Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children Ole Jörgen Moe, Alf Meberg & Jan Eng To cite this article: Ole Jörgen Moe, Alf Meberg & Jan Eng (1977) Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children, Scandinavian Journal of Infectious Diseases, 9:1, 31-36, DOI: 10.3109/inf.1977.9.issue-1.08 To link to this article: http://dx.doi.org/10.3109/inf.1977.9.issue-1.08
Published online: 02 Jan 2015.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [UQ Library]
Date: 07 May 2016, At: 20:54
Scand J Infect Dis 9: 3 1-36, 1977
Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children OLE JORGEN MOE,' ALF MEBERG'and JAN ENG2
Downloaded by [UQ Library] at 20:54 07 May 2016
From the 'Department of Paediatrfcs nncl the 2Microbiological Lnboratory. Ullevdl Hospital, Oslo, Norwny
ABSTRACT. 16 children, aged 1-10 years, suffering from urinary tract infection were randomly divided into two groups. Ten children were treated with ampicillin pediatric suspension in a dose of 100 mg ampicillin/kg/24 hours divided in 4 doses, and 6 children with pivampicillin base pediatric suspension in a dose of 64.8 mg/kg/24 hours divided in 4 doses (-50 mg ampicillin/ kg). The treatment period was 14 days with all infections being cured. Despite the fact that pivampicillin was administered in half of the dosage of ampicillin the resulting peak serum concentration was 65 % higher and was achieved more rapidly. The bioavailability and urine concentration were also greater. A marked change in the rectal aerobic bacterial flora occurred during both treatment regimens. In 13 children (81%) a shift took place from ampicillin-sensitive E. coli to ampicillin-resistant Klebsiella strains as the predominating microbe, equally often in both groups of treatment. Ampicillin-resistant E. coli appeared in one child in each group.
INTRODUCTION Ampicillin has proven useful in the treatment of urinary tract infection (UTI) in children. Oral ampicillin, however, is hampered by incomplete and variable absorption from the gastrointestinal tract (2). Only 25-30% is recovered in the urine (4, 11). In infections involving the renal tissue (pyelonephritis), high serum concentrations of ampicillin are needed to give adequate amounts of the drug in the parenchyma (3). Pivampicillin, the pivaloyloxymethyl ester of ampicillin, is rapidly hydrolysed into ampicillin and pivalic acid in the body after oral administration (4). The antimicrobial effect is attributed to released ampicillin. Marget et al. (10) compared the absorption and clinical effect of pivampicillin hydrochloride, administered as powder from commercially available capsules, and ampicillin suspension in children under 12 months of age. Considerably higher serum concentrations were obtained with the ester than with ampicillin. A similar comparative investigation in children with the commercially available ampicillin and pivampicillin pediatric suspensions has not been previously reported. The purpose of the present investigation was to
study the clinical effects, the concentrations of ampicillin in serum and urine, and the changes in the intestinal bacterial flora caused by commercially available oral suspensions of ampicillin and pivampicillin administered to children with UTI. MATERIALS AND METHODS Aiitibiorics Pivampicillin was administered a s a suspension of free pivampicillin base (32.4 mglml, equimolar t o 25 mg of ampicillin/rnl). The preparation was supplied by Leo Pharmaceutical Products, Copenhagen, Denmark. and is now commercially available (Pondocillin"). Ampicillin was administered as the commercially available suspension, Doktacillin" Astra (50 mglml). All of the ampicillin bottles were of the same batch. The drugs were administered in equal volumes, 0.5 ml/kg every 6 hours for 14 days. Thus a double molar dose of ampicillin was given compared to that of pivampicillin. The antibiotic administered was chosen at random. Pntierits
17 children were included in the investigation. They were divided into 2 groups depending upon the medication given. Table 1 lists their data. All patients were hospitalized during the absorption tests. Informed consent was obtained from the parents. None of the children had received any antibiotics during the last 3 weeks prior to hospitalization.
