ANTIBIOTIC CONCENTRATIONS AT TARGET SITES

2. ANTIBIOTIC CONCENTRATIONS AT TARGET SITES

It is well recognised that the efficiency of antibiotics in vivo is determined by their pharmacokinetics and pharmacodynamics (Wise, 2003). The former describes relatively simple processes of absorption, distribution, metabolism, and excretion of the antibiotic, which are properties of the molecules them- selves. Resistance selection is favoured among the microbial community if the drug does not reach the site of infection at sufficiently high concentrations to kill all of the microorganisms. Variable penetration of tissues will lead to het- erogeneity in the antibiotic concentration in different body compartments leading to eradication of organisms at one site but promoting resistance devel- opment at another. One of the significant attributes of fluoroquinolones is con- sidered to be the rapidity with which they are absorbed and distributed around the body—but even these antibiotics show low uptake into cerebrospinal fluid and fatty tissues (Wise, 2003). For ␤-lactams, a more restricted distribution may negatively impact their efficiency. Purulent fluid sampled from infected liver cysts in a patient on intravenous meropenem therapy contained only 1.2–5 mg/L compared with serum levels of 91.7 mg/L 30 min prior to surgery (Low et al., 2001). This may represent an extreme example, but similar ratios have been recorded for salivary concentrations of most ␤-lactams and sul- famethoxazole (Soriano and Rodriguez-Cerrato, 2002). Most antibiotics shared these characteristics with only the weakly basic antibiotics being con- centrated to high levels (⬎40% of serum concentration), for example, ciprofloxacin and trimethoprim. This study (Soriano and Rodriguez-Cerrato, 2002) sought to correlate the pharmacokinetic properties of different antibi- otics with their impact on the nasopharyngeal flora since the mucosa is coated with saliva. With the exception of antibiotics that are known to have low in vitro activity on the flora (e.g., ciprofloxacin), there was a reasonable corre- lation between salivary concentration and impact on the flora (Soriano and Rodriguez-Cerrato, 2002). However, in terms of either reducing the carriage of resistant streptococci or the development of resistance, there was a tendency

370 Ian R. Booth for ␤-lactams to eliminate only the sensitive strains creating the potential for

the expansion of the resistant and intermediate flora. It was considered that the low salivary concentration of some of these antibiotics, coupled with their low to moderate effectiveness in vitro, was a significant factor in determining their effectiveness. Antibiotics with a high in vitro activity proved more successful (Soriano and Rodriguez-Cerrato, 2002). The compounding problem is that selection for non-susceptible strains can lead to cross-resistance. In the ARISE project (Soriano and Rodriguez-Cerrato, 2002), it was observed that elimina- tion of 67% of the Streptococcus pneumoniae strains by treatment with peni- cillin (0.06 mg/L) led to an increase in non-susceptible strains but also doubled the incidence of clarithromycin-non-susceptible organisms. A similar finding was made for treatment with clarithromycin. These observations point to the importance of the antibiotic reaching the effective concentration at the target tissue in order to prevent the development, or enrichment, of resistant strains.

2.1. Mutant prevention concentration and mutant selection window

Pharmacodynamics deals with the relationship between antibiotic concentra- tion and bactericidal effects and post-antibiotic effects. Such relationships can only be examined using either animal or in vitro models or by collation of data obtained with human subjects. Wise (2003) has pointed out that the MIC is the major in vitro parameter studied with clinical isolates, but because this analyses bacterial growth at a fixed concentration, it cannot reflect in vivo activity very closely because here the concentration of the antibiotic varies with time. A num- ber of different pharmacodynamic parameters have been defined that relate the persistence of the antibiotic in the serum at concentrations above the MIC to the efficacy of the drug (Hyatt et al., 1995; Schentag et al., 2001). Which of these parameters is the most important depends on the antibiotic class being studied (Hyatt et al., 1995). For ␤-lactams, oxazolidinones, and macrolides, it has been suggested that the serum concentration needs to be maintained above the MIC for an effective treatment (Wise, 2003). In contrast to the aminoglycosides and fluoroquinolones, the ratio of maximum serum concentration to MIC is consid- ered to more important as a predictor of efficacy of treatment.

It is generally held that if the concentration of the antibiotic at the site of infection exceeds the MIC for the microorganism, then resistance can be avoided. This led Drlica and colleagues to propose the mutant prevention con- centration (MPC) for an antibiotic (Dong et al., 2000; Drlica, 2003; Sindelar et al., 2000). Based on their analysis of fluoroquinolone potency against Mycobacterium, they argued that the selection of mutations could be avoided if the antibiotic concentration could be maintained above one that prevented

Evolution of Antibiotic Resistance within Patients 371 the growth of cells that had acquired the first step mutation required for

increasing the MIC (Dong et al., 2000). The MPC definition was arrived at after in vitro studies of resistance development and considerations of extant clinical data and defines the MPC as the minimum concentration that allows

no mutant recovery when more than 10 10 cells are applied to drug-containing agar (Dong et al., 2000; Drlica, 2003). Many current antibiotics cannot achieve serum concentrations that are likely to exceed, or even approach, the MPC (Dong et al., 2000), suggesting that the selection of resistant clones will remain a significant issue for the immediate future. However, the definition of MPC does give a basis for the design of antibiotics to reduce the frequency with which mutations to resistance will arise.

The proposal of the MPC was developed from an analysis of the rise in resis- tance to fluoroquinolones in mycobacteria. These observations fit with other data on the pharmacodynamics of antibiotics, but the concept has been superceded by the mutant selection window, which is the idea that there is a range of concentra- tions of the antibiotic over which more resistant mutants are most frequently selected (Drlica, 2003). As the concentration of antibiotic increased, the sensitive flora died, but then a plateau in the kill was observed due to the presence within the population of resistant mutants. Progressively greater concentrations lead to a further decline in the numbers of survivors as the resistance is overcome. The selection window is that range of concentrations over which survival is essentially constant and represents the interval between the lower boundary, at which concentration-sensitive organisms are killed, and the upper boundary, which rep- resents the concentrations that kill cells that possess only a single mutation con- ferring resistance (Drlica, 2003). Wise (2003) documents a number of cases where high doses of antibiotics given for short periods resulted in eradication of the pathogen in a high percentage of patients and prevented the appearance of resistance. Thus, the pharmacokinetics and pharmacodynamics of antibiotics offer opportunities for limiting the development of resistance in patients.