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Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

Department of Medical Microbiology, Faculty of Medicine, University of Manitoba,² Departments of Clinical Microbiology,³ Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada¹

Received 11 October 2001/ Returned for modification 22 April 2002/ Accepted 10 August 2002

	ABSTRACT

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The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug C_p maximum of 2 µg/ml, t_1/2 of 6 h; in ELF, C_ELF(total) maximum of 35µg/ml, t_1/2 of 6 h; C_ELF(free) maximum of 14 µg/ml, t_1/2 of 6 h). Starting inocula were 10⁶ CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of 90% (AUC_0-24/MIC ratio, 61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC_0-24/MIC ratios of 30.5 to 38) resulted in a 1.2 to 2.0 log₁₀ CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of 8% (AUC_0-24/MIC ratio, 17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 µg/ml. However, mef(A) isolates for which MICs are 16 µg/ml along with erm(B) may result in bacteriological failures.

	TEXT

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Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide (20; M. Baer, R. Vuento, and T. Vesikari, Letter, Lancet 345:661, 1995; M. Lantero, A. Portillo, M. J. Gastanarea, F. Ruiz-Larrea, M. Zarazanaga, I. Olarte, et al., Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides, abstr. 3.10, 1998). It is the most common cause of community-acquired pneumonia, bacterial meningitis, and acute otitis media (8, 22, 27). Recent evidence suggests that an increase may be occurring in invasive and noninvasive pneumococcal infections (4, 11, 24, 26, 30, 31; Baer et al., letter), with an estimated mortality reaching 20 to 40% (19, 20; Lantero et al., Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides). Initially, all S. pneumoniae isolates were exquisitely susceptible to penicillin (MIC 0.06 µg/ml); however, beginning in the 1960s, resistance to penicillin and other agents began to be reported (5, 17, 20). Reports of an increase in prevalence of infections attributed to drug-resistant pneumococci appeared from various regions during the 1980s and have dramatically increased during the past 5 years (1, 2, 9, 15, 18, 28, 30, 31). Today, drug-resistant S. pneumoniae is recognized worldwide (15). In North America, recent surveys have shown an increase in the prevalence of resistance to penicillins (15, 23, 28-31) from less than 5% before 1989 to more than 50% in 1999 (9). In the United States in 1999-2000, of all tested S. pneumoniae isolates, 34.2% were intermediately resistant to penicillin (MICs of 0.12 to 1 µg/ml) while 21.5% were highly penicillin resistant (MIC 2 µg/ml) (9). During 1997 in Canada, 14.8 and 6.4% of respiratory tract isolates of S. pneumoniae (n = 1,180) were penicillin intermediate and penicillin resistant, respectively (31).

Most important and alarming is the finding that pneumococcal strains which are nonsusceptible (intermediate or resistant) to penicillin are more likely than penicillin-susceptible strains to be concomitantly resistant to other classes of antibiotics, including macrolides (4, 7, 9, 10, 15, 22, 28, 30, 31). Macrolide resistance in S. pneumoniae is presently 25% in the United States and approximately 8 to 9% in Canada (9, 32). Macrolide resistance in S. pneumoniae involves alteration of the ribosomal target site, or the production and utilization of an efflux mechanism (33). These two resistance mechanisms of macrolide resistance in S. pneumoniae are now manifesting both in vitro and in vivo (Lantero et al., Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides; D. Shortridge, C. Urban, J. J. Rahal, N. Mariano, N. Ramer, and S. K. Tanaka, Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides, abstr. 3.13, 1998; E. Tonoli, A. Marchese, E. A. Debbia, and G. C. Schito, Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides, abstr. 3.17, 1998). The first of these is the production of ribosomal methylase, which alters the ribosomal target site of the macrolide. This mechanism is coded for by the erm(B) gene and confers broad macrolide-lincosamide-streptogramin B (MLS_B) resistance (33). The second mechanism, which results in macrolide efflux, is encoded by the mef(A) gene (33). Efflux is macrolide specific (14- and 15-membered macrolides only) and does not affect the lincosamide or streptogramins (M-phenotype) (33; Tonoli et al., Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides). It is also important to note that erm(B)-producing S. pneumoniae isolates generally produce high-level macrolide resistance (MIC at which 90% of isolates are inhibited [MIC₉₀], 64 µg/ml), while mef(A)-producing S. pneumoniae strains produce low- to moderate-level resistance (MIC₉₀, 4 µg/ml) (16). Both of these mechanisms are transmissible to other isolates (Shortridge et al., Program Abstr. Fourth Int. Conf. Macrolides, Azalides, Streptogramins Ketolides). Presently in North America, both mef(A)- and erm(B)-producing S. pneumoniae strains are prevalent, while in Europe erm(B)-producing S. pneumoniae strains are more prevalent (16, 33).

