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The purpose of this article is to review and summarise those aspects of the pharmacokinetic behaviour of the penicillins that may be of particular interest to the clinician. While these antibiotics differ markedly in their acid stability and oral absorption, misleading inferences may be drawn from simple inspection of the maximal serum concentrations produced by a given dose administered orally. A more accurate picture emerges when serum protein binding and intrinsic activity of the drugs are taken into account. All of the penicillins are readily and actively secreted by the renal tubles and most are eliminated, almost completely unchanged, in the urine. The majority are excreted in small quantities in the bile, but this is a major route for elimination of nafcillin from the body. Distribution of the penicillins in 'non-specialised' sites is excellent. In contrast, penetration of the central nevous system and eye are poor, and of the prostate, minimal. Inflammation reduces the barries to penetration of these areas. However, quantitative data related to this phenomenon in man are few. Probenecid actively competes with the 'export' pump of the meninges and renal tubular cells. This results in an increase in concentrations of the penicillins in the blood and cerebrospinal fluid. The effect of this agent on active secretion of these antibiotics from the eye and biliary tract is minimal. While elimination of the penicillins from the body takes place largely via renal excretion, penicillin V and oxacillin are extensively degraded as well. In contrast to the situation with respect to 'natural' and 'broad-spectrum' penicillins, the serum half-life of the isoxazolyl congeners and nafcillin is only minimally prolonged in the presence of renal failure. These agents are only weakly haemodialyzable, while the other penicillins are rapidly removed from the circulation by this procedure.

The pharmacokinetics of mezlocillin were examined after single 2- and 4-g intravenous injections to three groups of male patients with creatinine clearances of I >/= 60, II = 21 to 59, and III

Piperacillin, ticarcillin, and carbenicillin were administered intravenously to 10 healthy volunteers in a three-way, crossover study. The pharmacokinetics of the three drugs were in general quite similar. The peak serum concentration of piperacillin achieved at the end of a 30-min intravenous infusion was 63.5 +/- 27.6 microgram/ml. During the first 8 h, 67.5% of the dose of piperacillin was excreted in the urine, and the urinary concentration was extremely high. All three penicillins had high volumes of distribution. The serum half-life of the beta elimination phase of carbenicillin was lower than that of either piperacillin or ticarcillin. The volunteers experienced no adverse reactions from the administration of the drugs.

A review is given of the selection and rational of optimal treatment regimens for patients with sexually transmitted pathogens, e.g. in cases of gonorrhea, chlamydial infections, chancroid, syphilis, pelvic inflammatory diseases and ophthalmia neonatorum. The scientific basis for the selection of a beta-lactam agent is discussed, including dose, MIC, the critical serum level and maintenance interval, and the duration of therapy. Except in the case of penicillinase-producing Neiserria gonorrhoeae, penicillin remained until recently the most effective agent available against many sexually transmitted diseases. However, ceftriaxone, a new third-generation cephalosporin, has been shown to have a long half-life (8 h) and excellent in vitro efficacy against Neiserria gonorrhoeae (including penicillinase-producing strains) and Haemophilis ducreyi. In view of its exceptional clinical efficacy against both gonorrhea and chancroid, clinical studies of its efficacy against other sexually transmitted diseases appear warranted.

