Modeling the growth dynamics of multiple Escherichia coli strains in the pig intestine following intramuscular ampicillin treatment.

BACKGROUND: This study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs. It also examined the dynamics of the composition of bacterial strains during and after the treatment. The growth responses of strains to ampicillin concentrations were determined using in vitro growth curves. Using these results as input data, growth predictions were generated using a mathematical model to simulate the competitive growth of E. coli strains in a pig intestine under specified plasma concentration profiles of ampicillin. RESULTS: In vitro growth results demonstrated that the resistant strains did not carry a fitness cost for their resistance, and that the most susceptible strains were more affected by increasing concentrations of antibiotics that the rest of the strains. The modeling revealed that short treatment duration resulted in lower levels of resistance and that dosing frequency did not substantially influence the growth of resistant strains. Resistance levels were found to be sensitive to the number of competing strains, and this effect was enhanced by longer duration of treatment. High excretion of bacteria from the intestine favored resistant strains over sensitive strains, but at the same time it resulted in a faster return to pre-treatment levels after the treatment ended. When the duration of high excretion was set to be limited to the treatment time (i.e. the treatment was assumed to result in a cure of diarrhea) resistant strains required longer time to reach the previous level. CONCLUSION: No fitness cost was found to be associated with ampicillin resistance in E. coli. Besides dosing factors, epidemiological factors (such as number of competing strains and bacterial excretion) influenced resistance development and need to be considered further in relation to optimal treatment strategies. The modeling approach used in the study is generic, and could be used for prediction of the effect of treatment with other drugs and other administration routes for effect on resistance development in the intestine of pigs.

Infective endocarditis caused by Enterococcus faecalis treated with continuous infusion of ampicillin without adjunctive aminoglycosides.

Aminoglycosides are useful antimicrobial agents for treating infective endocarditis; however, they occasionally cause troublesome side effects, such as nephrotoxicity and ototoxicity. We herein report a case of infective endocarditis caused by Enterococcus faecalis that was treated successfully with continuous infusion of ampicillin without adjunctive aminoglycosides. The serum ampicillin concentrations were higher than the minimal inhibitory concentration for the target strain. Although the use of ampicillin monotherapy is currently avoided because double ß-lactam therapy is reportedly more effective, continuous penicillin administration remains an effective therapeutic choice for treating infective endocarditis.

The disposition of five therapeutically important antimicrobial agents in llamas.

The disposition of five therapeutic antimicrobial agents was studied in llamas (Lama glama) following intravenous bolus administration. Six llamas were each given ampicillin, tobramycin, trimethoprim, sulfamethoxazole, enrofloxacin and ceftiofur at a dose of 12 mg/kg, 1 mg/kg, 3 mg/kg, 15 mg/kg, 5 mg/kg, and 2.2 mg/kg of body weight, respectively, with a wash out period of at least 3 days between treatments. Plasma concentrations of these antimicrobial agents over 12 h following i.v. bolus dosing were determined by reverse phase HPLC. Disposition of the five antimicrobial agents was described by a two compartment open model with elimination from the central compartment, and also by non-compartmental methods. From compartmental analysis, the elimination rate constant, half-life, and apparent volume of distribution in the central compartment were determined. Statistical moment theory was used to determine noncompartmental pharmacokinetic parameters of mean residence time, clearance, and volume of distribution at steady state. Based on the disposition parameters determined, and stated assumptions of likely effective minimum inhibitory concentrations (MIC) a dose and dosing interval for each of five antimicrobial agents were suggested as 6 mg/kg every 12 h for ampicillin; 4 mg/kg once a day or 0.75 mg/kg every 8 h for tobramycin; 3.0 mg/kg/15 mg/kg every 12 h for trimethoprim/sulfamethoxazole; 5 mg/kg every 12 h for enrofloxacin; and 2.2 mg/kg every 12 h for ceftiofur sodium for llamas. Steady-state peak and trough plasma concentrations were also predicted for the drugs in this study for llamas.

Clinical efficacy of ampicillin, pivampicillin and procaine penicillin G in a soft tissue infection model in ponies.

