Suboptimal Antibiotic Dosage as a Risk Factor for Selection of Penicillin-Resistant Streptococcus pneumoniae : In Vitro Kinetic Model

Abstract

Streptococcus pneumoniae is the most significant bacterial cause of community-acquired respiratory tract infections (23). During the last decade, the spread of penicillin nonsusceptible pneumococci with increased MICs has created clinically significant treatment problems, especially in infections against which therapeutic concentrations are difficult to achieve, such as meningitis (1,(15)(16)(17)(18)28). Clinical and animal studies indicate, however, that by optimizing the dosing regimen, it may still be possible in many cases to use penicillin for treatment of S. pneumoniae with decreased susceptibility (3-5, 8-10, 12-14, 25). Dosing regimens should, however, be optimized not only to obtain a maximal antibacterial effect but also to reduce the risk for the emergence of resistance (2,19,24). Little is known about the selective properties of different antibiotic regimens in a mixed culture of bacteria with different antibiotic susceptibilities. The normal nasopharyngeal flora of patients may be simultaneously colonized with different types of S. pneumoniae having a variable resistance pattern. A certain dosage regimen could select more resistant strains even if these at the time constitute a minority for the original population (11,21,26,27). The aim of the present investigation was to use an in vitro kinetic model to study the selective effects of different concentrations of benzylpenicillin on a culture containing a mixture of 90% penicillin-susceptible, 9% penicillin-intermediate, and 1% penicillin-resistant S. pneumoniae strains.(This study was presented in part at the 40th InterscienceConference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, on 17 to 20 September 2000.) MATERIALS AND METHODS Antibiotic.Benzylpenicillin was provided by AstraZeneca, Södertälje, Sweden. The antibiotic was obtained as a reference powder with known potency and dissolved in distilled water prior to each experiment.Bacterial strains. Three clinical strains of S. pneumoniae belonging to serotype 6B obtained from the Department of Microbiology, University Hospital, Reykjavik, Iceland, were used in the study: S. pneumoniae A 2000 (PSP), S. pneumoniae 9506 (PIP), and S. pneumoniae BCC-67 (PRP).Determination of MICs. The MICs for the three strains of S. pneumoniae were determined in fluid media by a macrodilution technique in duplicate on different occasions according to the National Committee for Clinical Laboratory Standards. Twofold serial dilutions of benzylpenicillin were added to broth and inoculated with a final inoculum of 10 5 CFU of the test strain per ml and incubated at 37°C in 5% CO 2 for 20 h. The MIC was defined as the lowest concentration of the antibiotic allowing no visible growth. The MICs of erythromycin were determined with E-test (Biodisk, Solna, Sweden).The MICs of penicillin were 0.031, 0.25, and 8 mg/liter, respectively. The PSP strain was erythromycin resistant (MIC Ͼ 128 mg/liter), whereas the two other strains were susceptible to erythromycin (MIC Ͻ 0.03 mg/liter).Concentrations of benzylpenicill...

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections

“…Our analysis indicates that as long as the dose is high enough, even if there are preexisting populations with reduced susceptibility, antibiotics can retard their rate of ascent and densities and thereby the likelihood that these "resistant cells" will be transmitted. For Streptococcus pneumoniae infections, for instance, there is both in vitro and in vivo evidence to show that, by using higher doses, β-lactam antibiotics can be used to treat some infections containing populations of bacteria that are officially "nonsusceptible" to the drug (69)(70)(71). Of course, because of toxicity and other side effects, there are limits to the concentrations at which most antibiotics can be used.…”

In Vitro Evaluation of the Antimicrobial Activity of Ceftaroline against Cephalosporin-Resistant Isolates of Streptococcus pneumoniae

“…Although the breakpoint for penicillin resistance for nonmeningeal isolates has recently been increased to 8 g/ml (6), highly penicillin-and cephalosporin-resistant pneumococci are still emerging (25,30), and the effectiveness of existing ␤-lactams in the treatment of such infections is unlikely to be successful, as determined on the basis of the pharmacokinetics and pharmacodynamics of existing agents (1,27,29). Ceftaroline is a novel parenteral cephalosporin with broad-spectrum in vitro antimicrobial activity against resistant gram-positive pathogens, including penicillin-resistant S. pneumoniae strains and methicillin-resistant Staphylococcus aureus strains (14,28), as well as common gram-negative organisms.…”

Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-ResistantEscherichia coli

“…A number of in vitro studies have examined the effect of different dosing regimens in order to suppress the resistant subpopulations (1,10,23,31,35). A study by Negri et al (31) revealed that low antibiotic concentrations can affect the selection of bacterial populations that show only small differences in susceptibility.…”