ANTIMICROBIAL AGENTS AND CHIMOTNERAPY, Jan. 1978, P. 90-96Copyright C 1978 American Society for Microbiology

Vol. 13, No. 1Printed in U.S.A.

Pharmacokinetics of Bacampicillin Compared with Those ofAmpicillin, Pivampicillin, and Amoxycillin

JAN SJOVALL,' LENNART MAGNI,2 AND TOM BERGAN3

Medical Department' and Research and Development Laboratory,2 Astra Ldkemedel AB, S-151 85Sodertdlje, Sweden, and Department ofMicrobiology, Institute ofPharmacy,

University ofOslo, Oslo, Norway3

Received for publication 27 June 1977

Bacampicillin, a new oral prodrug which in vivo is rapidly transformed toampicillin, was compared with ampicillin, pivampicillin, and amoxycillin in arandomized cross-over study on 11 healthy volunteers. All drugs were given inoral doses equimolar to 400 mg of bacampicillin (800 ,umol). The mean of theindividual peak concentrations in serum was 8.3 jig/ml for bacampicillin, 7.1,ug/ml for pivampicillin, 7.7 ,ug/ml for amoxycillin, and 3.7 ,ug/ml for ampicillin.Furthermore, bacampicillin had a higher absorption rate than all the otherdrugs, although there were statistically significant differences only versusampicillin. The peak serum levels of the individual subjects were more dispersedwith ampicillin and amoxycillin, suggesting a more uniform absorption ofbacampicillin and pivampicillin. The relative bioavailability of bacampicillinand pivampicillin was comparable, whereas ampicillin was only 2/3 that of theothers.

Ampicillin combines a low toxicity and broadantibacterial spectrum, but one disadvantageis its incomplete absorption. Small modifica-tions of the molecule such as the insertion of ahydroxy group on the benzene ring in amoxycil-lin have improved absorption without essen-tially altering the antibiotic spectrum (27),although less activity in vitro against somespecies (3, 21, 32) and clinical inferiority (20)against Shigella have been noted in compari-son with ampicillin. An improvement has beenachieved by esterification of the carboxyl groupwith radicals which leads to increased lipidsolubility and improved absorption. Upon up-

take, the radicals are rapidly detached by hy-drolysis, and free ampicillin is made availablein blood and tissues. Examples of this class ofcompounds are pivampicillin (28, 29) and tal-ampicillin (5, 25).A systematic search for a new ampicillin

ester combining good bioavailability with vir-tual lack of gastrointestinal distress and diar-rhea has led to bacampicillin [1'-ethoxycarbon-yloxyethyl-6-(n-a-aminophenylacetamido)-pen-icillinate]. This is rapidly absorbed and trans-formed to ampicillin with a concomitant rapidbreakdown of the ethoxycarbonyloxyethyl estergroup to acetaldehyde, ethanol, and carbondioxide. The hydrolysis proceeds so rapidly thatno systemic bacampicillin has been detected(4). In animals, the new antibiotic is better

absorbed than amp- iilin, giving higher andearlier peak blood,7evels of ampicillin (4, 9a).Studies with bacampicillin in healthy volun-teers gave peak serum levels approximately2.5 times higher than those after an equimolardose of ampicillin. Mean individual peak serumlevels after administration of 200, 400, and 800mg of bacampicillin were 5.3, 8.9, and 16.5 ,ug/ml, respectively (18). Bacampicillin has ren-dered bioavailabilities of 87 to 95% (26; T.Bergan, submitted for publication).With the various modifications of ampicillin

and ampicillin-like antibiotics presently at theresearch stage, careful pharmacokinetic evalu-ations in controlled cross-over studies are im-portant to reveal the points of distinction be-tween them. The purpose of the present studywas to compare the pharmacokinetics ofbacam-picillin, ampicillin, pivampicillin, and amoxy-cillin.

MATERIALS AND METHODS

Subjects. The study was carried out with 11healthy volunteers, 5 females and 6 males, 21 to 40years old, with body weights ranging from 42 to 72kg. All were healthy, as evidenced by clinical andlaboratory examinations, and without known al-lergy to penicillins or cephalosporins. Before theinvestigation, tests relevant to the function of theliver (alkaline phosphatase, bilirubin, lactic dehy-drogenase, serum glutamic oxalacetic transami-

90

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

PHARMACOKINETICS OF BACAMPICILLIN

nase, serum glutamic pyruvic transaminase, andthymol) and kidney (blood urea nitrogen and serumcreatinine) as well as hemoglobin and erythrocytesedimentation rate were within the normal ranges.All subjects were informed of the nature of thestudy, possible side effects, and the potential role ofampicillin and amoxycillin as allergens. They wereinsured against mishaps during the study.