Penicillin is undoubtedly the antibiotic most effective on Treponema pallidum, but is it possible to prescribe it according to a standard regimen? Experimentation proves that such a uniform therapeutic plan cannot be determined for the following reasons: 1) Treponema pallidum may divide every 30 to 33 hours, but this concept is only established during the period of exponential growth in the initial lesion. Moreover, if Treponema pallidum are very quickly disseminated throughout the organism, then they do not divide at the same rate. In addition, we take into account a whole series of factors which can interfere with their rate of multiplication. 2) A penicillinemia of 0.03 U/ml may kill all the Treponema pallidum when they divide, but Dr. Eagle's data, although this would be a fairly active serum level, showed that the effective maximal serum concentration should be far higher, about 0.820 U/ml. The experimental data prove it is not possible to point out an accurate correlation between blood and tissue levels; thus, the penicillin levels in the cerebrospinal fluid are about 1/100 lower than those obtained in the serum. Among other factors it is necessary to take into account not only the age of the patient but also the penicillin complex chosen. Although the total of injected penicillin can be the same, the kinetics of serum levels are essentially variable, both regarding the increase of levels and duration according to the drug used. 3) As noted it follows that penicillinotherapy prescribed early with high and prolonged doses may allow a bacteriologic sterilization of primary syphilis.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple enzymatic assay for simultaneous determinations of amino-/ureidopenicillins and clavulanic acid concentrations in various body fluids is described; no pretreatment of the samples is required. The assay is based on the competitive inhibition of the chromogenic compound Padac by clavulanic acid in the presence of Proteus vulgaris beta-lactamase. Detection limit for clavulanic acid amounts 0.02 mg/l. Interferences with other antibiotics such as aminoglycosides, macrolides, quinolones etc. can be ruled out.

The binding of the acylureidopenicillins azlocillin and mezlocillin to serum proteins was investigated by means of equilibrium dialysis and ultracentrifugation. The penicillin concentrations were determined by the agar diffusion test and by circular dichroism. The degree of binding is dependent on the penicillin concentration. At a mean penicillin concentration of 20 microgram/ml 39% of azlocillin is bound by serum proteins and 35% of mezlocillin. The acylureidopenicillins are bound to about the same degree by the two proteins albumin and gamma globulin, which occur in different concentrations in serum. The binding affinity delta F degree for the interaction between azlocillin and mezlocillin to human albumin is equal to -15,389 J/mol. The corresponding values for the binding of ampicillin and carbenicillin are -17,340 and -16,800 J/mol. Albumin has one binding site of a high affinity and two binding sites of a low affinity for the acylureidopenicillins. Measurements of partition coefficients of the penicillins for isobutanol and aqueous solution show that the interaction between acylureidopenicillins and serum is mainly hydrophobic in nature. This can be deduced from the fact that for example in the presence of sisomicin azlocillin is not displaced from its albumin binding site, in contrast to carbenicillin. The reason for this difference in behaviour lies in the fact that carbenicillin, like sisomicin, is bound to the serum proteins mainly by ionic bonds. In the case of azlocillin, however, hydrophobic bounds predominate which are not influenced by the ionic bonds of sisomicin.

The pharmacokinetics of mezlocillin after intravenous infusion of 5 g over 30 minutes was compared in 15 patients divided into 3 groups. Group I patients had normal renal function, group II patients had moderate chronic renal impairment and group III patients were under haemodialysis. Plasma mezlocillin levels were measured by the microbiological method. Plasma kinetic values were calculated from a linear two-compartment model, using global estimation of macroconstants by the non-linear least square method. The elimination half-life was 1.19 +/- 0.107 h in group I patients 1.98 +/- 0.19 h in group II patients and 2.34 +/- 0.11 h in group III patients. Renal impairment did not significantly alter the apparent volume of distribution but influenced the total plasma clearance which was 139 +/- 9 ml/min, 87 +/- 9 ml/min and 61 +/- 8 ml/min in groups I, II and III patients respectively. There was a slight decrease of V1 (central compartment) and a noticeable increase of V2 (peripheral compartment), depending on the degree of renal impairment. The total volume of distribution (V1 + V2) remained relatively constant between 12 and 14 litres. Homogeneous results were obtained in each group of patients, thus confirming the regularity of the mezlocillin kinetic model at the dose administered. This should enable dosage adjustment according to renal function, as assessed by laboratory criteria.

For the more than three decades since benzathine penicillin G was discovered it remains unique as the only antibiotic formulation that can provide serum drug concentrations for several weeks following a single intramuscular injection. Benzathine penicillin G has withstood the test of time as the ideal drug to treat early, infectious syphilis and to prevent and treat Group A streptococcal infections. It has proved to be extraordinarily effective for the prevention of rheumatic fever recurrences and is a major reason for the marked reduction in the morbidity and mortality in countries where carefully monitored prophylaxis programs have been established.

