Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections

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1 International Journal of Antimicrobial Agents 28S (2006) S35 S41 Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections Teresita Mazzei, Maria Iris Cassetta, Stefania Fallani, Silvia Arrigucci, Andrea Novelli Department of Pharmacology, University of Florence, Viale Pieraccini 6, Firenze, Italy Abstract Uncomplicated urinary tract infections (UTI) are treated with -lactams, co-trimoxazole, quinolones and fosfomycin tromethamine. Due to increasing resistance of causative pathogens, antibiotics should be used by considering their pharmacodynamic and pharmacokinetic characteristics. -lactams have time-dependent activity and should not be used once-daily. Co-trimoxazole should be restricted due to increasing chemoresistance. Fluoroquinolones play a primary role in the treatment of serious and complicated infections. Fosfomycin tromethamine is active against most urinary tract pathogens. In vitro time-kill kinetics of fosfomycin against Escherichia coli and Proteus mirabilis showed primarily concentration-dependent activity, with a prolonged post-antibiotic effect (3.4 to 4.7 h). Based on these results a single 3 g dose of fosfomycin guarantees optimal efficacy against common uropathogens with an AUC(urine)/MIC ratio of Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Fosfomycin; Time-kill kinetic studies; Post-antibiotic effect; Urinary tract infection 1. Introduction Uncomplicated urinary tract infections (UTI) are usually caused by Escherichia coli or, to a lesser extent, by other enterobacteria, staphylococci or enterococci [1]. The chemosensitivity of these pathogens differs when comparing data relating to community infections with nosocomial infections or bacteriuria in patients hospitalized for long periods [1,2]. As time goes on, there is a tendency for both Gram-negative and Gram-positive strains to increase their resistance to commonly used agents, especially to trimethoprim/sulfamethoxazole or co-trimoxazole [3].Given the increasing rates of co-trimoxazole resistance among uropathogens that cause acute uncomplicated cystitis, the -lactams, fluoroquinolones, nitrofurantoin and fosfomycin tromethamine are often considered as alternative empirical therapy [1]. All of these compounds are usually used for a short treatment period or even as single-shot doses. It is necessary to utilize the different classes of antibiotics in the best way possible. The correct use of these drugs should consider Corresponding author. Tel.: ; fax: address: mazzei@ds.unifi.it (T. Mazzei). the different pharmacodynamic (PD) and pharmacokinetic (PK) characteristics. 2. General PK PD aspects of antimicrobial chemotherapy Modern pharmacology is going through a period of critical review of the rules for selecting antibiotics and their ideal dosage regimen for the control of infections, with the goals of increasing treatment efficacy and reducing the risk of selecting multiresistant pathogens [4 7]. Two fundamental pharmacological components regarding the role of drug dosing and regimen are the PK and PD. Pharmacokinetics involves absorption, tissue distribution, metabolism and drug elimination, whereas PD analyses antimicrobial activity. The main PD parameters include the: (i) minimum inhibitory concentration (MIC); (ii) minimum bactericidal concentration (MBC); (iii) post-antibiotic effect (PAE); and (iv) killing rate. On the basis of their different patterns of bactericidal activity (killing curves), we can divide antibiotics into two groups: time dependent or concentration dependent. The -lactams, glycopeptides, erythromycin and oxazolidinones are time dependent, whereas the aminoglycosides, /$ see front matter 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi: /j.ijantimicag