Pharmaceutical preparations. Bacampicillin,synthesized at the Research and Development Lab-oratories, Astra Lakemedel AB, was used as thehydrochloride. Bacampicillin was administered as400-mg tablets (batch no. 141 A), ampicillin as 278-mg tablets (batch no. 740329), pivampicillin as 398-mg capsules (batch no. 741010), and amoxycillin as291-mg tablets (batch no. 30). Pivampicillin sub-stance was obtained from a commercially availablecapsule preparation, Pondocillin, from Lovens Kem-iske Fabrik, Denmark, and amoxycillin from Bee-cham Pharmaceuticals, England; bacampicillin andampicillin trihydrate were manufactured by AstraLakemedel AB, Sweden. All formulations were pre-pared by Astra Lakemedel AB.

Iodometric analysis of the actual contents perdosage unit showed only insignificant deviationfrom intended amounts. The difference was lessthan 1% for bacampicillin and ampicillin, 1.5% forpivampicillin, and 2% for amoxycillin.

Dosage. The drugs were given in single equi-molar (800 Amol) doses: bacampicillin, 400 mg; am-picillin, 278 mg; pivampicillin, 398 mg; and amoxy-cillin, 291 mg. The doses were taken under supervi-sion with 100 ml of water.

Experimental design. The study was carried outin a complete cross-over fashion, i.e., all subjectsreceiving all four preparations. Each subject re-ceived the drugs in a randomized order, implyingthat different preparations were given to the sub-jects on the same day. One week elapsed betweendoses. No food was allowed from midnight beforeuntil 2 h after swallowing the tablets. Intake ofwater was permitted ad libitum except during thelast hour before and the first after medication. Thevolunteers were instructed not to take any otherdrug during the period of study.

Sampling. Samples (12 ml) of blood were with-drawn from the antecubital vein before and 0.5, 1,1.5, 2, 3, 4, 6, and 8 h after drug administration.Samples were allowed to clot for 1 to 2 h at 4 to 8°Cbefore separation of serum with sterile Pasteurpipettes. The urine was voided immediately beforedrug intake and thereafter collected at 2-h intervalsduring an 8-h period. From each interval, two 10-ml samples were taken. All samples were stored at-20°C until analyzed.

Microbiological assay. Stock solutions of ampicil-lin and amoxycillin containing 4 Ag/ml in pooledhuman serum and 1,000 jig/ml in Sorensen phos-phate buffer (pH 7.0) were frozen and stored to-gether with serum and urine samples until analyzedwithin 2 weeks. The antibiotic concentrations weredetermined by the cylinder-plate method with Mi-crococcus luteus ATCC 9341 as test organism (13).The Micrococcus culture was mixed with the agar(antibiotic medium 1; Difco Laboratories, Detroit,

Mich.) at 48 to 500C before the plates were poured.Assay standards in a twofold dilution series ofampicillin and amoxycillin in concentrations from 2to 0.03 ,ug/ml were used. As diluent for samples andstandards, pooled human serum was used for theassay of serum specimens and Sorensen phosphatebuffer (pH 7.0) for urine samples.

Pharmacokinetic calculations. In the presentstudy, the one-compartment open model was as-sumed. The model equation is:

c(t) = co - t)Lg/ml (1)

c(t) being serum concentration at time t, k, the firstorder absorption rate constant, k2 the overall firstorder elimination rate constant, and c0 the fictiveserum concentration at time t = 0.The validity of this assumption was tested by

plotting against time:t

,ftt) = c(t) + k2 c(t)dt (2)

When the one-compartment open model applies, theresulting curves should level off asymptotically withtime.

Amoxycillin (7, 8), bacampicillin (11, 18), andpivampicillin (16) have previously shown a linearrelationship between dose and area under the serumconcentration-time curve. Assuming that the sameproportion of each dose is absorbed, this indicatesdose-independent kinetics, which is a prerequisitefor the applicability of the first order, one-compart-ment open model.