The pharmacokinetics of azlocillin were studied in 16 patients with varying degrees of renal impairment (creatinine clearance Ccr ranging from 0 to 52 ml/min/1.73 m2) and on and off sessions in 4 of these patients on periodical haemodialysis. A single dose of azlocillin 80 mg/kg was given by intravenous infusion over 30 min. Maximum concentrations in the sera of patients with renal impairment were the same as in normal subjects, ranging from 300 to 400 micrograms/ml. The elimination half-life (t 1/2) increased as renal function deteriorated, with values of 1.11 h in subjects with healthy kidneys to 5.66 h in patients with Ccr less than 15 ml/min (maximum 8.38 h). The apparent volume of distribution (Vd) was unchanged in patients with renal impairment but was significantly increased in patients on haemodialysis. The mean percentage of the dose administered excreted in the urines decreased from 60-70% in normal subjects to about 11% in patients with severe renal failure, but urinary concentrations remained above therapeutic levels. The extra-renal elimination of azlocillin was unmodified by renal impairment. Azlocillin is easily removed by dialysis: t 1/2 values between and during 6 h sessions of haemodialysis were 6.55 h and 2.81 h respectively, corresponding to a 45.8% extraction on the dialyser. These results are comparable to those found in the literature and can be used as a basis for adjusting azlocillin dosage to the degree of renal function.

The contributions of granulocytes to the prevention and therapy of Streptococcus sanguis endocarditis with procaine benzylpenicillin (PBP) was investigated in rabbits. Depletion of granulocytes by treatment with mechlorethamine appeared to have no significant effect on either the prophylactic or therapeutic activities of PBP. Administration of 3,000 IU of PBP before inoculation with S. sanguis retarded the course of the endocarditis for only 24 h whether granulocytes were normal or depressed in numbers. Prophylaxis with either 15,000 or 30,000 IU of PBP was equally effective in non-granulocytopenic and granulocytopenic rabbits. Treatment of established infections with PBP at doses of 3,000 to 300,000 IU of PBP at 12-h intervals for 48 h was equally effective in rabbits with normal and depressed numbers of granulocytes. The effect of 3,000 IU of PBP was equivalent, however, to that of granulocytes alone, as shown by the fact that the numbers of CFU per gram of vegetation in the granulocytopenic rabbits treated with this dose of PBP and in the non-PBP-treated control rabbits were not significantly different.

The pharmacokinetics of temocillin, a new semisynthetic parenteral penicillin, were studied in 10 healthy volunteers. Doses of 0.5, 1.0, and 2.0 g were administered by intravenous bolus injection at weekly intervals, and serum and urine samples were assayed by an agar diffusion method. Mean peak serum concentrations were: 77.9 (+/- 28.4) mg/L (0.5 g), 160.8 (+/- 58.2) mg/L (1.0 g), and 236.1 (+/- 93.3) mg/L (2.0 g), with serum concentrations still being measurable after 12 hours for all doses [7.9 (+/- 3.7) mg/L, 12.9 (+/- 5.2) mg/L, 14.8 (+/- 6.3) mg/L]. According to a 2-compartment open model, the mean terminal half-lives of 0.5, 1.0, and 2.0 g doses were 5.2 (+/- 0.3), 5.0 (+/- 0.2), and 5.0 (+/- 0.2) hours, respectively. The total volume of distribution averaged 0.15 (+/- 0.01), 0.17 (+/- 0.01), and 0.24 (+/- 0.01) L/kg bodyweight, respectively, mean renal clearances were 18.5 (+/- 3.2), 19.6 (+/- 5.0), and 29.8 (+/- 2.6) ml/min, respectively, and the area under the serum concentration time curve (AUC) was 344.1 (+/- 18.7), 573.3 (+/- 27.8), and 784.5 (+/- 47.1) mg X h/L, respectively. At 74 (+/- 12.9)%, the 24-hour urinary recovery was highest for the low dose, followed by 68.1 (+/- 6)% for the 2.0 g dose, and 66.1 (+/- 16.8)% for the 1.0 dose. No untoward side effects were recorded. Thus, temocillin appears to be a penicillin with a prolonged half-life and high AUC.

