New drugs for Gram-positive uropathogens

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1 International Journal of Antimicrobial Agents 24S (2004) S39 S43 New drugs for Gram-positive uropathogens F.M.E. Wagenlehner, K.G. Naber Department of Urology, Hospital St. Elisabeth, St. Elisabeth Straße 23, D Straubing, Germany Abstract Complicated urinary tract infections (UTIs) are frequent nosocomial infections. The bacterial spectrum encompasses Gram-negative but also Gram-positive pathogens in up to 30 40%. The existing treatment for Gram-positive pathogens is not always optimal. Antimicrobials for the treatment of Gram-positive uropathogens comprise older agents, such as aminopenicillins with or without -lactamase inhibitors and vancomycin, as well as newer fluoroquinolones, such as levofloxacin or gatifloxacin. However, resistant bacteria such as vancomycin-resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) (except vancomycin-resistant) are generally also not susceptible to the fluoroquinolones. Therefore new agents need to be assessed in the treatment of UTI. Daptomycin and linezolid are new antimicrobial agents with good efficacy against Gram-positive uropathogens as shown by their minimal inhibitory concentrations. In a phase II study the urinary bactericidal activity of linezolid versus ciprofloxacin in volunteers showed comparable activity of both drugs against fluoroquinolone susceptible Gram-positive uropathogens, whereas linezolid was also as active against fluoroquinolone resistant ones. The pharmacokinetics and the mode of action of these two antibiotics are discussed together with some clinical data in the context of therapeutic use in patients with complicated UTIs Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Urinary tract infections; Gram-positive bacteria; Levofloxacin; Gatifloxacin; Daptomycin; Linezolid 1. Introduction Urinary tract infections (UTIs) are among the most common bacterial infections with several million cases treated annually in the United States and with a similar incidence world-wide. The majority of UTIs are uncomplicated in otherwise healthy individuals and are usually due to Gram-negative bacteria [1]. Uncomplicated UTIs occur more often in women than in men, and typically respond rapidly to oral antimicrobial treatment although resistance to some commonly prescribed antibiotics (e.g. trimethoprim-sulfamethoxazole) is increasing [2]. For all age groups, UTIs remain a significant cause of morbidity and health care expenditures [3]. UTIs are the most common infections in nursing home residents. Complicated UTIs present a more difficult medical challenge than uncomplicated UTIs and existing treatment is not always optimal. Complicated UTIs occur in both sexes where structural or functional impairment of the urinary sys- Corresponding author. Tel.: ; fax: address: naberk@klinikum-straubing.de (K.G. Naber). tem is present. Other complicating factors may be involved, including the presence of chronic indwelling catheters and an impaired host defence due to diabetes or immunosuppressive drugs. Bacteremia can occur particularly where parenchymal infection (e.g. pyelonephritis) or obstruction (e.g. prostatic hyperplasia, calculi) is present [4]. These characteristics of complicated UTIs generally mandate hospitalisation and treatment with parenteral antibiotics. Secondary complications, including potential systemic complications, may occur with bacteremic UTIs [5]. The pathogens associated with complicated UTIs tend to be more resistant to treatment than those from uncomplicated UTIs [1]. As with uncomplicated infections, Gram-negative bacteria are the most common pathogens in complicated cases; however, Gram-positive bacteria are not uncommon in patients with complicated UTIs where they account for up to 30 40% of isolates [6]. 2. Significance of Gram-positive uropathogens In uncomplicated UTIs caused by Gram-positive uropathogens, only staphylococci, mainly Staphylococcus saprophyticus, play a significant role and contribute to /$ see front matter 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi: /j.ijantimicag