32
0 .J . Moe et (11.
Table I . Data on 17 children with UTI trecrtecl ornlly with suspensions of crinpicilliri ( i t i d pivritnpicilliri bcise
Downloaded by [UQ Library] at 20:54 07 May 2016
Drug
Total no. of patients Girls A. Acute infection Recurrent infections B. Intravenous urography Normal Scarring (slight) Ureter duplex C. Cystourethrography Normal “Irregular bladder mucosa” D. Cystoscopy Normal Hyperemic bladder mucosa E. Infecting organism E. coli Proteus Enterobacter No growth Age range in years Mean age in years
Ampicillin
Pivampicillin
10
1
7“ 6 3 4 7 6 I 0
5
5
3
3
2
2 0
2 2 I
2
1
5
7 0 0
7 4 6 10
8 1
I I 3 1-10
6
0 5-9 64
and deoxycholate agar and incubated for 18 hrs at 37°C. The aerobic organism predominating in the flora was identified and its antibiogram was determined. Absorptioti studies On the 5th day of treatment samples for antibiotic assays in blood and urine were collected. Blood samples were taken in conjunction with the second dose of antibiotic. The patients were in the semifasting state (4 hrs after breakfast) and food was not given for 2 hrs after medication. Samples were taken in a cubital vein through an indwelling cannula. The cannula was flushed with heparin between samples. Blood samples were taken before medication, 15, 30, 60 min and 2, 4, and 6 hrs after the test dose of ampicillin (25 mg/kg) or pivampicillin (equimolar to 12.5 mg of ampicillin/kg). The absorption study failed in 2 patients treated with ampicillin (due to technical error). Urine was sampled during the test period (6 hrs). The blood and urine specimens were refrigerated at 4°C. The concentrations of ampicillin were measured on the following day. The assay of ampicillin concentration in serum and urine was done by the paper disc method (7). Ten 11.1 of serum was transferred to a circular disc of filter paper with a diameter of 6 mm. The discs with serum, and a standard series of discs containing log,-varyi‘ig concentrations of ampicillin diluted in pooled human plasma (AB Biodisk Stockholm, Sweden), were placed on PDM antibiotic sensitivity agar medium seeded with Sarcina lutea ATCC 9341. The plates were incubated at 37°C for 18 hrs. Concentrations of ampicillin in the samples were calculated by plotting the zones of growth inhibition around the
Treatment was discontinued after 4 days in one patient due to exanthema, probably induced by the medication. Serum Concentrations (pglnil)
Criteriu for infection The diagnosis of U T I was made on symptoms (dysuria, pollakiuria), pathological urinary sediment (pyuria, bacteriuria) and on positive bacteriological culture from urine (>lo5 bacterialml in pure culture in 2 samples) in 14 patients, and in the remaining 3 cases on clinical symptoms combined with pathological sediment. Microscopy of the urine was performed before treatment, on the 5th day of treatment, and 2 4 4 8 hrs after the treatment was terminated. Microbiologicd itivesrigcrtiotis Samples of urine were cultivated before treatment, on the 5th day of treatment, and 24-48 hrs post-treatment. The cultivations were performed on blood agar and lactose-bromthymol blue agar using a semiquantitative loop technique. The cultures were incubated at 37°C for 18 hrs. The isolated organisms were tested for sensitivity to antibiotics by the method of Ericsson and Sherris ( 6 ) on PDM antibiotic sensitivity agar medium (AB Biodisk. Stockholm, Sweden). The aerobic bacterial flora in rectum was investigated before treatment started, on the 5th day of treatment, and 2 4 4 8 hrs after the termination of treatment. Rectal swabs were inoculated on lactose-bromthymol blue agar
y,lB%+ 130
3 00
4 30
6 00
7 30
Hours
Fig. I . Serum concentrations of ampicillin after oral administration of ampicillin suspension corresponding to
25 mg ampicillin per kg bodyweight to 8 semifasting children with UTI.