An intravenous administration set designed for delivery of drug doses to pediatric patients was tested in vitro for the effect of fluid density and flow rate on drug delivery, and delivery of drug by this extension set was compared in vivo with delivery by other methods. Gentamicin (as the sulfate salt) and penicillin G potassium were used to represent low-density and high-density drugs, respectively; a 1-mL solution of each drug, labeled with carbon 14, was tested with each of two primary infusion solutions: 0.45% sodium chloride injection and 10% dextrose injection. The drug dose was injected via a port into a piston-containing chamber from which an equivalent amount of the primary fluid was displaced. Serial samples collected from the end of the filter-containing extension set were analyzed for drug concentration using a liquid scintillation technique. In 12 infants receiving i.v. gentamicin, this delivery method was compared in a randomized crossover trial with delivery by a syringe pump and by i.v. push. Each delivery system was used on one of three consecutive days, and serum gentamicin concentrations were measured by enzyme-multiplied immunoassay. The time required for in vitro delivery of the dose was dependent on flow rate. Density of the drug solution or the primary i.v. fluid did not significantly affect drug delivery. Serum gentamicin concentrations were not significantly different for the three delivery methods, but variability of drug delivery was greatest with the pediatric extension set. This pediatric extension set provides accurate and reliable drug delivery at primary infusion flow rates slower than 10 mL/hr when the drug dosage volume is 2-3 mL or less.

A review is given of work utilizing the serum bactericidal test for preclinical evaluation of agents considered for treatment of gram-negative sepsis among neutropenic cancer patients. Following a description of the methodology of the two major groups, the results of the various antibiotic trials are summarized. First the extended-spectrum cephalosporins (cefotaxime, cefoperazone, and moxalactam) were tested and found to be, at best, of limited value as single agents for Pseudomonas aeruginosa, a common pathogen of neutropenic cancer patients. When the extended-spectrum penicillins became available, the serum bactericidal levels in volunteers of mezlocillin and piperacillin were compared alone or in combination with an aminoglycoside to ticarcillin with or without aminoglycoside against the same organisms. Piperacillin proved to be most effective followed by mezlocillin and then ticarcillin; in each case the addition of the aminoglycoside improved serum bactericidal activity. Recent studies suggest that imipenem alone is as active as the combination of a broad-spectrum penicillin plus an aminoglycoside and is worthy of a carefully controlled clinical trial. These types of volunteer-based evaluations of the serum bactericidal activity of new compounds may help predict useful clinical approaches for the future.

In maxillary sinusitis, the blood circulation is supposed to be impaired in the oedematous sinus mucosa, and in such cases the transport of antibiotics into the maxillary sinus should be reduced. To prove the accuracy of this assumption a comparison has been made between the concentrations of penicillin and doxycycline (Vibramycin, Pfizer) in sinus mucosa and secretions and the serum concentrations in patients under treatment with these antibiotics. Measureable concentrations of penicillin (greater than 0.2 mug/ml) were reached in the secretions only if the serum concentration was high (greater than 4-5 mug/ml). In contrast, measurable concentrations of doxycycline were achieved in both mucosa and secretions in all patients treated with this antibiotic. This must depend on the fact that doxycycline, due to its optimal lipid solubility, was able to penetrate poorly vascularized tissue. In most cases, the concentrations of doxycycline far exceeded the minimum inhibitory concentrations of the isolated organisms, and in some cases the local concentrations were higher than those found in the serum. The clinical response to doxycycline was good and correlated well to the laboratory data.