For each subject, the constants (kl, k2, c0) of thetime-concentration curves were estimated using aniterative, nonlinear regression analysis technique(BMD 07R) (9).The serum half-life, tl/2, was calculated from k2:

tl n2=(h)k2

The apparent absorption lag time, i.e., the timefrom drug administration until absorption started,was estimated graphically (22).The area under the serum concentration-time

curve (AUC) was calculated by the trapezoidal rulebased on measured values, and the estimated areafrom the last sampling time to infinity was calcu-lated by:

AUC - c(t)k2 (4)

An estimation of the relative bioavailability wasmade by comparing the average areas under theserum concentration-time curves after bacampicil-lin with those of ampicillin and pivampicillin. Sinceamoxycillin is active as such and no, converted toampicillin, the area under the serum concentration-time curve cannot be used in a bioavailability com-parison to the ampicillin drugs.

Statistical evaluation. Concerning the estimationof the pharmacokinetic constants, it is a well-knownfact (31) that the results from models involving

VOL. 13, 1978 91

(3)

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

92 SJOVALL, MAGNI, AND BERGAN

linear combinations of exponentials are numericallyunstable. This is especially so, for example, inequation (1) when the true values of k, and k2 areclose together, as is frequently seen with drugs thathave a short half-life like the penicillins.We have experienced this problem for some of

the estimated curves. However, comprehensivecomputer experimentation has convinced us thatthe relationship between drugs regarding the esti-mated parameters is very little influenced by thisinstability. This justifies the inclusion of all esti-mated curves in the material although some ofthese produce unsatisfactory estimates of the indi-vidual parameters.

Since the true underlying distribution of some ofthe studied variables is typically non-normal, thenonparametric Friedman analysis of variance wasuniformly applied in the statistical analysis. In thefirst stage, the overall hypothesis of equal locationof a variable for the compared drugs was tested. Ifthis hypothesis was rejected, the analysis was fol-lowed up with a multiple-comparison procedurebased on the Friedman rank sums, where all pair-wise comparisons were performed (12).

A400 mg bacampicillin

Hours after administration

E

I.S

E

B278 mg ampicitlin

ANTIMICROB. AGENTS CHEMOTHER.

RESULTS

Serum concentrations. In Fig. 1 are shownthe serum concentrations of each individualvolunteer. Pre-administration samples showedno antibiotic activity. The peak serum levelswere above 5 ,ug/ml in all subjects after bacam-picillin and in all but one after pivampicillin,whereas, after amoxycillin and ampicillin,three and eight subjects, respectively, werebelow this level. Figure 2 shows the meanserum concentration curves for each antibiotic.Amoxycillin being active as such and not asampicillin, the amoxycillin curve has beendrawn in an equimolar scale with ampicillin,and the right hand ordinate indicates the ac-tual amoxycillin concentrations. The meancurve for bacampicillin showed a tendency toboth an earlier and a higher peak than theothers. The means of the individual peak levels(Table 1) of bacampicillin (8.27 ,ug/ml), pivam-picillin (7.14 ,ag/ml), and amoxycillin (7.68 jig/

12

E10. 398 mg pivampicillin C6-'05 lo 15 20 30 4.0 60 80

Hours after administration

12_D

lo.1 291 mg amoxycillhn

8

Hours after administration Hours after administration

FIG. 1. Individual serum concentrations after single oral administration of (A) bacampicillin (400 mg)and equimolar (800 pnol) doses of (B) ampicillin, 278 mg; (C) pivampicillin, 398 mg; and (D) amoxycillin,291 mg. Cross-over study in 11 healthy volunteers.

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

PHARMACOKINETICS OF BACAMPICILLIN

-bacampicillinpivampicillinamoxycillin

--ampicillin

18

E7 ,

e

6 ==. _

SEa4 °

0

3 EE

X22tf2'

Q51 1.52 4 6 8Hours after administration

FIG. 2. Mean serum concentrations after singleoral administration of bacampicillin (400 mg) andequimolar (800 jA&mol) doses ofampicillin (278 mg),pivampicillin (398 mg), and amoxycillin (291 mg).Cross-over study in 11 healthy volunteers. Theamoxycillin curve has been drawn on a scale equi-molar to bacampicillin on the left ordinate and inreal values on the right axis.