Despite reports of macrolide-resistant S. pneumoniae, monotherapy with an oral macrolide is the most common regimen used for the outpatient treatment of community-acquired pneumonia (12). In fact, both the Infectious Diseases Society of America and Canadian community-acquired pneumonia (CAP) guidelines support the use of macrolides as first-line treatment of community-acquired pneumonia (3, 21). Because the choice of initial therapy in the treatment of community-acquired respiratory infections is empirical (i.e., made without the benefit of knowing the pathogen and its antibiotic susceptibility), and in view of the increasing prevalence of macrolide-resistant pneumococci, at what level of resistance will we no longer be able to use macrolides as the empirical therapy? Presently, this question cannot be answered, although it is clear that cases of macrolide failure due to macrolide-resistant S. pneumoniae are not that common (3, 12, 21, 30). A possible explanation for the apparent lack of macrolide failure in respiratory infections caused by macrolide-resistant S. pneumoniae may be due to the high macrolide concentrations achieved in respiratory tissues and fluids, such as the epithelial lining fluid (ELF), relative to those in serum (25, 32).

The purpose of this study was to assess the pharmacodynamic activity of clarithromycin by simulating clinically achievable concentrations of both free drug in serum and total and free drug in ELF against macrolide-resistant S. pneumoniae isolates. The hypothesis was that the high concentrations of clarithromycin achieved in ELF may eradicate low-level macrolide-resistant S. pneumoniae.

Seven macrolide-resistant strains of S. pneumoniae were evaluated (Tables 1 and 2). Isolates were obtained from the Canada Respiratory Organisms Susceptibility Study (31). Isolate 11771 was PCR negative for both mef(A) and erm(B). Isolates 12808, 3860, 12629, 3910, and 1217 were all positive for mef(A) but negative for erm(B) (resistant to clarithromycin [MIC 1 µg/ml] but susceptible to clindamycin [MIC 0.12 µg/ml]). Isolate 2670 was negative for mef(A) but positive for erm(B) (both macrolide and clindamycin resistant). Isolates were chosen to represent a variety of clarithromycin resistance phenotypes (MICs of 1 to 128 µg/ml). The method and conditions used for PCR determination of mef(A) and erm(B) have been previously described (16).

The in vitro pharmacodynamic model used in this study has been previously described (34). Logarithmic-phase cultures were prepared using a 0.5 McFarland (10⁵ CFU/ml) standard by suspending several colonies in cation-supplemented Mueller-Hinton broth with 2% lysed horse blood (Oxoid, Nepean, Ontario). This suspension was diluted 1:100, and 20 µl of the diluted suspension was further diluted in 60 ml of cation-supplemented Mueller-Hinton broth with 2% lysed horse blood. The resulting suspension was allowed to grow overnight at 35°C (34). After a maximum of 17 h, the suspension was further diluted to 1:10, and 60 ml of the diluted suspension was added to the in vitro pharmacodynamic model. Viable bacterial counts consistently yielded a starting inoculum of approximately 10⁶ CFU/ml (34). This final inoculum was introduced into the central compartment (volume, 610 ml) of the in vitro pharmacodynamic model.