Pharmacokinetics of the novel combination of ticarcillin with the beta-lactamase inhibitor clavulanic acid (BRL 28500, Timentin, Betabactyl) was investigated in order to calculate the dose reduction factor (DRF) and elaborate dosage recommendations for patients with varying degrees of renal impairment. Serum and urine levels of ticarcillin and clavulanic acid have been determined following the i.v. application of 3.2 g and 5.2 g BRL 28500 consisting of 3.0 g and 5.0 g ticarcillin, respectively, and 0.2 g of clavulanic acid each. 10 healthy volunteers and 9 patients received the 5.2 g formulation, and 6 normal subjects and 9 patients the 3.2 g formulation. The pharmacokinetics of both components of BRL 28500 behave fairly similarly and provides the combination with a logic basis. The dose reduction factor, being 1 by definition in normal renal function, rises in final renal failure to 2-3 for clavulanic acid and to 4-5 for ticarcillin. A dosis reduction to 1/2-1/4 will roughly produce the same AUC in a patient with terminal renal insufficiency as the normal dosage in a healthy subject. The distribution volume of ticarcillin and clavulanic acid was found to be enlarged probably due to overhydration in this group of patients. The recovery of both BRL 28500 components decreased with impaired renal function. The recovery 6 h after administration of 0.2 g clavulanic acid in the 5.2 g (3.2 g) BRL 28500 formulation fell from 58 +/- 12% (52 +/- 6) in healthy subjects to 25 +/- 14% (25 +/- 13) in patients with renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a "high-performance" liquid-chromatographic method for simultaneously measuring various penicillin and cephalosporin antibiotics. After extraction from serum, which in general is quantitative, the drugs are separated by use of a "Bondapak phenyl" column and a gradient mobile phase. For these drugs retention times depend on the pH of the mobile phase; we present retention times under selected pH conditions.

Inadequate therapeutic results in the treatment of bacterial infections in patients with Cystic Fibrosis prompted a reevaluation of pharmacokinetic parameters of orally and parenterally administered drugs in these patients. Gentamicin, Azlocillin and Ticarcillin are eliminated faster in patients with Cystic Fibrosis. Serum concentrations show a rapid decrease over 60 to 90 minutes and surpass MIC values of Pseudomonas isolates for a maximum of only 60 minutes. 70% to 90% of the administered amount of drug is eliminated within two hours in the urine. Concomitantly determined clearance rates for creatinine didn't show abnormalities, however they pointed towards an additional tubular secretion of Gentamicin which is not seen in healthy controls. Cephalexin, Epicillin and both components of Cotrimoxazol show a delay in oral absorption. The renal elimination of Cephalexin and Trimethoprim is unaltered, but the excretion of Epicillin and Sulfametrol is enhanced again. This is seen by a delay and decrease in the maximal serum concentration (Cmax), but increased urine recovery. Doubling of the dose of gentamicin administered as i. v. infusion over 45 to 60 minutes results in smooth serum curve, the MIC values of most encountered organisms are surpassed for 3 hours and more. The clinical applicability of this recommendation however awaits further investigations concerning efficacy and safety.

Chemical delivery systems (CDS's) based on a dihydropyridine----quaternary pyridinium ion redox system analogous to the naturally occurring NADH----NAD+ system were synthesized for a group of staphylococcal penicillinase resistant penicillins, including methicillin, oxacillin, cloxacillin, and dicloxacillin, in order to improve their penetration of the central nervous system (CNS). The CDS's are penicillin monoesters of gem-diols in which the other hydroxyl group is esterified by the dihydrotrigonelline carrier. The CDS's were found to be much more lipopholic than the parent drugs by comparing their log k' values used as lipophilicity indexes. A study of the chemical oxidation of the CDS's performed by a UV spectrophotometric method showed relatively slow reaction. Stability studies were performed in buffers and different animal tissues for both the CDS's and the quaternary salt type derivatives. These studies showed that the CDS's were oxidized to the quaternary salt forms at neutral and basic pH and added water at lower pH. The quaternary salts released the parent drugs both in buffers and in vitro. A preliminary in vivo distribution study in the rat and rabbit demonstrated blood-brain barrier (BBB) penetration by the CDS, whereas no drug was detected by administering the drug itself.