TABLE 1. Mean individual peak serum levels a

Mean peakDrug level SD CV (

(j.g/ml)Bacampicillin 8.27 1.63 20Ampicillin 3.70 1.25 34Pivampicillin 7.14 1.33 19Amoxycillin 7.68 2.74 36

a Variation of absorption expressed by standarddeviation (SD) and coefficients of variation (CV) ofthe individual peak serum concentrations afterequimolar 800 ,umol) oral doses of bacampicillin(400 mg), ampicillin (278 mg), pivampicillin (398mg), and amoxycillin (291 mg).

ml) on the one hand and that of ampicillin(3.70 ,ug/ml) on the other were significantlydifferent (P < 0.001, P < 0.01, P < 0.05,respectively).The mean area under the serum concentra-

tion-time curves (±+ standard deviation) (inhours times microgram per milliliter) was 15.5+ 3.6 after bacampicillin, 10.3 + 2.9 afteranipicillin, 15.2 + 3.0 after pivampicillin, and17.7 + 4.1 after amoxycillin. All drugs differedsignificantly from ampicillin (P < 0.01). Cal-

culations on the observed values gave essen-tially the same results as when the estimatedcurve was used.Table 1 shows the variation of the individual

peak concentrations expressed by the coeffi-cient of variation, i.e., the ratio between thestandard deviation and mean concentration.Generally, the higher the concentrations, themore individual variation is to be expected.Thus, the smaller coefficients of variation seenafter the ampicillin esters are notable. Sincethere is no established method for makingstatistical comparisons of coefficients of varia-tion, the conclusions in this case are essentiallyof a descriptive nature.

Absorption. The median apparent absorptionlag time was 0 h with bacampicillin and amox-ycillin, compared with 0.2 and 0.35 h withpivampicillin and ampicillin. The ranges of theindividual values, in hours, were 0 to 0.25 withbacampicillin, 0.12 to 0.80 with ampicillin, 0 to0.40 with pivampicillin, and 0 to 0.55 withamoxycillin. The shorter range for bacampicil-lin is also reflected by the higher peak serumlevel after bacampicillin (Fig. 2). The lag timefor bacampicillin was significantly shorter thanthat for ampicillin (P < 0.01).The rate constants of absorption, k, were

highest for bacampicillin (Table 2). The meandifference of k, between bacampicillin and am-picillin was statistically significant at P <0.01, and between bacampicillin and amoxycil-lin atP < 0.05.

Elimination. There were small differencesin the elimination rates (h-1) of the four com-pounds (Table 2), the mean values rangingfrom 1.00 for bacampicillin to 0.66 for ampicil-lin, corresponding to serum half-life values of0.75 to 1.09 h.Renal elimination. The percentage of uri-

nary recovery of the antibiotics in active formis shown in Fig. 3. During the 8-h collectionperiod, 71.5 + 10.5% (mean + standard devia-tion) of the ampicillin in bacampicillin wasrecovered. The corresponding figures for pi-vampicillin, ampicillin, and amoxycillin were64.7 ± 19.1, 44.6 + 14.8, and 73.5 + 9.4%,respectively. The difference between excretionafter bacampicillin and after ampicillin wasstatistically significant (P < 0.01), as was thatbetween the latter and amoxycillin (P < 0.05).

Bioavailability. The relative bioavailabilitycompared with bacampicillin was 0.67 for am-picillin and 0.98 for pivampicillin. Comparedwith bacampicillin, the relative urinary recov-ery of active ampicillin was 0.62 for ampicillinand 0.91 for pivampicillin.

E0,M.l

.aa._Ea

-60

E

93VOL. 13, 1978

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

94 SJOVALL, MAGNI, AND BERGAN

TALE 2. Rates ofantbiotic transport afterequimolar (800 pmol) oral doses of bacampicillin(400 mg), ampicillin (278 mg), pivampicillin (398

mg), and amoxycillin (291 mg)Subject no. ki (h-') k2 (h-') t1,2 (h)

II. A

I4

/--,' - bacmpicillin

pivampici-llin-amoxycillin-- ampicillin

0-2 0-4 0-6 0-8Sampling interval, hours

FIG. 3. Mean cumulative urinary recovery of ac-tive penicillin after single oral administration ofbacampicillin (400 mg) and equimolar (800 pmol)doses of ampicillin (278 mg), pivampicillin (398mg), and amoxycillin (291 mg). Cross-over study in11 healthy volunteers.

DISCUSSIONThe mean serum concentration curves (Fig.