2 S36 T. Mazzei et al. / International Journal of Antimicrobial Agents 28S (2006) S35 S41 oral absorption, faster elimination etc.) and bacterial strain characteristics (lower susceptibility, virulence factors etc.) may have an important role. Finally, since dose effect relationships have now been reasonably well established for most antibiotics, these should be used to re-appraise current clinical breakpoints, giving the clinician more information on resistance and, consequently, on treatment choices [8]. 3. Antimicrobial agents for the treatment of uncomplicated urinary tract infection 3.1. Nitrofurantoin Fig. 1. Pharmacodynamic activity of antimicrobial agents. quinolones, semisynthetic macrolides, azalides and ketolides tend to be concentration dependent in their activity (Fig. 1) [4 7]. Some important PK PD parameters have shown good correlation between in vitro and in vivo animal infection models and the therapeutic efficacy of antibiotics [5 7]. The first of these is the duration of time that antibiotic concentrations exceed the MIC (T > MIC); the second is the ratio between peak concentration (C max ) and MIC (C max /MIC); and the third is the ratio between the area under the curve (AUC) of blood concentrations and the MIC (AUC/MIC). The T > MIC is recognized as being the predictor of clinical and microbiological success or failure for time-dependent antibiotics (in vitro, animal and human data). C max /MIC and AUC/MIC are the PK PD parameters that predict the efficacy of concentration-dependent drugs, even though there are some important clinical data demonstrating that the AUC/MIC might also be useful for assessing the effectiveness of time-dependent antimicrobial agents (Fig. 1). The study of antibiotic PK PD holds great promise, not only for optimizing posology and outcome but also for limiting or preventing bacterial resistance to old and new antibiotics. It might be argued that PK PD parameters are less useful for the treatment of uncomplicated UTI because the chosen antibiotics are usually capable of reaching and maintaining relatively high urinary concentrations that are much greater than the MIC of the causative pathogens. Thus, the need for a critical PK PD analysis for success is theoretically diminished. Nevertheless, in our opinion, the theoretical urinary PK PD thresholds should be considered even in these infections because the patient s condition (i.e. urinary ph, different risk factors such as pre-existing diseases, reduced Nitrofurantoin, a synthetic nitrofurane derivative, still maintains relatively high activity against E. coli and Enterococcus faecalis uropathogens, although in a recent survey performed in Italy, more than 20% of E. coli strains were resistant to the drug [9,10]. Moreover, nitrofurantoin is inactive against Proteus mirabilis. After an oral dose of 100 mg, concentrations higher than 100 mg/l are usually achievable in the urine, leading to a bactericidal effect against susceptible organisms. However, there might be different side effects, generally after long-term therapy, including chronic hepatitis and acute, subacute and chronic pulmonary reactions. Although the occurrence of both pulmonary and hepatic toxicity caused by this antibiotic is exceedingly rare, the considerable morbidity and mortality of nitrofurantoin-induced disease, as well as increasing resistance, make this antibiotic no longer suitable as a first choice for the treatment of uncomplicated UTI, either in women or men [10,11] Co-trimoxazole Co-trimoxazole is a synergistic combination of trimethoprim and sulfamethoxazole (TMP/SMX), which has been employed for more than 30 years as a first-line therapy for UTI. However, the wide use of TMP/SMX has also resulted in the progressive emergence of resistance, and increasing values of over 20% have been reported in several European countries and in the USA, hence limiting the clinical usefulness of this therapy in the modern management of UTI. Co-trimoxazole is used less and less, also owing to problems of tolerability [12] β-lactams The -lactams, which are characterized by a mechanism of activity against the bacterial cell wall, are generally active against Gram-positive and Gram-negative bacteria. Resistance in enterobacteria is mainly the result of inactivation owing to hydrolytic enzyme production ( -lactamases). Therefore, there is a tendency to use aminopenicillins in combination with suicide inhibitors (e.g. amoxicillin clavulanic acid) or oral cephalosporins, mainly third-generation derivatives, because of their higher potency against Gram-negative

