Abstract
We examined the bactericidal activities of penicillin, cefprozil, cefixime, cefaclor, and loracarbef against three clinical isolates of Streptococcus pneumoniae which were susceptible, moderately susceptible, and resistant to penicillin. An in vitro two-compartment glass infection model was used to simulate human pharmacokinetics in the presence of bacteria. Also, changes in organism susceptibility and development of resistant subpopulations were evaluated. Simulated pediatric dosage regimens and target peak concentrations in the central compartment were as follows: penicillin V-potassium, 26 mg/kg of body weight every 6 h (q6h) and 14 micrograms/ml; cefaclor, 13.4 mg/kg q8h and 16 micrograms/ml; loracarbef, 15 mg/kg q12h and 19 micrograms/ml; cefprozil, 15 mg/kg q12h and 11 micrograms/ml; and cefixime, 8mg/kg q24h and 4 micrograms/ml. Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h for cefprozil; and 3.5 h for cefixime. Growth controls were performed at two different pump rates, 0.8 and 2.0 ml/min (half-lives = 3.5 and 1 h, respectively). Each isolate demonstrated autolysis at the lower rate which was attributed to a decreased supply of fresh nutrients available to the organisms in the infection compartment. Against the susceptible isolate, the time to 99.9% killing was statistically significant between penicillin V-potassium and both cefaclor and cefixime (P < 0.029). Loracarbef never achieved a 99.9% reduction in the inoculum. At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. Against the intermediately resistant isolate, cefprozil was superior to all other regimens with respect to rate of killing (P < 0.013) and extent of killing at 24 h (P < 0.0003). At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. All of the regimens exhibited inferior activity against this penicillin-resistant isolate. A 99.9% kill was never obtained with any of the regimens, nor was there an appreciable decrease in the colony counts. In conclusion, it appears that cefprozil, penicillin, and cefaclor are effective therapies against sensitive and even intermediately sensitive isolates of S. pneumoniae. However, none of the oral therapies appear to be of any benefit against penicillin-resistant isolates. The in vitro model may be an effective tool in evaluating other multiple-dose therapies against this fastidious organism, since the continual supply of fresh medium maintains the viability of S. pneumoniae with minimal stationary-phase autolysis.
Full Text
The Full Text of this article is available as a PDF (251.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Appelbaum P. C. Antimicrobial resistance in Streptococcus pneumoniae: an overview. Clin Infect Dis. 1992 Jul;15(1):77–83. doi: 10.1093/clinids/15.1.77. [DOI] [PubMed] [Google Scholar]
- Cappelletty D. M., Kang S. L., Palmer S. M., Rybak M. J. Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model. Antimicrob Agents Chemother. 1995 Aug;39(8):1797–1801. doi: 10.1128/aac.39.8.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DeSante K. A., Zeckel M. L. Pharmacokinetic profile of loracarbef. Am J Med. 1992 Jun 22;92(6A):16S–19S. doi: 10.1016/0002-9343(92)90602-8. [DOI] [PubMed] [Google Scholar]
- Haag R., Lexa P., Werkhäuser I. Artifacts in dilution pharmacokinetic models caused by adherent bacteria. Antimicrob Agents Chemother. 1986 May;29(5):765–768. doi: 10.1128/aac.29.5.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamme C., Lundgren K., Rundcrantz H. The concentration of penicillin V in serum and middle ear exudate in acute otitis media in children. Scand J Infect Dis. 1969;1(2):77–83. doi: 10.3109/inf.1969.1.issue-2.02. [DOI] [PubMed] [Google Scholar]
- Krause P. J., Owens N. J., Nightingale C. H., Klimek J. J., Lehmann W. B., Quintiliani R. Penetration of amoxicillin, cefaclor, erythromycin-sulfisoxazole, and trimethoprim-sulfamethoxazole into the middle ear fluid of patients with chronic serous otitis media. J Infect Dis. 1982 Jun;145(6):815–821. doi: 10.1093/infdis/145.6.815. [DOI] [PubMed] [Google Scholar]
- Kusmiesz H., Shelton S., Brown O., Manning S., Nelson J. D. Loracarbef concentrations in middle ear fluid. Antimicrob Agents Chemother. 1990 Oct;34(10):2030–2031. doi: 10.1128/aac.34.10.2030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lahikainen E. A. Penicillin concentration in middle ear secretion in otitis. Acta Otolaryngol. 1970 Nov-Dec;70(5):358–362. doi: 10.3109/00016487009181897. [DOI] [PubMed] [Google Scholar]
- Lundgren K., Ingvarsson L., Rundcrantz H. The concentration of penicillin-V in middle ear exudate. Int J Pediatr Otorhinolaryngol. 1979 Jul;1(1):93–96. doi: 10.1016/0165-5876(79)90033-8. [DOI] [PubMed] [Google Scholar]
- Nelson J. D., Ginsburg C. M., Mcleland O., Clahsen J., Culbertson M. C., Jr, Carder H. Concentrations of antimicrobial agents in middle ear fluid, saliva and tears. Int J Pediatr Otorhinolaryngol. 1981 Dec;3(4):327–334. doi: 10.1016/0165-5876(81)90057-4. [DOI] [PubMed] [Google Scholar]
- Shyu W. C., Haddad J., Reilly J., Khan W. N., Campbell D. A., Tsai Y., Barbhaiya R. H. Penetration of cefprozil into middle ear fluid of patients with otitis media. Antimicrob Agents Chemother. 1994 Sep;38(9):2210–2212. doi: 10.1128/aac.38.9.2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simon H. J., Yin E. J. Microbioassay of antimicrobial agents. Appl Microbiol. 1970 Apr;19(4):573–579. doi: 10.1128/am.19.4.573-579.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spika J. S., Facklam R. R., Plikaytis B. D., Oxtoby M. J. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal Surveillance Working Group. J Infect Dis. 1991 Jun;163(6):1273–1278. doi: 10.1093/infdis/163.6.1273. [DOI] [PubMed] [Google Scholar]