2) show that bacampicillin appears more rap-idly and renders higher peak concentrationsthan pivampicillin and, on a molar basis, thanamoxycillin. However, statistically significantdifferences were observed only between ampi-cillin and the others.The serum concentrations were as expected

compared with previous studies with similardoses (7, 8, 13, 18, 24), except that a study byMiki (19) showed somewhat lower levels ofamoxycillin. Considering that 70 to 80% ofrandomly selected Escherichia coli strainshave minimum inhibitory concentrations below5 ,ug of ampicillin per ml (23), it is notable thatthe individual peak serum levels were abovethis level in all the subjects after bacampicillinand in all but one after pivampicillin. Foramoxycillin, on the other hand, the peak serumlevels were below this level in three subjects.Similarly, only in three volunteers were serumlevels of 5 ,tg/ml briefly reached after theampicillin tablets. Also, when the uniformityof the individual peak concentrations for eachdrug is compared (Table 1), the situation ismost favorable for the ampicillin prodrugs bac-ampicillin and pivampicillin, which had a coef-ficient of variation of 20 and 19% in contrast to34 and 36% for ampicillin and amoxycillin. Amore prolonged absorption phase probably ex-plains the larger inter-individual variation ob-served for ampicillin and amoxycillin. A uni-

c 80

I-

0 60I-

aC- 400

a

-3E 2C

U

Bacampicillin1*123

-4567891011

MeanSD

Ampicillin1234S67891011

MeanSD

Pivampicillin1234567891011

MeanSD

Amoxycillin1234567891011

MeanSD

1.171.695.493.011.582.141.862.062.622.220.882.251.23

1.370.841.030.951.180.851.230.840.690.811.050.990.21

1.051.101.040.950.911.051.411.591.431.021.251.160.22

0.951.251.310.880.950.881.461.721.071.090.771.120.29

0.860.950.640.551.041.481.051.161.471.040.781.000.30

0.890.520.680.630.900.750.540.600.490.640.620.660.14

0.690.750.470.660.640.730.910.950.900.710.88

0.750.15

0.660.821.050.600.800.630.791.060.640.750.550.760.17

0.810.731.081.260.660.470.660.600.470.670.890.750.24

0.781.331.021.100.770.921.281.161.411.081.121.090.21

1.000.921.471.051.080.950.760.730.770.980.79

0.960.21

1.050.850.661.160.871.100.880.651.080.921.260.950.20

ANTiMICROB. AGZNTS CHZMOTHZR.,

)r

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

PHARMACOKINETICS OF BACAMPICILLIN

form absorption is important and should implymore reliable antibiotic treatment.The differences in the area under the serum

concentration-time curves were small betweenbacampicillin, pivampicillin, and amoxycillin.The same ranking order of amoxycillin, pivam-picillin, and ampicillin was observed by Lodeet al. (15) for a higher dose. Other reports haveshown bioavailabilities of 47 to 49% with ampi-cillin (16, 17), 82 to 89% with pivampicillin(16), and 74 to 89% with amoxycillin (2, 33).The amounts recovered in the urine also

reflect the bioavailability of each drug. Again,ampicillin was at the bottom with an 8-h excre-tion of 44.6 ± 14.8% (mean + standard devia-tion) of the dose as active ampicillin. Theelimination had leveled off at this time. Thethree other compounds gave numbers of thesame order ranging from 64.7 + 19.1% forpivampicillin to 73.5 ± 9.4% for amoxycillin.Amoxycillin had the highest mean value, whilebacampicillin and pivampicillin had changedranking order compared with the values of thearea under the serum concentration-timecurves. Precautions were taken so that break-down of the antibiotic during collection wassmall, but, due to the considerable instabilityof the 84-lactam ring, one may view the serumdata with more confidence. Furthermore, Coleet al. (6) and Miki (19) have shown that theportion excreted in the urine as antibacteriallyinactive ampicillin or amoxycillin penicilloateis in the order of 4 to 11 and 8 to 25%, respec-tively.The relative bioavailability calculated from

urinary recovery and area under the serumconcentration-time curves showed good agree-ment.The course of the serum curve reflects both

the absorption rate constant (k,), and the elim-ination rate constant (k2). The k2 is somewhathigher and consequently t42 somewhat lowerafter bacampicillin than after the other com-pounds, implying that a prolonged absorptionmight have caused underestimates of the cal-culated k2 values for the other drugs.The better characteristics of bacampicillin

are largely explained by the high degree andrate of absorption. Since the elimination rateis approximately equal for the four drugs, thedifferences in absorption rate explain why ba-campicillin has favorable characteristics, i.e.,the rapid appearance of ampicillin in serumand the high peaks.Experimental studies indicate that the anti-

biotic concentration in the tissue is propor-tional to the peak serum level attained (1, 30).High concentrations of antibiotics in the bloodmight render better diffusion into tissues be-cause of the greater concentration gradient.