Clarithromycin was modeled simulating a dosage of 500 mg per os (p.o.), twice a day (BID) (32). It was added into the central compartment at concentrations representing free drug in serum and both total (free and protein bound, assuming 60% protein binding) and free-drug concentrations in ELF as follows: serum C_p maximum, 2 µg/ml, t_1/2 6 h; in ELF, C_ELF(total), 35 µg/ml; t_1/2, 6 h; C_ELF(free) 14 µg/ml, t_1/2, 5 h (25, 31). As the protein binding of clarithromycin in ELF was not known, we simulated both free-drug as well as total (free and protein-bound) drug concentrations. Pharmacodynamic experiments were performed at least in triplicate on alternate days in ambient air at 37°C. Samples were obtained over 24 h for both pharmacokinetic and pharmacodynamic assessments (34). Clarithromycin concentrations in the pharmacodynamic model were determined microbiologically with a bioassay (6). Clarithromycin concentrations were determined in quadruplicate using Bacillus subtilis ATCC 6633 as the test organism, with a lower limit of quantification of 0.025 µg/ml. The plates were incubated aerobically for 18 h at 37°C. Concentrations were determined in relation to the diameters of the inhibition zones caused by the known concentrations from the standard series. Pharmacodynamic sampling was performed over 24 h with viable bacterial counts assessed by plating serial 10-fold dilutions onto cation-supplemented Mueller-Hinton agar with 2.0% lysed horse blood. Plates were incubated overnight at 37°C in ambient air. The lowest dilution plated was 0.1 µl of undiluted sample and the lowest level of detection was 200 CFU/ml.

Table 1 shows the MICs of clarithromycin for the seven clinical isolates utilized in this study. The strains were chosen to span macrolide-susceptible (wild type) and low-level (MIC, 1 to 4 µg/ml), intermediate (MIC, 8 µg/ml), and high-level (MIC, 16 µg/ml) macrolide-resistant mef(A) isolates and erm(B)-producing S. pneumoniae isolates. Target (simulated) and actual (achieved) pharmacokinetic parameters of clarithromycin achieved in serum were as follows: (i) free-drug C_p maximum of 2 µg/ml, AUC_0-24 of 35 µg · h/ml, t_1/2 of 6 h and C_p maximum of 2.3 ± 0.6 µg/ml, AUC_0-24 of 35.2 ± 5.1 µg · h/ml, t_1/2 of 5.5 ± 0.9 h, respectively; (ii) total drug in ELF C_ELF(total) maximum of 35 µg/ml, AUC_0-24 of 606 µg · h/ml, t_1/2 of 6 h and C_ELF(total) maximum of 32.4 ± 8.9 µg/ml, AUC_0-24 of 601 ± 85 µg · h/ml, t_1/2 of 6.1 ± 0.8 h, respectively; (iii) free drug in ELF C_ELF(free) maximum of 14 µg/ml, AUC_0-24 of 242 µg · h/ml, t_1/2 of 6 h and C_ELF(free) maximum of 13.8 ± 2.2 µg/ml, AUC_0-24 of 240 ± 40.5 µg · h/ml, t_1/2 of 6.2 ± 0.7 h, respectively. The actual pharmacokinetic parameters achieved in the model were similar (within 15%) to targeted pharmacokinetic parameters.