Can penicillin be considered as an infallible treatment for syphilis? Some practitioners have hoped and even believed that this antibiotic would be able to eradicate this infection. To support their thesis, they have put forward an uniform standard therapeutic plan capable of being applied to any stage of the disease and which is based upon the following syllogism: a) all T.p. would divide every 30-33 hours. b) a level of penicillinemia of 0.03 IU/ml would destroy all Treponema when they divide. c) thus, a penicillin therapy administered 3 times giving such levels in serum during a period of 33 hours would produce a bacteriological sterilization of the infected organism. But statistics have shown that these conceptions were wrong. As a matter of fact: 1) every biological research has clearly proved that it is wrong to assert such a rhythm of division for all T.p. Since this multiplication is submitted to a succession of factors that we know more or less well, thus, during the latency phase, T.p. vegetate inside the tissues without apparently multiplying so quickly. 2) For lack of being able to cultivate T.p., it is not possible to state which is the activity level of penicillin on this germ. 3) Finally, the kinetic elimination of penicillin varies extremely, particularly depending on the drug which is used with patients, and on the localization of these germs. All experimental and clinical studies agree and insist on the fact that penicillin therapy must be given early in the infection, at a prolonged and high dose; results having to be estimated on the serological answers, especially with repeated TPI and FTA tests. As far as the late phases of the disease are concerned, for lack of being able to cultivate T. pallidum and because we do not have any absolute criterion of any bacteriological sterilization, the serological answers being often positive, circumspection has always to be a rule: it is better to admit what we do not know rather than to assert without any proof.

In a comparative kinetic study of the serum concentrations of two penicillin complexes--medium-long-acting (benethamine penicillin) and long-acting (benzathine bipenicillin)--after a single injection in young adults and elderly people, the following results were confirmed statistically: (a) age was a major factor in the variations in serum penicillin concentrations and in their persistence in the serum; (b) the penicillin was absorbed faster in young than in elderly subjects even when a long-acting complex was used; (c) serum concentrations below the level regarded as lethal for treponemes appeared much earlier and more frequently in young than in old people; and (d) the bioequivalence between penicillin preparations could not be estimated solely for the number of units of the agent used but from the bioavailability of the chosen formulation. Thus a uniform and standard penicillin dosage allowing no safety margin may help in the superficial healing of a syphilitic chancre or the resolution of a roseola but it will certainly be insufficient to kill Treponema pallidum. It seems essential therefore to provide an antibiotic cover at high dosage over a long period of time.

Ten healthy volunteers received 1 g of BRL-36650, a new formamido-penicillin derivative, given by intravenous infusion over 15 min. Levels in serum were measured microbiologically 30, 60, and 120 min after the start of the 15-min infusion and were (mean +/- standard deviation) 102.7 +/- 28.4, 59.7 +/- 11.5, and 9.6 +/- 1.9 mg/liter, respectively. A total of 10 strains each of Escherichia coli, Klebsiella pneumoniae, Serratia spp., and Enterobacter spp. and 14 strains of Pseudomonas aeruginosa were selected according to their susceptibility or resistance to piperacillin for the study of serum bactericidal activity (SBA). The MICs and MBCs of these strains were influenced by the choice of medium. Median SBA against E. coli and K. pneumoniae were greater than or equal to 1:2,048 and 1:512, respectively. The SBA against piperacillin-susceptible Serratia spp. (1:256), Enterobacter spp. (1:128), and P. aeruginosa (1:32) were significantly higher than against piperacillin-resistant strains (1:32, 1:8, and 1:4, respectively). Killing curves confirmed the high bactericidal activities obtained against the majority of strains. In the case of one Enterobacter sp. and one P. aeruginosa isolate with an MBC greater than or equal to 32, the absence of killing was noted.