Downloaded by [UQ Library] at 20:54 07 May 2016
Treatment
of urinary tract infection in children
33
Fig. 3. Mean serum concentrations of ampicillin in 6 children after oral suspension of (A) pivampicillin base (-12.5 mg ampicillin per kg bodyweight), and 8 children after oral suspension of ampicillin in a dose of 25 mg per kg bodyweight (B). Fig. 2 . Serum concentrations of ampicillin after oral administration of pivampicillin base in suspension corresponding to 16.2 mg per kg bodyweight (-12.5 mg ampicillin per kg) to 6 semifasting children with UTl.
sample discs against those of the standard series. The assays of ampicillin concentration in urine were done with the same technique after diluting the urine I : 100. A blind technique was used for all assays. Hemutology, blood chemistry, und side-effects Hemoglobin, ESR, hematocrit, erythrocyte count, leucocyte and thrombocyte counts, glutamic oxaloacetic acid transaminase (aspartate aminotransferase, ASAT), glutamic pyruvic transaminase (alanine aminotransferase, A L A T ) , alkaline phosphatase, serum urea and creatinine were determined before and after treatment. Side-effects such as diarrhoea, vomitus and exanthema were registered. Cnlcriiutioti und gruphical representotions of results
The serum levels of ampicillin were processed by computer using a method developed by H. Engberg-Pedersen ( 5 ) and curves were fitted to the experimentally obtained serum data for each individual subject. These curves were subsequently used to calculate mean values of peak concentrations, the time for onset of peak, the area under the
curve as well as mean curves for the study groups. Rest concentrations of ampicillin in the samples taken before the test dose are corrected for, and prolongation of the curves beyond the 6-hr test period is also due to this statistical method.
RESULTS UTI The organisms responsible for the infections are presented in Table I. Rapid effect on symptoms was achieved in both groups of treatment, with no difference between the groups. The children showed no significant growth of microbes in the urine after 5 days of treatment or 24-28 hrs of post-treatment. Urine microscopy was normal in all patients after 5 days. Treatment with pivampicillin was discontinued in one patient after 4 days due to exanthema.
Effect on the
Absorption studies
Figs. 1 and 2 illustrate the individual serum curves for children treated with ampicillin or pivampicillin. Fig. 3 shows the mean curves for the two groups.
34
0 .J . Moe et al.
Table 11. Mean values of peak concentrations of ampicillin in serum (C,,,,), the time for its occurrence (T,,,), the area under the serum curve and the mean urinary concentration (C,,) after administration of oral doses of suspensions of ampicillin arid pivampicillin base to semifisting children aged 1-10 years sufferingfiorn UTI
Downloaded by [UQ Library] at 20:54 07 May 2016
Ampicillin Pivampicillin
Dose per kg bodyweight (mg of C m a x (wzlml) ampicillin)
Tmax
25 12.5
82 55
1.9 13
Table I1 gives the mean values of peak concentrations, time for onset of peak, bioavailability (area under the curves) and urine concentrations. The peak concentration of ampicillin in serum was higher and obtained more rapidly in children treated with pivampicillin than in children treated with ampicillin (Fig. 3). Bioavailability of pivampicillin was greater. Urine concentration was higher in the pivampicillin group than in the ampicillin group. Effect on hematology ~ n blood d chemistry Leucocytosis and high ESR were normalized during treatment. Hemoglobin, hematocrit, erythrocyte and thrombocyte counts, ASAT, ALAT, alkaline phosphatase, serum urea and creatinine were normal before and after treatment in all patients. Effect on the intestinal bactericil flora Escherichia coli was the predominant aerobic organism cultivated from rectal swabs in all of the patients prior to treatment. All but one of the strains were “fairly sensitive” to ampicillin (l