Bacterial killing (decrease in the log₁₀ CFU per milliliter at 24 h versus initial inoculum) by clarithromycin concentrations that simulated clinically achievable free-drug concentrations in serum as well as total and free-drug concentrations in ELF after standard dosing (500 mg, p.o., BID) are depicted in Table 2. As shown, achieving clarithromycin T/MIC values of 90% (AUC_0-24/MIC ratio, 61) resulted in complete bacterial eradication from the model with no regrowth over 24 h (or 48 h [data not shown]), while clarithromycin T>MIC values of 40 to 56% (AUC_0-24/MIC ratios, 30.5 to 38) resulted in a 1.2 to 2.0 log₁₀ CFU/ml decrease at 24 h versus initial inoculum. Clarithromycin T/MIC values of 8% (AUC_0-24/MIC ratio, 17.3) resulted in a static effect or bacterial regrowth. Figure 1 depicts clarithromycin killing of macrolide-susceptible and macrolide-resistant S. pneumoniae isolates, simulating the serum free-drug concentration (Fig. 1A), total drug concentration in ELF (Fig. 1B), and the free-drug concentration in ELF (Fig. 1C). Macrolide-susceptible S. pneumoniae [mef(A)-negative and erm(B)-negative; MIC, 0.12 µg/ml] cells were killed (3.5 log₁₀ CFU/ml decrease at 24 h versus initial inoculum) by the serum drug concentration as well as total and free-drug concentrations of clarithromycin in ELF (Fig. 1). Serum concentrations of clarithromycin (C_p maximum, 2 µg/ml) resulted in 2 log₁₀ CFU/ml killing and a static effect for macrolide-resistant strains [mef(A) positive, erm(B) negative]; clarithromycin MICs of 1 and 2 µg/ml, respectively) and regrowth for macrolide-resistant strains [mef(A) positive and erm(B) negative; clarithromycin MICs of 4, 8, and 16 µg/ml] or [mef(A) negative and erm(B) positive; clarithromycin MIC of 128 µg/ml] (Fig. 1A). Total drug concentrations of clarithromycin in ELF (C_p maximum, 35 µg/ml) killed (decrease of 3.5 log₁₀ CFU/ml at 24 h versus initial inoculum, with no regrowth after 24 h) both macrolide-susceptible and mef(A)-positive strains of S. pneumoniae with clarithromycin MICs from 1 to 8 µg/ml, inclusive (Fig. 1B). Total drug concentrations of clarithromycin in ELF resulted in a 1.2 log₁₀ CFU/ml killing of macrolide-resistant strains [mef(A)-positive and erm(B)-negative; clarithromycin MIC of 16 µg/ml] and regrowth for macrolide-resistant strains [mef(A)-negative and erm(B)-positive; clarithromycin MIC of 128 µg/ml] (Fig. 1B). Free-drug concentrations of clarithromycin in ELF (C_p maximum, 14 µg/ml) killed (3.5 log₁₀ CFU/ml decrease at 24 h versus initial inoculum, with no regrowth after 24 h) both macrolide-susceptible and mef(A)-positive strains of S. pneumoniae with clarithromycin MICs from 1 to 4 µg/ml, inclusive (Fig. 1C). Free-drug concentrations of clarithromycin in ELF resulted in 1.0 log₁₀ CFU/ml killing for macrolide-resistant strains [mef(A)-positive and erm(B)-negative; clarithromycin MIC of 8.0 µg/ml) and regrowth for macrolide-resistant strains [mef(A)-positive and erm(B)-negative, clarithromycin MIC of 16.0 µg/ml; and mef(A)-negative and erm(B)-positive, clarithromycin MIC of 128 µg/ml) (Fig. 1C).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Clarithromycin killing of macrolide-resistant S. pneumoniae isolates, simulating free-drug concentrations in serum (A), total drug concentrations in ELF (B), and free-drug concentrations in ELF (C) (in log10 CFU per milliliter of reduction at 24 h), relative to that of the initial inoculum.

At the present time, there is discordance between the prevalence of macrolide-resistant S. pneumoniae and bacteriological and clinical cure rates using macrolides (13, 14, 32). According to a review by Gotfried, although recent surveillance studies indicate that in vitro S. pneumoniae resistance to macrolides is high (40%), clinical success rates using macrolides are as high as 92% (14). Similarly, a 1999 study of hospitalized adult patients infected with susceptible strains of S. pneumoniae and adult patients infected with S. pneumoniae strains that were resistant to penicillin, macrolides, or both indicated no difference in treatment outcomes between those patients with susceptible strains and those patients with resistant strains (13). Limited data do exist describing macrolide failures in outpatient respiratory infections (21, 32). Upon inspection, the macrolide-resistant S. pneumoniae strains implicated in these clinical failures had erm(B) phenotypes and genotypes (MIC 64 µg/ml) or mef(A) phenotypes and genotypes with macrolide MICs of 8 to 16 µg/ml. To the best of our knowledge no data exist that document clinical failures when using macrolides in patients infected with low-level macrolide-resistant (MICs, 1 to 4 µg/ml) S. pneumoniae strains.