Furthermore, a correlation has been found be-tween antimicrobial peak activity in serumand clinical outcome (14). Thus, one may con-clude that the high and more-uniform peakserum levels attained with bacampicillin are ofpotential clinical importance.

Consequently, bacampicillin represents a fa-vorable development in ampicillin therapyfrom a pharmacokinetic point of view.

ACKNOWLEDGMENTSWe thank B. Huitfeldt and 0. Stockman for critical

evaluation and statistical assistance.

LITERATURE CITED1. Barza, M., and L. Weinstein. 1974. Penetration of

antibiotics into fibrin loci in vivo. I. Comparison ofpenetration of ampicillin into fibrin clots, abscesses,and "interstitial fluid." J. Infect. Dis. 129:59-65.

2. Barza, M., and L. Weinstein. 1976. Pharmacokineticsof the penicillins in man. Clin. Pharmacokin. 1:297-308.

3. Bodey, G. P., and J. Nance. 1972. Amoxicillin: in vitroand pharmacological studies. Antimicrob. AgentsChemother. 1:358-362.

4. Bodin, N.-O., B. Ekstr6m, U. Forsgren, L.-P. Jalar,L. Magni, C.-H. Ramsay, and B. Sjoberg. 1975.Bacampicillin: a new orally well-absorbed derivativeof ampicillin. Antimicrob. Agents Chemother. 8:518-525.

5. Clayton, J. P., M. Cole, S. W. Elson, and H. Ferres.1974. BRL.8988 (Talampicillin), a well-absorbed oralform of ampicillin. Antimicrob. Agents Chemother.5:670-671.

6. Cole, M., M. D. Kenig, and V. A. Hewitt..1973. Metab-olism of penicillins to penicilloic acids and 6-amino-penicillanic acid in man and its significance in assess-ing penicillin absorption. Antimicrob. Agents Chem-other. 3:463468.

7. Croydon, E. A. P., and R. Sutherland. 1971. a-Amino-p-hydroxybenzylpenicillin (BRL 2333), a new semi-synthetic penicillin: absorption and excretion in man,p. 427-430. Antimicrob. Agents Chemother. 1970.

8. Croydon, E. A. P., and R. Sutherland. 1972. Microbiol-ogy and human pharmacology of amoxycillin (BRL2333), p. 975-979. In M. Heizlar, M. Semonsky, andS. Mas6k (ed.), Advances in antimicrobial and anti-neoplastic chemotherapy, vol. 1/2. Urban andSchwarzenberg, Munich.

9. Dixon, W. J. 1973. BMD, biomedical computer pro-grams, p. 387-396. University of California Press,Berkeley.

9a. Ekstrom, B., U. Forsgren, L.-P. Jalar, L. Magni, B.Sjoberg, and J. Sjovall. 1977. Preclinical studies withbacampicillin-a new orally well absorbed prodrugof ampicillin. Drugs Exp. Clin. Res. 3:3-10.

10. Grove, D. C., and W. A. Randall. 1955. Assay methodsof antibiotics: a laboratory manual. Medical Encyclo-pedia, New York.

11. Hallander, H. O., A. Flodstrom, and J. Sjovall. 1977.Pharmacological and clinical study of bacampicillinin acute peritonsillitis-a comparison with ampicil-lin. Antimicrob. Agents Chemother. 11:185-190.

12. Hollander, M., and D. A. Wolfe. 1973. Nonparametricstatistical methods, p. 151-158. John Wiley and Sons,New York.

13. Jordan, M. C., J. B. de Maine, and W. M. M. Kirby.1971. Clinical pharmacology of pivampicillin as com-pared with ampicillin, p. 438-441. Antimicrob.Agents Chemother. 1970.

VOL. 13, 1978 95

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.

96 SJOVALL, MAGNI, AND BERGAN

14. Klastersky, J., D. Daneau, G. Swings, and D. Weerts.1974. Antibacterial activity in serum and urine as atherapeutic guide in bacterial infections. J. Infect.Dis. 129:187-193.

15. Lode, H., P. Janisch, G. Kupper, and H. Weuta. 1974.Comparative clinical pharmaclogy of three ampicil-lins and amoxycillin administered orally. J. Infect.Dis. 129(Suppl.):156-168.