Tissue chambers, implanted subcutaneously in ponies, were inoculated with Streptococcus zooepidemicus. The animals received either no antibiotics or one of the following treatments: pivampicillin per os (19.9 mg/kg, equivalent to 15 mg/kg ampicillin, every 12 h) for 7 or 21 days (7 and 5 ponies, respectively), procaine penicillin G intramuscularly (12 mg/kg = 12,000 IU/kg, every 24 h) for 7 days (7 ponies), or ampicillin sodium intravenously (equivalent to 15 mg/ kg ampicillin, every 8 h) for 1 day (5 ponies). Only intravenous administration was started before infection (prophylactically), the other treatments were started 20 h after infection (curatively). A total of 7 ponies received no antibiotics. In untreated controls, the infection led to abscessation of the tissue chamber in 4 to 10 days. Curative treatment with either pivampicillin or procaine penicillin G for 7 days resulted in a reduction of viable bacteria in the tissue chamber but did not eliminate the infection, resulting in abscessation in 5 to 14 days. However, administration of pivampicillin for 21 days eliminated the streptococci in five out of five ponies and prophylactic administration of ampicillin was successful in three out of five ponies.

Comparison of daptomycin, vancomycin, and ampicillin-gentamicin for treatment of experimental endocarditis caused by penicillin-resistant enterococci.

Infections with enterococci that are resistant to multiple antibiotics are an emerging clinical problem. We evaluated the antibiotic treatment of experimental enterococcal endocarditis caused by two strains with different mechanisms of penicillin resistance. Enterococcus faecalis HH-22 is resistant to aminoglycosides and penicillin on the basis of plasmid-mediated modifying enzymes; Enterococcus raffinosus SF-195 is susceptible to aminoglycosides but is resistant to penicillin on the basis of low-affinity penicillin-binding proteins. Animals infected with strain HH-22 received 5 days of treatment with the following: no treatment; daptomycin (20 mg/kg of body weight twice daily [b.i.d.], intramuscularly [i.m.]), vancomycin (20 mg/kg b.i.d., intravenously), or ampicillin (100 mg/kg three times daily, i.m.) plus gentamicin (2.5 mg/kg b.i.d. i.m.). Although vancomycin was superior to ampicillin-gentamicin (P less than 0.01), daptomycin was significantly better than all other treatment regimens (P less than 0.01) in reducing intravegetation enterococcal densities, although no vegetations were rendered culture negative by this agent. Animals infected with strain SF-195 received 5 days of no therapy, ampicillin, ampicillin-gentamicin, vancomycin, or daptomycin (all at the dosage regimens described above). Daptomycin, vancomycin, and ampicillin-gentamicin each lowered intravegetation enterococcal densities significantly better than did ampicillin monotherapy or no treatment (P less than 0.01); moreover, these three treatment regimens rendered significantly more vegetations culture negative than did ampicillin monotherapy or no treatment (P less than 0.05). Serum daptomycin levels remained above the MICs and MBCs for both enterococcal strains throughout the 12-h dosing interval used in the study. Daptomycin and vancomycin were both active in vivo in these models of experimental enterococcal endocarditis caused by penicillin-resistant strains, irrespective of the mechanism of resistance. This activity correlated with the unique cell wall sites of action of these agents (binding to lipoteichoic acid and pentapeptide precursor, respectively) compared with the sites of action of beta-lactams (penicillin-binding proteins). Beta-Lactamase production by strain HH-22 precluded in vivo efficacy with ampicillin-gentamicin combinations. In contrast, this combination was active in vivo against strain SF-195, which exhibited intermediate-level penicillin resistance (MIC, 32 micrograms/ml), likely reflecting the ability of high-dose ampicillin to achieve enough binding to low-affinity penicillin-binding proteins to cause augmented aminoglycoside uptake.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.

[Serum antibacterial activity during antibiotic treatment in automated bacteriology]. / Etude de l'activité antibactérienne sérique au cours des traitements antibiotiques en automate de bactériologie.