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children Ole Jörgen Moe, Alf Meberg & Jan Eng To cite this article: Ole Jörgen Moe, Alf Meberg & Jan Eng (1977) Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children, Scandinavian Journal of Infectious Diseases, 9:1, 31-36, DOI: 10.3109/inf.1977.9.issue-1.08 To link to this article: http://dx.doi.org/10.3109/inf.1977.9.issue-1.08
Published online: 02 Jan 2015.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [UQ Library]
Date: 07 May 2016, At: 20:54
Scand J Infect Dis 9: 3 1-36, 1977
Ampicillin and Pivampicillin in the Treatment of Urinary Tract Infection in Children OLE JORGEN MOE,' ALF MEBERG'and JAN ENG2
Downloaded by [UQ Library] at 20:54 07 May 2016
From the 'Department of Paediatrfcs nncl the 2Microbiological Lnboratory. Ullevdl Hospital, Oslo, Norwny
ABSTRACT. 16 children, aged 1-10 years, suffering from urinary tract infection were randomly divided into two groups. Ten children were treated with ampicillin pediatric suspension in a dose of 100 mg ampicillin/kg/24 hours divided in 4 doses, and 6 children with pivampicillin base pediatric suspension in a dose of 64.8 mg/kg/24 hours divided in 4 doses (-50 mg ampicillin/ kg). The treatment period was 14 days with all infections being cured. Despite the fact that pivampicillin was administered in half of the dosage of ampicillin the resulting peak serum concentration was 65 % higher and was achieved more rapidly. The bioavailability and urine concentration were also greater. A marked change in the rectal aerobic bacterial flora occurred during both treatment regimens. In 13 children (81%) a shift took place from ampicillin-sensitive E. coli to ampicillin-resistant Klebsiella strains as the predominating microbe, equally often in both groups of treatment. Ampicillin-resistant E. coli appeared in one child in each group.
INTRODUCTION Ampicillin has proven useful in the treatment of urinary tract infection (UTI) in children. Oral ampicillin, however, is hampered by incomplete and variable absorption from the gastrointestinal tract (2). Only 25-30% is recovered in the urine (4, 11). In infections involving the renal tissue (pyelonephritis), high serum concentrations of ampicillin are needed to give adequate amounts of the drug in the parenchyma (3). Pivampicillin, the pivaloyloxymethyl ester of ampicillin, is rapidly hydrolysed into ampicillin and pivalic acid in the body after oral administration (4). The antimicrobial effect is attributed to released ampicillin. Marget et al. (10) compared the absorption and clinical effect of pivampicillin hydrochloride, administered as powder from commercially available capsules, and ampicillin suspension in children under 12 months of age. Considerably higher serum concentrations were obtained with the ester than with ampicillin. A similar comparative investigation in children with the commercially available ampicillin and pivampicillin pediatric suspensions has not been previously reported. The purpose of the present investigation was to
study the clinical effects, the concentrations of ampicillin in serum and urine, and the changes in the intestinal bacterial flora caused by commercially available oral suspensions of ampicillin and pivampicillin administered to children with UTI. MATERIALS AND METHODS Aiitibiorics Pivampicillin was administered a s a suspension of free pivampicillin base (32.4 mglml, equimolar t o 25 mg of ampicillin/rnl). The preparation was supplied by Leo Pharmaceutical Products, Copenhagen, Denmark. and is now commercially available (Pondocillin"). Ampicillin was administered as the commercially available suspension, Doktacillin" Astra (50 mglml). All of the ampicillin bottles were of the same batch. The drugs were administered in equal volumes, 0.5 ml/kg every 6 hours for 14 days. Thus a double molar dose of ampicillin was given compared to that of pivampicillin. The antibiotic administered was chosen at random. Pntierits
17 children were included in the investigation. They were divided into 2 groups depending upon the medication given. Table 1 lists their data. All patients were hospitalized during the absorption tests. Informed consent was obtained from the parents. None of the children had received any antibiotics during the last 3 weeks prior to hospitalization.