3 T. Mazzei et al. / International Journal of Antimicrobial Agents 28S (2006) S35 S41 S37 Table 1 Main pharmacokinetic parameters of oral -lactams (mean values) [12 15] -Lactam Dose (mg) C max (mg/l) T max (h) t 1/2 β (h) Bioavailability (%) Dosing interval (h) Fu (%) Amoxicillin/clavulanic acid 875/ / /1 90/ /60 Cefuroxime axetil a Cefixime b Ceftibuten b T max, time to maximum concentration; t 1/2 β elimination half-life; Fu, fraction recovered in urine. a Pro-drug. b Intrinsic bioavailability. rods, even if they are not active against Enterococcus sp. Many cephalosporins do not have high oral bioavailability and require administration as pro-drugs (i.e. various esters). Finally, they generally have a relatively brief elimination halflife, which means they should not be administered once-daily, with the possible exclusion of both cefixime and ceftibuten (Table 1) [13 16]. Pivmecillinam, a pro-drug of mecillinam, has been widely used for the treatment of acute lower UTI, mainly in Northern Europe. This derivative has high activity against Gramnegative organisms such as E. coli, with a low level of resistance (<2%). This -lactam is not available in Italy [17] Quinolones/fluoroquinolones The quinolones can be divided into three generations. The first is represented by nalidixic acid and its derivatives. The second generation comprises wide-spectrum quinolones, such as ciprofloxacin, ofloxacin, lomefloxacin, norfloxacin and prulifloxacin, and are still used for treating UTI. The third generation includes recent derivatives that are especially active against Gram-positive bacterial species and anaerobes and, therefore, are less indicated for UTI [18], with the exception of levofloxacin. The differences among the various generations are the result of modifications in the structural formula, which determines different activity [19]. The action mechanism of these antibiotics is due to the inhibition of DNA gyrase and partly to bacterial topoisomerase IV, with resulting cell death due to complex binary or tertiary formations among DNA, the enzyme and the antibiotic [18,19]. These are bactericidal antibiotics, and the mechanisms of bacterial resistance are primarily linked to modifications at the binding site or active drug extrusion from the bacteria through efflux pumps [18,19]. The second- and third-generation molecules have favourable kinetic characteristics with high oral bioavailability, good tissue penetration and primarily renal elimination (Table 2) [18,20 25]. As mentioned previously, these are concentrationdependent antibiotics, and to avoid increased resistance and guarantee potential efficacy it is necessary (at least against Gram-negative bacteria) to obtain peak/mic ratios of 10:12 and AUC/MIC ratios of about 100:125. These values have been documented not only in animal models but also in serious infections in hospitalized patients [26,27]. The fluoroquinolones are generally well tolerated, although they can cause (with varying incidence) gastrointestinal and neurological disturbances, the latter because of gamma-aminobutyric acid (GABA) inhibition, as well as cardiovascular sideeffects with a prolonged QT interval [28,29]. The administration of these antibiotics together or within a few hours of antacids containing Zn 2+,Al 2+ or Mg 2+ causes a significant reduction in their oral absorption and constitutes an important pharmacological interaction [28,29]. The fluoroquinolones are generally very efficacious, but because of their microbiological, pharmacological and toxicological characteristics, they should be used only for the most serious conditions and in special populations. Table 2 Main pharmacokinetic parameters of quinolones (mean values) [3,19 23] Quinolones Dose (mg) C max (mg/l) t 1/2 β (h) Bioavailability (%) PB (%) Metabolism (%) Fu (%) Urinary C max (mg/l) First generation Nalidixic acid Pipemidic acid < Second generation Norfloxacin Ofloxacin < Ciprofloxacin Prulifloxacin < Third generation Levofloxacin 500 a t 1/2 β elimination half-life; PB, protein binding; Fu, fraction recovered in urine; C max, peak concentration. a 250 mg dose is recommended for UTI.