The conventional serum-dilution bactericidal test used for monitoring antibiotic therapy in severely infected in patients requires 72 h. Use of an automaton would be expected to provide faster results. We tested the MS-2 diagnostic automaton which performs kinetic analysis of bacterial growth. A relation between exponential growth onset time and initial bacterial concentration of the inoculum was first determined using successive ratio 10 dilutions. Sixty-two serum samples from twenty-one patients with endocarditis or septicemia were examined. A selection of findings is presented. Results of the automatic method and serum-dilution bactericidal test are studied comparatively. From our data we define the major advantages of automation: only 0.65 ml of serum and 10 minutes are needed to perform the test and results are obtained in five to twelve hours according to the bacterial strain. This new technique could be integrated in the monitoring protocol of severe infections.

Intra-operative irrigation of the peritoneal cavity with ampicillin in experimental posttraumatic peritonitis.

Penetrating abdominal wounds with injury to the intestines were inflicted on 24 anaesthetized pigs. The injured gut was resected. During this operation the peritoneal cavity in 9 pigs was irrigated with 3 litres of antibiotic solution (ampicillin 2 g/l). In 15 pigs the irrigation was done with 3 litres of saline solution only. During the postoperative observation period the animals were in continuous anaesthesia. Absorption of ampicillin, reduction of the peritoneal bacterial flora and emergence of resistant strains were evaluated. Ampicillin was rapidly absorbed to the systemic circulation, with an average peak concentration of 42.4 +/- 1.7 mg/l. The average half-life of the drug in serum was 54 +/- 4 min. The average density of the total aerobic flora decreased during the operation from 10(4.74) CFU/ml peritoneal exudate fo 10(1.20) CFU/ml, but increased to 10(5.16) CFU/ml during the posttraumatic observation period. Total anaerobic counts changed to similar extent. The results were not significantly different from the values in the saline-irrigation group. Ampicillin irrigation led to a significant increase of resistant strains, from 25% before irrigation to 97% at the end of the observation period.

[Therapeutic efficacy of KS-R1, an ampicillin suppository, against experimental infections in mice].

In experimental infections induced with S. aureus, S. pneumoniae, E. coli, K. pneumoniae, P. mirabilis and H. influenzae in mice, the therapeutic efficacies of ampicillin (ABPC) after its rectal administration were compared with those obtained after its oral and subcutaneous administration, and the following results were obtained. Generally, in experimental intraperitoneal infections of mice, the effects of ABPC after rectal administration were inferior to those after subcutaneous administration and superior to those after oral administration. In experimentally induced intraperitoneal and urinary tract infection of E. coli KC-14, similar results were obtained. The plasma levels were reflected as the difference between various administration in the therapeutic efficacies observed with ABPC.

Bactericidal versus bacteriostatic antibiotic therapy of experimental pneumococcal meningitis in rabbits.

A rabbit model of pneumococcal meningitis was used to examine the importance of bactericidal vs. bacteriostatic antimicrobial agents in the therapy of meningitis 112 animals were infected with one of two strains of type III Streptococcus pneumoniae. Both strains were exquisitely sensitive to ampicillin, minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)<0.125 mug/ml. The activity of chloramphenicol against the two strains varied: strain(1)-MIC 2 mug/ml, MBC 16 mug/ml; strain(2)-MIC 1 mug/ml, MBC 2 mug/ml. Animals were treated with either ampicillin or chloramphenicol in dosages that achieved a peak bactericidal effect in cerebrospinal fluid (CSF) for ampicillin against both strains. Two different dosages were used for chloramphenicol. The first dosage achieved a peak CSF concentration of 4.4+/-1.1 mug/ml that produced a bacteriostatic effect against strain(1) and bactericidal effect against strain(2). The second dosage achieved a bactericidal effect against both strains (mean peak CSF concentration 30.0 mug/ml). All animals were treated intramuscularly three times a day for 5 d. CSF was sampled daily and 3 d after discontinuation of therapy for quantitative bacterial cultures. Results demonstrate that only antimicrobial therapy that achieved a bactericidal effect in CSF was associated with cure. Over 90% of animals treated with one of the bactericidal regimens (i.e., animals in which the bacterial counts in CSF dropped >5 log(10) colony-forming units [cfu]/ ml after 48 h) had sterile CSF after 5 d of treatment. On the other hand, the regimen that achieved bacteriostatic concentrations (CSF drug concentrations between the MIC and MBC) produced a drop of 2.4 log(10) cfu/ml by 48 h; however, none of the animals that survived had sterile CSF after 5 d. These studies clearly demonstrate in a strictly controlled manner that maximally effective antimicrobial therapy of experimental pneumococcal meningitis depends on achieving a bactericidal effect in CSF.