Cancer chemotherapeutic agents and antimicrobial antibiotics are often given concomitantly. Cisplatin, which has become increasingly important in cancer treatment, has shown nephrotoxicity as a dose-limiting feature. The alpha-carboxy-penicillin ticarcillin (tc) has a wide spectrum of antimicrobial activity, especially against Pseudomonas. The plasma half-life of tc is correlated with renal function. The combined use of cisplatin (20 mg/m2, days 1-5) and tc (3 X 5 g/24 h, days 1-5) with renal protection by vigorous hydration (2400 ml of 0.9% NaCl/24 h continuous infusion, days 1-5) in a group of 12 cancer patients did not alter the BUN and creatinine serum levels. The mean serum concentration of tc, which was monitored in a patient 15, 30, and 45 min after injection of 5 g on 4 consecutive days together with cisplatin, did not differ from the levels of tc reported when used without concomitant cisplatin therapy. Thus these preliminary data show that the pharmacology of tc may not be altered significantly when applied together with cisplatin and that cumulative nephrotoxicity must not be expected with this combination when sufficient hydration is used.

The pharmacokinetics of azlocillin have been studied in healthy subjects and in patients, in children and in adults, using different doses, either single or repeated. Following intravenous injection of doses ranging from 1 to 5 g, plasma concentrations increase in relation to dosage. Maximum concentrations at the end of an injection or infusion average 100-200 micrograms/ml with 1 g and 400-500 micrograms/ml with 5 g. Azlocillin has a low degree of plasma protein binding: 30% to 40% depending on concentrations. Its volume of distribution is approximately 0.2 l/kg. Tissue distribution has been studied by various authors: with a 2 to 5 g dose, therapeutically active concentrations have been found in a variety of tissues, including bronchial secretions, bone, etc. Azlocillin crosses the placenta; the ratio of maternal to foetal plasma concentrations is 0.50. Azlocillin undergoes little metabolic degradation and its metabolites (penicilloates) amount to less than 15% of the dose administered. Most of the drug is excreted by the kidneys, 50% to 70% of the dose injected being recovered in the 24 h urines; the remainder is excreted in the bile, and biliary concentrations may be as high as 15-fold the corresponding plasma concentrations. Azlocillin is rapidly cleared. Its plasma half-life varies from 45 to 75 min according to different authors. The fact that it increases slightly with dosage suggests the kinetics of the drug might be dose-dependent. In view of the intervals between doses, this is certainly not of therapeutic importance. Total and renal clearance values are 150-200 ml/min and 100-140 ml/min respectively. In patients with renal impairment azlocillin is eliminated more slowly, with a half-life of up to 6-10 h when creatinine clearance is below 5 ml/min. The reduced urinary excretion may partly be compensated for by increased biliary excretion. The proportion of drug removed by haemodialysis is 40-50%. Azlocillin excretion is slowed down in children under 3 months of age, with half-lives of 4.5 h, 3.0 h and 2.0 h respectively in prematures, neonates and infants.

Two new penicillins and a new cephalosporin have been synthesized by condensing 2-hydroxy-1-naphthaldehyde with epicillin, 6-aminopenicillanic acid and cephradine, and subsequently reducing the SCHIFF bases with NaBH4. The antimicrobial activities of these compounds are also described.

Mecillinam is a new antibiotic related to the penicillins but more active than ampicillin against salmonellae, including Salmonella typhi. Mecillinam must be administered parenterally, but the ester, pivmecillinam, is absorbed from the gut. Eight patients suffering from typhoid fever and one suffering from paratyphoid fever were treated with the antibiotic, and seven responded satisfactorily. One patient could not tolerate pivmecillinam because of vomiting but there were no other adverse reactions. Serum and bile levels of mecillinam were many times the minimum inhibitory concentrations for most salmonellae. The antibiotic is a promising addition to the agents available for treating typhoid.