4 S38 T. Mazzei et al. / International Journal of Antimicrobial Agents 28S (2006) S35 S41 Fig. 2. Structural formula of fosfomycin tromethamine [27] Fosfomycin tromethamine Fosfomycin is a phosphonic acid derivative with a broad spectrum of antibacterial activity (Fig. 2). It is bactericidal owing to the inhibition of a cytoplasmic enzyme (pyruvyltransferase) that is active during the first step of bacterial cell wall (peptoglycan) synthesis [30]. Notwithstanding the possible mechanisms of bacterial resistance, this antibiotic has maintained good activity against the main bacterial species responsible for urinary infection [31,32]. After oral administration of 3 g of the tromethamine salt of fosfomycin, high urinary concentrations ( mg/l) are achieved and remain at 100 mg/l for at least h, guaranteeing good efficacy in the treatment of uncomplicated UTI even after a single administration [33,34] (Table 3). Fosfomycin tromethamine is generally well tolerated and has been used successfully as a single dose even when treating lower UTI in pregnant women [34]. 4. In vitro PD study with fosfomycin 4.1. Materials and methods There are no published studies that have specifically examined the intrinsic PD characteristics of fosfomycin. We do not know if it has a consistent post-antibiotic effect or whether it is predominantly a time- or concentration-dependent antibiotic. Therefore, we conducted an in vitro PD study to better characterize this molecule for its clinical use in patients with uncomplicated UTI. The killing activity of fosfomycin over time was evaluated in liquid medium (Mueller Hinton Broth II (BBL)) with the addition of 25 g/ml of glucose 6-phosphate (Sigma Chemical Co., St. Louis, MO, USA) at 37 C while shaking. The Table 3 Main pharmacokinetic parameters of fosfomycin tromethamine (mean values) [28] Bioavailability (%) C max (mg/l) t 1/2 β (h) AUC 0 (mg/l h) Urinary C max (mg/l) 4415 Fu (%) 48 h C max, peak concentration; t 1/2 β elimination half-life; AUC, area under the concentration time curve of blood concentrations; Fu, fraction recovered in urine. Fig. 3. Fosfomycin tromethamine: in vitro activity (killing curves, mean values) against Escherichia coli isolates (a) LC405 (MIC = 8 mg/l); and (b) LC406 (MIC = 8 mg/l). CFU, colony-forming units; MIC, minimum inhibitory concentration. activity was examined against E. coli and P. mirabilis clinical isolates at a final concentration of between 10 6 colonyforming units (CFU)/mL and 10 7 CFU/mL in either the presence or absence of fosfomycin at concentrations increasing from the MIC to 64 times the MIC. The MIC values were determined according to the National Committee for Clinical Laboratory Standards (NCCLS, now CLSI) guidelines [35]. Bacterial growth was evaluated at time zero (before the addition of the antibiotic) and at different times in the following 24 h both in the control and antibiotic samples, using the CFU/mL count method [35]. Results are reported in Figs. 3 and Results Analysis of the killing curves indicates that the antibacterial activity of fosfomycin on the two E. coli strains (both with a MIC of 8 mg/l) was especially marked, with inhibition of bacterial growth for 14.1 h at MIC and for 24 h at 2 MIC, whereas there was no regrowth observed even after 24 h at 4, 8, 16, 32 and 64 MIC (Fig. 3). A concentrationdependent bactericidal activity with sterilization at 6 8 h at concentrations 4 MIC was observed, with a reduction in the bacterial count of 3 4 log compared to the control in the first 2 h (Fig. 3). Overall, a similar activity was obtained for the two P. mirabilis strains, as was observed with the E. coli strains, although a relatively high concentration was needed for P. mirabilis. Growth was inhibited for 6.5 and 8.5 h at the MIC and 2 MIC, respectively, and increased to 18 h at 4 MIC. At concentrations 8 MIC there was no re-growth for more

