/kg per day in three divided doses every h. Both drugs were administered as oral suspensions either with or after the meals. Results The mean values of cefadroxil in serum and saliva were calculated separately for infants and young children (Figure ). In order to show interindividual variations the peak serum concentrations measured at - h after drug administration are given (Tables I and II). Mean peak concentrations were 4- ±5- mg/ for infants and mg/ for young children, which was not a statistically significant difference. Thecefadroxil plasma half-life was h in infants and h in young children. The peak salivary concentrations of cefadroxil ranged between -+- ( h) and - + ( h) mg/ and were higher than the minimal inhibitory concentrations (MIC) for three important pathogens: Str. pyogenes, Sir. pneumoniae and Staphylococcus aureus. Concentrations at h were too low to measure.

3 Phannacokinetics and clinical studies with cefadroxil in paediatrics 7 Infants ( - ) Serum (O-O) Salivo rv Young children ( - ) Serum (O-O) Soliva Staph. aureus Str. pneumonias Staph. aureus Str. pneumoniae Str. pyogenes I I I I I I I I I I 4579 II Str. pyogenes I I I I I I I I I I I II Time (h) Figure. Mean serum and salivary concentrations of cefadroxil after 5 mg/kg body weight to infants (n = ) and young children (n = ). Minima) inhibitory concentrations of cefadroxil for staphylococci and streptococci. Table I. Peak serum and sahvary concentrations of cefadroxil and elimination half-life in infants after an oral dose of 5 mg/kg Patient no Mean + s.e. Age 4 months 7 months 4 months 5 weeks 9 months months 7 months months Peak serum level [mg/ (h)] (h) ( h) 5- ( h) - ( h) 4-9 ( h) 5- ( h) - ( h) 9-5 ( h) Elimination half-life 7j(h) I Peak salivary cone (mg/) Table EL Peak serum and salivary concentrations of cefadroxil and elimination half-life in young children after an oral dose of 5 mg/kg Patient no Mean + s.e. Age (years) Peak serum level [mg/ (h)] 9 ( h) 4- ( h) - ( h) 5-7 ( h) -7 ( h) 9- ( h) 7-9 ( h) 4-( h) 7- (lh) 5- ( h) 4 ( h) - ( h) Elimination half-life 7j(h) M Peak salivary cone (mg/)

4 A. Windorfer and P. Bauer Table m. Comparison of cefadroxil and cefaclor in children with respiratory tract infections: patient characteristics prior to treatment Number of patients... Age (months) Severity of infection Mild Moderate Severe Pre-treatment duration of illness (days) Sex Male Female General condition ± ±7-4 - ± ±4-5 Table IV. Comparison of cefadroxil and cefaclor in children with respiratory tract infections: bacteriological data Causative pathogen H. influenzae Staph. aureus Str. pneumoniae Str. pyogenes K. pneumoniae (Number of bacteria eradicated in parentheses) There were two isolates from one patient n = (4) 9() KD 5(5) (*) * = () (4) 5(5) () () (9) In the study of respiratory infections children were treated with cefaclor and 9 with cefadroxil. The general condition prior to treatment was good or fair in most of the children: only were in poor general condition (Table III). The pathogens isolated and their response to the trial drugs are shown in Table IV. Each of the trial medications failed in cases to eradicate the infecting organism: cefadroxil eradicated 4 of the isolates of Haemophilus influenzae and of the 9 isolates of Staph. aureus, while cefaclor failed to eradicate of the isolates of Staph. aureus and one of the Klebsiella pneumoniae isolates but eradicated all of the isolates of//, influenzae. The overall efficacy of the trial medications in respiratory tract infections is shown in Table V. Both antibiotics were equally effective in improving the signs of infection as indicated by the time elapsed until body temperature returned to normal. On the basis of our results cefadroxil or cefaclor were considered to be equivalent in the doses given. The duration of treatment was the same for both preparations. In the study of 9 children with urinary-tract infections treatment either with cefadroxil or cefaclor was given using the same design as in respiratory tract infections. Table VI summarizes the clinical data of the patients. Table VII lists the causative pathogens

5 Phannacokinen'cs and clinical studies with cefadroxil in paediatrics 9 Table V. Clinical and bacteriological response to cefadroxil and cefaclor in children with respiratory tract infections * Same patient Time until body temperature returned to normal (days) Bacteriological cure (% of patients) Clinical response (no. of patients) Excellent Adverse drug reactions Exanthem Diarrhoea Mean duration of treatment (days) (5 mg/kg b.i.d) % * * -47±4- (5 mg/kg t.i.d.) 4±l- Table VI. Comparison of cefadroxil and cefaclor in children > vith urinary tract infections: patient characteristics prior to treatment Number of patients... Age (months) Severity of infection Mild Moderate Severe Pre-treatment duration of illness (days) Sex Male Female General condition ± % 5-4± ± identified in the pre-treatment urine culture and their response to the treatment, which proves that both drugs were equally effective in eradicating the infecting organism. No treatment failure occurred in this study. The equivalence of cefadroxil and cefaclor is shown also by the clinical response, by the time between the beginning of treatment and the return of body temperature to normal values, and by the duration of treatment (Table VIII). In all patients the efficacy of the drugs was rated good or excellent by the investigators. The tolerability of the trial medications was good, only eight patients (9%) developing adverse drug reactions in the form of diarrhoea and rash, which were mild and transient