16. Loo, J. C. K., E. L. Foltz, H. Wallick, and K. C.Kwan. 1974. Pharmacokinetics of pivampicillin andampicillin in man. Clin. Pharmacol. Ther. 16:35-43.

17. MacLeod, C., H. Rabin, R. Ogilvie, J. Ruedy, M.Caron, D. Zarowny, and R. 0. Davies. 1974. Practicalconcepts of drug absorption, distribution and loss.Can. Med. Assoc. J. 111:341-346.

18. Magni, L., B. Sjoberg, J. Sjovall, and J. Wessman.1976. Clinical pharmacological studies with bacam-picillin, p. 109-114. In J. D. Williams and A. M.Geddes (ed.), Chemotherapy, vol. 5: penicillins andcephalosporins. Plenum Press, New York.

19. Miki, F. 1974. Absorption, excretion, distribution andmetabolism of amoxycillin. Excerpta Med. Int.Congr. Ser. 326:25-38.

20. Nelson, J. D., and K. C. Haltalin. 1974. Amoxicillinless effective than ampicillin against Shigella invitro and in vivo: relationship of efficacy to activityin serum. J. Infect. Dis. 129(Suppl.):222-227.

21. Neu, H. C. 1974. Antimicrobial activity and humanpharmacology of amoxicillin. J. Infect. Dis.129(Suppl.):123-131.

22. Portmann, G. A. 1970. Pharmacokinetics, p. 1-56. InJ. Swarbrick (ed.), Current concepts in the pharma-ceutical sciences: biopharmaceutics. Lea & Febiger,Philadelphia.

23. Quinn, E. L., F. Cox, D. Jones, and L. Zarins. 1965.Clinical experience with parenteral ampicillin, p.226-232. Antimicrob. Agents Chemother. 1964.

24. Rozencweig, M., M. Staquet, and J. Klastersky. 1976.Antibacterial activity and pharmacokinetics of ba-campicillin and ampicillin. Clin. Pharmacol. Ther.19:592-597.

25. Shiobara, Y., A. Tachibana, H. Sasaki, T. Watanabe,and T. Sado. 1974. Phthalidyl D-a-aminobenzylpeni-cillinate hydrochloride (PC-183), a new orally activeampicillin ester. I. Absorption, excretion and metab-olism of PC-183 and ampicillin. J. Antibiot. 27:665-673.

26. Simon, C. 1976. Antibiotikaspiegel in Serum, Speichel,Trin- und Hautblasenfl0ssigkeit. Infection 4(Suppl.2):91-94.

27. Sutherland, R., and G. N. Rolinson. 1971. a-Amino-p-hydroxybenzylpenicillin (BRL 2333), a new semisyn-thetic penicillin: in vitro evaluation, p. 411-415. An-timicrob. Agents Chemother. 1970.

28. von Daehne, W. T., E. Frederikaen, E. Gundersen, F.Lund, P. M*rch, H. J. Petersen, K. Roholt, L.Tybring, and W. 0. Godtfredsen. 1970. Acyloxyme-thyl esters of ampicillin. J. Med. Chem. 13:607-612.

29. von Daehne, W., W. 0. Godtfredsen, K. Roholt, andL. Tybring. 1971. Pivampicillin, a new orally activeampicillin ester, p. 431-437. Antimicrob. AgentsChemother. 1970.

30. Weinstein, L., G. K. Daikos, and T. S. Perrin. 1951.Studies on the relationship of tissue fluid and bloodlevels of penicillin. J. Lab. Clin. Med. 38:712-718.

31. Westlake, W. J. 1971. Problems associated with analy-sis ofpharmacokinetic models. J. Pharm. Sci. 60:882-885.

32. Williams, J. D., and J. Andrews. 1974. Sensitivity ofHaemophilus influenzae to antibiotics. Brit. Med. J.1:134-137.

33. Zarowny, D., R. Ogilvie, D. Tamblyn, C. MacLeod,and J. Ruedy. 1974. Pharmacokinetics of amoxycillin.Clin. Pharmacol. Ther. 16:1045-1051.

ANTiMICROB. AGENTS CHZMOTHZR.

Dow

nloa

ded

from

http

s://j

ourn

als.

asm

.org

/jour

nal/a

ac o

n 08

Feb

ruar

y 20

22 b

y 17

8.17

3.21

6.13

.