5 T. Mazzei et al. / International Journal of Antimicrobial Agents 28S (2006) S35 S41 S39 Table 4 In vitro post-antibiotic effect (mean values, h) of fosfomycin tromethamine against clinical isolates of Escherichia coli and Proteus mirabilis Concentration E. coli LC406 (MIC 8 mg/l) 0.25 MIC MIC MIC MIC MIC, minimum inhibitory concentration. P. mirabilis LC901 (MIC 8 mg/l) Fig. 4. Fosfomycin tromethamine: in vitro activity (killing curves, mean values) against Proteus mirabilis isolates (a) LC901 (MIC = 8 mg/l); and (b) LC903 (MIC = 64 mg/l). CFU, colony-forming units; MIC, minimum inhibitory concentration. than 24 h. Sterilization of P. mirabilis was obtained in 6 8 h at concentrations 8 MIC, with a reduction in bacterial count of at least 3 log in the first 2 h compared with the control (Fig. 4). Despite different MIC values (8 mg/l for LC901 strain and 64 mg/l for LC903 strain), there were no significant differences in the concentration-dependent antimicrobial activity of fosfomycin against these two strains (Fig. 4). The PAE of fosfomycin in vitro was determined as described elsewhere [36]. Briefly, E. coli and P. mirabilis strains at final concentrations of CFU/mL were exposed to fosfomycin at concentrations of 0.25 MIC, MIC, 4 MIC and 8 MIC. After 2 h of exposure in a shaking incubator at 35 C, the antibiotic was removed by centrifugation and the bacterial cells were washed and resuspended in antibiotic-free medium. The same procedure was followed for the control cells. Bacterial counts were carried out at the start and every 1 2 h thereafter for 12 h by plating serial dilutions in agar. The PAE was calculated as the difference in the time required by the test and control samples to increase by 1 log in the CFU count [36]. The results obtained are reported in Table 4. Against both bacterial species fosfomycin demonstrated a long PAE even at sub-inhibitory concentrations (0.25 MIC) that lasted h, which then increased with concentrations MIC ( h), thus confirming a tendency to have a concentration-dependent effect (Table 4). On the basis of our results, and keeping in mind that concentrations >500 mg/l for at least h after a 3-g dose of fosfomycin tromethamine have been observed [30], it is evident that a single administration guarantees adequate coverage against some Enterobacteriaceae spp. (including P. mirabilis), for which sterilization after 8 h at MIC up to mg/l is predicted. Using the mean serum and urine peak concentrations and AUC over time reported by Patel et al. [30], it is possible to determine the theoretical C max /MIC and AUC/MIC in both serum and urine (Table 5). These PK PD parameters are both very high, particularly at the urinary level, even against potential pathogens with a MIC of 64 mg/l. This particularly high MIC value is not often found for pathogens of uncomplicated UTI mostly caused by E. coli (MIC 90 = 8 mg/l) [10], even after considering the possible underestimation of the MIC owing to enrichment of broth cultures with glucose-6-phosphate, which is normally absent in urine. In fact, the AUC/MIC and C max /MIC values are at least four times higher than the standard values predictive of efficacy for concentration-dependent drugs ( for AUC/MIC and approximately 12 for C max /MIC) (Table 5). However, these PK PD indices are presently validated only as predictive plasmatic parameters for efficacy in different infections. These kinds of correlations would be very useful for UTI but are still lacking. Table 5 Fosfomycin tromethamine: pharmacokinetic pharmacodynamic correlations in serum and urine against clinical isolates of Escherichia coli and Proteus mirabilis [30] Microorganism MIC (mg/l) AUC/MIC serum AUC/MIC urine C max /MIC urine E. coli LC E. coli LC P. mirabilis LC P. mirabilis LC MIC, minimum inhibitory concentration; AUC, area under the concentration time curve; C max, peak concentration. AUC 0 serum = mg/l per h. AUC 0 urine = 31,955 mg/l per h. C max urine = 4415 mg/l.

6 S40 T. Mazzei et al. / International Journal of Antimicrobial Agents 28S (2006) S35 S Conclusion On the basis of our in vitro results, fosfomycin tromethamine demonstrates a high bactericidal activity against Enterobacteriaceae with a PAE that is sufficiently long even at concentrations MIC with efficacy tending to be concentration dependent. 5. Discussion In conclusion, therapy of uncomplicated UTI involves primarily the use of -lactams, quinolones and fosfomycin tromethamine. The -lactams, because of their timedependent activity, should not be administered as once-daily or as a single dose. These drugs must be administered for at least 3 days. The fluoroquinolones are generally very active against the pathogens responsible for infection and possess favourable PK. Nevertheless, because of their importance in the treatment of serious infections and owing to the risk of increasing chemoresistance, they should be used with caution for uncomplicated UTI. 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