6 9 A. Windorfer and P. Bauer Table VII. Comparison of cefadroxil and cefaclor in children with urinary tract infections: bacteriological data Causative pathogen (n = *) (n = 9*) K. pneumoniae () E. coli 9 (9) 9 (9) Pr. vulgar is () () Number of organisms eradicated in parentheses. * One patient had two pathogens. Table VHI. Clinical and bacteriological response to cefadroxil and cefaclor in chidren with urinary tract infections Time until body temperature returned to normal (days) Bacteriological cure (% of patients) Clinical response (no of patients) Excellent Adverse drug reactions Exanthem Diarrhoea Mean duration of treatment (days) Total quantity of drug administered (g) (5 mg/kg b.i.d.) ±l % ±- (5 mg/kg t.i.d.) -9± - % 4-±5-9-4±9-9 in six children. Only in one child the route of administration had to be changed from oral to parenteral cephacetrile because of severe diarrhoea. With the exception of those pathological findings that were due to the infection and which returned to normal during therapy, blood chemistry and haematological data as well as urinalysis did not reveal any abnormalities attributable to the trial medications. Discussion In a study using cephalexin (Marget & Daschner, 95) at 5 mg/kg, half-life times ranging between -5 and h were found in infants of 4- months of age, with peak drug serum levels of -7 mg/ measured at - h after drug administration. These values are well ^low the peak serum levels and drug concentrations at h obtained with cefadroxil. In their extensive studies on the elimination half-lives of various oral cephalosporins, Ginsburg et al. (97) found a half-life for cefadroxil of ---5 h in infants and young children, which is lower than that obtained in our study. However, they administered lower doses of cefadroxil and consequently obtained lower serum concentrations ranging between and 4 mg/. The elimination of cefadroxil is dose-dependent (Pfeffer et al.,

7 Pharmacokinetics and clinical studies with cefadroxil in paediatrics 9 977). According to Pfeffer et al. (977), the renal tubular secretion mechanism becomes saturated at the relatively low drug-serum concentration of mg/ for cefadroxil at which tubular secretion proceeds at its maximum rate (T m ) of about 5 mg/h. This may be the primary reason for the longer elimination Half-life of cefadroxil. The pharmacokinetic properties of cefadroxil appear to justify the dosage regimen of 5 mg/kg twice daily in children beyond the age of month. This dosage recommendation is supported by clinicalfindingsreported by Santella and Battin as well as our own which showed that the twice-daily administration of 5 mg/kg of cefadroxil was as effective as 5 mg/kg of cephalexin given four times daily. The low incidence of adverse drug reactions corresponds well with that reported by Ginsburg et al. (97), which was 5% for cefadroxil and less than % for cefaclor. It must be emphasized that both types of manifestations (intestinal disturbances and cutaneous reactions) were considerably less pronounced and of shorter duration than the adverse reactions observed after administration of ampicillin or amoxycillin. We observed good activity of cefadroxil against H. inflnenzae clinically, which is in line with the findings of Santella et al. (97) who, in a world-wide study carried out in 97, reported a % rate of bacterial eradication of these pathogens achieved by treatment with cefadroxil. Our findings confirm that the twice-daily dosage regimen of cefadroxil provides satisfactory treatment of respiratory and urinary tract infections comparable to that obtained with other antibiotics. Patient compliance is a serious problem, particularly in young children, not only in long-term treatment, but also with treatment regimens of shorter duration. Charney et al. (97) found a compliance rate of % in children with acute diseases on the fifth day of treatment, which decreased to 5% on treatment-day 9. In a study performed in a small number of children receiving a sulphonamide combination for the treatment of acute bacterial infections we obtained similar results (Windorfer, Rabl & Kaferlein, 9). The compliance rate was clearly higher in children re-examined on treatment days and than in those re-examined on day only. This means that even in acute diseases the patient compliance declines with the improvement of the acute signs of infection. A drug which has to be taken only twice daily (in urinary tract infections even once-daily use might be feasible) will certainly improve the patient compliance and may consequently provide more effective treatment. References Charney, E., Bynum, R., Eldredge, D., Frank, D., MacKinney, O. B., McNabb, N., Scheiner, A., Sumpter, E. A. & Iker, H. (97). How well patients take oral penicillin? A collaborative study in private practice. Pediatrics 4,. Ginsburg, C. M., McCracken, G. H., Clahsen, G. & Thomas, M. L. (97). Clinical pharmacology of cefadroxil in infants and children. Antimicrobial Agents and Chemotherapy, 45-. Marget, W. & Daschner, F. (99). Untersuchungen zur Anwendung von Cephalexin im Kindesalter. Arzneimittel Forschung 9, 95. Pfeffer, M., Jackson, A., Ximenes, J. & Perche de Menezes, J. (977). Comparative human oral clinical pharmacology of cefadroxil, cephalexin and cephradine. Antimicrobial Agents and Chemotherapy, -. Santella, P. J., Tanrisever, B. & Berman, E. (97). An overview of results of world-wide clinical trials with cefadroxil. Journal of International Medical Research,, 44. Windorfer, A., Alterthum, K. & Bauer, P. (9). Untersuchungen zur Pharmakokinetic von Im Kindesalter. Infection Suppl. 5, 57. Windorfer, A., Rabl, W. & Kaferlein, W. (9). Untersuchungen fiber das Medikamenteneinnahmeverhalten bei akuten Erkrankungen im Kindesalter. Kinderarzt,