32
0 .J . Moe et (11.
Table I . Data on 17 children with UTI trecrtecl ornlly with suspensions of crinpicilliri ( i t i d pivritnpicilliri bcise
Downloaded by [UQ Library] at 20:54 07 May 2016
Drug
Total no. of patients Girls A. Acute infection Recurrent infections B. Intravenous urography Normal Scarring (slight) Ureter duplex C. Cystourethrography Normal “Irregular bladder mucosa” D. Cystoscopy Normal Hyperemic bladder mucosa E. Infecting organism E. coli Proteus Enterobacter No growth Age range in years Mean age in years
Ampicillin
Pivampicillin
10
1
7“ 6 3 4 7 6 I 0
5
5
3
3
2
2 0
2 2 I
2
1
5
7 0 0
7 4 6 10
8 1
I I 3 1-10
6
0 5-9 64
and deoxycholate agar and incubated for 18 hrs at 37°C. The aerobic organism predominating in the flora was identified and its antibiogram was determined. Absorptioti studies On the 5th day of treatment samples for antibiotic assays in blood and urine were collected. Blood samples were taken in conjunction with the second dose of antibiotic. The patients were in the semifasting state (4 hrs after breakfast) and food was not given for 2 hrs after medication. Samples were taken in a cubital vein through an indwelling cannula. The cannula was flushed with heparin between samples. Blood samples were taken before medication, 15, 30, 60 min and 2, 4, and 6 hrs after the test dose of ampicillin (25 mg/kg) or pivampicillin (equimolar to 12.5 mg of ampicillin/kg). The absorption study failed in 2 patients treated with ampicillin (due to technical error). Urine was sampled during the test period (6 hrs). The blood and urine specimens were refrigerated at 4°C. The concentrations of ampicillin were measured on the following day. The assay of ampicillin concentration in serum and urine was done by the paper disc method (7). Ten 11.1 of serum was transferred to a circular disc of filter paper with a diameter of 6 mm. The discs with serum, and a standard series of discs containing log,-varyi‘ig concentrations of ampicillin diluted in pooled human plasma (AB Biodisk Stockholm, Sweden), were placed on PDM antibiotic sensitivity agar medium seeded with Sarcina lutea ATCC 9341. The plates were incubated at 37°C for 18 hrs. Concentrations of ampicillin in the samples were calculated by plotting the zones of growth inhibition around the
Treatment was discontinued after 4 days in one patient due to exanthema, probably induced by the medication. Serum Concentrations (pglnil)
Criteriu for infection The diagnosis of U T I was made on symptoms (dysuria, pollakiuria), pathological urinary sediment (pyuria, bacteriuria) and on positive bacteriological culture from urine (>lo5 bacterialml in pure culture in 2 samples) in 14 patients, and in the remaining 3 cases on clinical symptoms combined with pathological sediment. Microscopy of the urine was performed before treatment, on the 5th day of treatment, and 2 4 4 8 hrs after the treatment was terminated. Microbiologicd itivesrigcrtiotis Samples of urine were cultivated before treatment, on the 5th day of treatment, and 24-48 hrs post-treatment. The cultivations were performed on blood agar and lactose-bromthymol blue agar using a semiquantitative loop technique. The cultures were incubated at 37°C for 18 hrs. The isolated organisms were tested for sensitivity to antibiotics by the method of Ericsson and Sherris ( 6 ) on PDM antibiotic sensitivity agar medium (AB Biodisk. Stockholm, Sweden). The aerobic bacterial flora in rectum was investigated before treatment started, on the 5th day of treatment, and 2 4 4 8 hrs after the termination of treatment. Rectal swabs were inoculated on lactose-bromthymol blue agar
y,lB%+ 130
3 00
4 30
6 00
7 30
Hours
Fig. I . Serum concentrations of ampicillin after oral administration of ampicillin suspension corresponding to
25 mg ampicillin per kg bodyweight to 8 semifasting children with UTI.