The results of studies on the pharmacokinetics of azlocillin in the perilymph of the guinea pig following the intramuscular administration of 200 mg per kg body weight are shown graphically. Similar to mezlocillin and the aminoglycoside antibiotics, this new acylureido penicillin is retained in the inner ear. The results of our studies, together with the data on the in vitro and in vivo activity of azlocillin and gentamicin and the applicable dosage for clinical purposes, indicate that the azlocillin levels in the perilymph are considerably more effective against Pseudomonas aeruginosa and many times more effective against the other microorganisms usually involved in acute otitis media than those of the aminoglycosides.

Azlocillin, a new semisynthetic penicillin with a wide spectrum of antimicrobial activity and a member of the ureidopenicillin group, was administered to ten adults in a dosage of 2 g by intravenous bolus injection. The determination of antibiotic activity in serum and urine demonstrated an average concentration of 58.9 mug/ml after one hour, 28.1 mug/ml after two hours and 6.1 mug/ml after four hours. The total urinary excretion was 60% within six hours. The pharmacokinetic parameters were calculated for the one and two compartment models, respectively. Mathematical analysis according to an open two-compartment model resulted in better curve adjustment as judged from the sum of the deviant squares. The resulting parameters for volume of distribution and rate of elimination show only minor differences however. Similar results were seen on comparison with the respective data for ampicillin.

6-[(R)-2-[3-methylsulfonyl-2-oxo-imidazolidine-1-carboxamido]-2-phenyl-acetamido]-penicillanic acid sodium salt (mezlocillin, Baypen) in doses of 5.0 g was given i.v. as an infusion or as a bolus injection to 5 healthy volunteers. 5 min after the completion of the infusion, the mean serum concentration was 430 +/- 81 microgram/ml compared to 424 +/- 91 microgram/ml after the bolus injection. The half-lives were 1.31 +/- 0.24 h and 1.72 +/- 0.21 h, respectively. These results indicate that differences in serum concentrations between various investigators probably can be attributed to differences in body size and do not seem to depend on the administration route.

Serum and urinary levels of PIPC (sodium piperacillin) in patients with liver disease were investigated. Serum and urinary levels of PIPC are affected by the degree of liver disease which is estimated most exactly by KICG, and it is available for determination of dose and administration interval. When PIPC was administered intravenously at a dose of 2 g, serum level in patients with liver disease was showed high and prolonged. Therefore this is convenient for PIPC of which biological half life is comparatively short. In patients with serious liver cirrhosis, PIPC is probably cumulated by continuous administration and in this case, dose and administration interval will be needed to regulate.

The pharmacokinetics of intravenous (bolus) temocillin 1 g were studied in 6 healthy male volunteers, and a cantharides blister method was used to estimate tissue penetration of the antibiotic. The mean elimination half-life was 4.5 hours. Temocillin penetrated blister fluid rapidly and reached concentrations of about 50% of those in serum by 2 to 3 hours after administration. Over an 8-hour period, the serum and blister fluid concentrations exceeded the MIC90 of susceptible bacteria by 2-fold or greater, suggesting that twice or even once daily dosing with temocillin may be sufficient.

Although there is sufficient information on the pharmacology and therapeutic application of the antimicrobial drugs to permit their effective use, they are still often misused in canine practice. This paper collates the data on drug dose rate/plasma concentration relationships observed in dogs after the administration of specific members of the major antimicrobial drug groups and on the possible impact of drug disposition (distribution and elimination) on therapeutic effect. Some information gleaned from studies in other animal species is added.

The pharmacokinetic properties of piperacillin, a piperazine derivative of ampicillin, were determined in seven patients with creatinine clearances less than 7 ml/min who were undergoing chronic, intermittent hemodialysis. A two-compartment linear model was used to analyze the data. Mean elimination half-life was 1.26 +/- 0.1 h; the mean elimination constant was 0.95 +/- 0.08 h-1; the mean volume of distribution was 0.16 +/- 0.02 liters/kg of body weight; the mean volume of the central compartment was 0.10 +/- 0.01 liters/kg of body weight; and the mean clearance was 0.09 +/- 0.01 liters/h per kg of body weight. Mean elimination half-life while off dialysis of 2.1 h.