Our hypothesis in this study was that achievement of significantly higher clarithromycin concentrations in ELF (the primary site of extracellular respiratory pathogens such as S. pneumoniae) relative to serum drug concentrations would result in inhibition of low-level macrolide-resistant(MIC, 1 to 4 µg/ml) S. pneumoniae isolates possessing the mef(A) genotype. Thus, to test this hypothesis and to define more clinically predictive breakpoints for clarithromycin against S. pneumoniae in the treatment of community-acquired respiratory infections caused by macrolide-resistant S. pneumoniae, we conducted this pharmacodynamic study. In our pharmacodynamic model, we found that simulating free (unbound) concentrations of clarithromycin in serum after a 500-mg, p.o., BID regimen did not eradicate mef(A) strains for which MICs were 2 µg/ml, compared to macrolide-susceptible S. pneumoniae isolates (Fig. 1A). Simulation of clinically achievable total and free-drug concentrations of clarithromycin in ELF completely eradicated macrolide-susceptible and mef(A) strains of S. pneumoniae, with clarithromycin MICs that ranged from 1 to 8 µg/ml and 1 to 4 µg/ml, respectively (Fig. 1B and C). Simulating clinically achievable total and free-drug concentrations of clarithromycin in ELF resulted in 1 to 2 log₁₀ CFU/ml killing of mef(A) strains of S. pneumoniae, with clarithromycin MICs of 16 and 8 µg/ml, respectively. However, even the high drug concentrations in ELF obtained with clarithromycin failed to inhibit erm(B) S. pneumoniae isolates (MIC, 128 µg/ml).

Despite the limited ability of clarithromycin concentrations in serum to eradicate mef(A)-resistant strains of S. pneumoniae, concentrations of clarithromycin in ELF have the potential to eradicate mef(A) strains, with clarithromycin MICs of up to and including 8 µg/ml. Our own data suggest that in Canada as well as in the United States, the majority of macrolide-resistant mef(A) S. pneumoniae isolates have macrolide MICs of 1 to 8 µg/ml (9, 31). These findings help explain the lack of clinical failures with macrolides in the treatment of respiratory infections despite reports of the high prevalence of macrolide-resistant S. pneumoniae strains. Although the NCCLS lists an S. pneumoniae resistance breakpoint of 1 µg/ml (for clarithromycin and erythromycin), our data suggest that a breakpoint of 8 to 16 µg/ml is more predictive of bacteriologic failure. mef(A)-producing S. pneumoniae isolates for which the MIC is 16 µg/ml and erm(B)-producing S. pneumoniae strains (MIC₉₀ 256 µg/ml) are likely to result in bacteriological failure despite the high drug concentrations in ELF achieved with clarithromycin. It should be mentioned that our in vitro model simulates an immunocompromised situation, as no immune-related components are added to the model. What role the immune system would have in interacting with macrolide therapy to eradicate mef(A)-producing S. pneumoniae strains for which macrolide MICs are 16 µg/ml is unknown. Ongoing surveillance will be critical in assessing macrolide MIC creep in S. pneumoniae.

	ACKNOWLEDGMENTS

 
The study was supported in part by the Manitoba Medical Services Foundation and by Abbott Laboratories (Canada and United States).

The secretarial assistance of M. Wegrzyn is highly appreciated.

	FOOTNOTES

 
* Corresponding author. Mailing address: Department of Clinical Microbiology, Health Sciences Centre, MS673-820, Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada. Phone: (204) 787-4902. Fax: (204) 787-4699. E-mail: ggzhanel{at}pcs.mb.ca.

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