Downloaded by [UQ Library] at 20:54 07 May 2016
Treatment
of urinary tract infection in children
33
Fig. 3. Mean serum concentrations of ampicillin in 6 children after oral suspension of (A) pivampicillin base (-12.5 mg ampicillin per kg bodyweight), and 8 children after oral suspension of ampicillin in a dose of 25 mg per kg bodyweight (B). Fig. 2 . Serum concentrations of ampicillin after oral administration of pivampicillin base in suspension corresponding to 16.2 mg per kg bodyweight (-12.5 mg ampicillin per kg) to 6 semifasting children with UTl.
sample discs against those of the standard series. The assays of ampicillin concentration in urine were done with the same technique after diluting the urine I : 100. A blind technique was used for all assays. Hemutology, blood chemistry, und side-effects Hemoglobin, ESR, hematocrit, erythrocyte count, leucocyte and thrombocyte counts, glutamic oxaloacetic acid transaminase (aspartate aminotransferase, ASAT), glutamic pyruvic transaminase (alanine aminotransferase, A L A T ) , alkaline phosphatase, serum urea and creatinine were determined before and after treatment. Side-effects such as diarrhoea, vomitus and exanthema were registered. Cnlcriiutioti und gruphical representotions of results
The serum levels of ampicillin were processed by computer using a method developed by H. Engberg-Pedersen ( 5 ) and curves were fitted to the experimentally obtained serum data for each individual subject. These curves were subsequently used to calculate mean values of peak concentrations, the time for onset of peak, the area under the
curve as well as mean curves for the study groups. Rest concentrations of ampicillin in the samples taken before the test dose are corrected for, and prolongation of the curves beyond the 6-hr test period is also due to this statistical method.
RESULTS UTI The organisms responsible for the infections are presented in Table I. Rapid effect on symptoms was achieved in both groups of treatment, with no difference between the groups. The children showed no significant growth of microbes in the urine after 5 days of treatment or 24-28 hrs of post-treatment. Urine microscopy was normal in all patients after 5 days. Treatment with pivampicillin was discontinued in one patient after 4 days due to exanthema.
Effect on the
Absorption studies
Figs. 1 and 2 illustrate the individual serum curves for children treated with ampicillin or pivampicillin. Fig. 3 shows the mean curves for the two groups.
34
0 .J . Moe et al.
Table 11. Mean values of peak concentrations of ampicillin in serum (C,,,,), the time for its occurrence (T,,,), the area under the serum curve and the mean urinary concentration (C,,) after administration of oral doses of suspensions of ampicillin arid pivampicillin base to semifisting children aged 1-10 years sufferingfiorn UTI
Downloaded by [UQ Library] at 20:54 07 May 2016
Ampicillin Pivampicillin
Dose per kg bodyweight (mg of C m a x (wzlml) ampicillin)
Tmax
25 12.5
82 55
1.9 13
Table I1 gives the mean values of peak concentrations, time for onset of peak, bioavailability (area under the curves) and urine concentrations. The peak concentration of ampicillin in serum was higher and obtained more rapidly in children treated with pivampicillin than in children treated with ampicillin (Fig. 3). Bioavailability of pivampicillin was greater. Urine concentration was higher in the pivampicillin group than in the ampicillin group. Effect on hematology ~ n blood d chemistry Leucocytosis and high ESR were normalized during treatment. Hemoglobin, hematocrit, erythrocyte and thrombocyte counts, ASAT, ALAT, alkaline phosphatase, serum urea and creatinine were normal before and after treatment in all patients. Effect on the intestinal bactericil flora Escherichia coli was the predominant aerobic organism cultivated from rectal swabs in all of the patients prior to treatment. All but one of the strains were “fairly sensitive” to ampicillin (l