Comparison of cotrimoxazole, ampicillin, and chloramphenicol in treatment of experimental Haemophilus influenzae type B meningitis.

To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.

[Comparative experimental study of cyclacillin and ampicillin]. / Sravnitel'noe izuchenie tsiklatsillina i ampitsillina v éksperimente.

Cyclacillin was compared with ampicillin by its bacteriostatic efficiency in vitro, chemotherapeutic efficiency in experimental infections of mice and rats and pharmacokinetic characteristics. It was found that cyclacillin was not superior to ampicillin by its antibacterial action. By a number of characteristics it was even significantly inferior. The pharmacokinetic advantages of cyclacillin were not considered significant.

Evaluation of amino penicillins in experimental infections in mice.

The therapeutic activity of bacampicillin compared to that of ampicillin and amoxycillin was evaluated against experimental infections in mice. Median curative doses (CD50) were determined in groups of animals challenged with bacterial suspensions injected intraperitoneally together with mucin and treated orally with the penicillins. When treated directly after the infection bacampicillin was slightly more active than ampicillin, whereas it was significantly more active than ampicillin and at least as active as amoxycillin when the treatment was instituted not until four hours after infection. Bacterial counts made on various organ homogenates from infected animals four hours after the infection showed that a generalized infection with high bacterial concentrations had developed. Penicillin administration caused a significant reduction in the bacterial counts and the bactericidal activity in vivo obtained after administration of bacampicillin appeared as good as that of amoxycillin.

Antibiotics and the Aberdeen typhoid outbreak in 1964.

This paper gives an abbreviated account of part of a research programme which followed the Aberdeen typhoid outbreak in 1964. Chloramphenicol, the main antibiotic used in treatment, was shown to have a minimum inhibitory concentration (MIC) of between 5 and 2-5 mug./ml. for the S. typhi phage type 34 of the outbreak. The MIC for methacycline was between 5 and 2-5 and 2 mug./ml. Whereas the deep and shallow broth techniques used gave similar results with these antibiotics, the MIC for ampicillin, and also cephaloridine, was less in the deep than in the shallow broths. Serum assays in patients given ampicillin or cephaloridine yielded abnormally high concentrations of both antiboitics when S. typhi phage type 34 was the test organism whereas, with other test organisms, the concentrations were within expectation. These abnormally high values fell within expected values when the sera under investigation had first been heated to 56 degrees C. for 30 min. before assay against the S. typhi of the outbreak. The findings with ampicillin suggested that dosages given were satisfactory. With cephaloridine the concentrations found in patients' sera seemed to show that twice daily doses of 0-5 g. fell short of adequacy.

Comparative assessment of cylacillin and ampicillin by experimental therapy and by serum level determinations in rats and mice.

Therapy of chronic E. coli pyelonephritis in rats was equally effective with cyclacillin and oral ampicillin, whereas intramuscular ampicillin had a significantly higher therapeutic activity than oral cyclacillin. Serum concentrations in rats and mice were consistently higher with cyclacillin than with ampicillin and showed great variations depending on the animal species. It was concluded that there is a good correlation between in vivo and in vitro activity of both antibiotics, provided that the serum levels are taken into consideration. On this basis it may be predicted that a man cyclacillin will exhibit lower therapeutic activity in gram-negative infections than ampicillin.

In vitro and in vivo microbiological evaluation of Cephapirin, a new antibiotic.

The microbiological properties of cephapirin, a new semisynthetis cephalosporin, have been studied. This antibiotic, if compared with ampicillin, shows a greater activity against gram positive bacteria, a lack of sensitivity to staphlococcal beta-lactamase, and a lower sensitivity to those produced by gram-negative bacteria. Useful therapeutic of cephapirin levels can be detected in human serum 6 h after administration of 500 and 1,000 mg parenterally.