2 S40 F.M.E. Wagenlehner, K.G. Naber / International Journal of Antimicrobial Agents 24S (2004) S39 S43 about 5 15% of cases [7]. Enterococci, if present in uncomplicated UTI, are usually found in mixed infections, making it difficult to define their specific role whether as pathogens, colonisers or contaminants. In complicated UTIs, staphylococci and enterococci are the main Gram-positive uropathogens. These organisms have become common in hospitals, nursing homes and chronic care facilities. UTIs caused by these organisms are associated with serious underlying illness and institutionalisation. Increasing proportions of these isolates are resistant to available antibiotics including vancomycin [8]. The rate of methicillin-resistant Staphylococcus aureus (MRSA) is gradually increasing in Germany making up 22% of S. aureus isolates in 2001 [9]. MRSA is not a major urinary pathogen. However in one study, one-third of S. aureus causing UTIs were MRSA [10]. Most infections are caused by a single pathogen but mixed infections with more than one pathogen can occur, adding further complexity to treatment decisions. 3. Antimicrobial agents for Gram-positive uropathogens and their antimicrobial activity Antibiotics used for the therapy of UTI in general need be in high concentrations in the urine. Only a limited number of antibiotic substances, which are effective against Gram-positive pathogens however, show sufficient urinary excretion and antimicrobial activity. Ampicillin or amoxicillin (with or without -lactamase inhibitors), as well as oxacillin or flucloxacillin are excreted in more than 90% in urine [11]. Although aminopenicillins have been extensively studied in the treatment of UTI, mainly E. coli in uncomplicated UTI was the target in these studies and therefore little experience exists in the treatment of Gram-positive uropathogens in complicated UTIs [12]. Fluoroquinolones can be classified into four groups [13]. Substances of group three and four are more active against Gram-positive bacteria. Amongst these only two antibiotics, levofloxacin and gatifloxacin, show sufficient renal excretion for the treatment of more severe UTIs. The renal excretion of unmetabolised levofloxacin is 80 95% and that of gatifloxacin is 80% [11]. In clinical studies ciprofloxacin was usually used as the comparative fluoroquinolone, e.g. for levofloxacin [14,15]. In one clinical study, gatifloxacin and ciprofloxacin showed equivalence regarding efficacy and safety in the treatment of complicated UTI in a dose of 400 mg once daily, as compared to 500 mg twice daily [16]. There exists however strong cross-resistance amongst fluoroquinolones, e.g. the population of enterococci and staphylococci resistant to ciprofloxacin is comparably resistant to levofloxacin and gatifloxacin (Table 1). Some pathogens also possess a high rate of parallel resistance, such as methicillin-resistant S. aureus. About 90% of MRSA isolates are also resistant against fluoroquinolones [9]. Vancomycin has become the standard treatment for infections with MRSA and MRSE since the rates of resistance have become clinically significant. Vancomycin is administered intravenously; having a serum half-life of about 6 h and protein binding of approximately 55%. Eighty to ninety percent of vancomycin is excreted unmetabolized in urine [11]. The pharmacodynamic parameter that predicts best outcome is AUC/MIC [17]. Thus far, there have been no clinical studies to assess the efficacy in complicated UTIs. Resistant bacteria such as MRSA or vancomycin-resistant enterococci (VRE) are a potential threat because in serious infections, such as bacteraemia, frequently there is inadequate initial treatment, which leads to higher mortality, compared to adequate initial treatment [17]. There are two new antimicrobial substances (linezolid, daptomycin) that may address the medical need for better treatments of complicated UTIs caused by Gram-positives Daptomycin Daptomycin is a unique lipopeptide antibiotic. It belongs to a new class of antibiotics and may therefore offer significant advantage in treating Gram-positive infections. Daptomycin is rapidly batericidal and there is so far no known cross-resistance with other antibiotics. The antibacterial mode of action is through several potential mechanisms including the inhibition of peptidoglycan biosynthesis, dis- Table 1 In vitro antibacterial activity of ciprofloxacin, levofloxacin and gatifloxacin against urinary pathogens (Naber KG, unpublished data) Microorganism Drug Number of strains having MIC (mg/l) of S. aureus (n = 28) CIPX LEVX GATX Coagulase negative staphylococci (n = 57) CIPX LEVX GATX Enterococci (n = 126) CIPX LEVX GATX CIPX: ciprofloxacin, LEVX: levofloxacin and GATX: gatifloxacin.

3 F.M.E. Wagenlehner, K.G. Naber / International Journal of Antimicrobial Agents 24S (2004) S39 S43 S41 Table 2 Distribution of minimal inhibitory concentrations (MIC in mg/l) of daptomycin against uropathogens Pathogen MIC in (mg/l) Total a MSSA MRSA MSSE MRSE E. faecalis E. faecium Total Cumulative total Cumulative percentage MSSA: methicillin-susceptible S. aureus, MRSA: methicillin-resistant S. aureus, MSSE: methicillin-susceptible coagulase-negative staphylococci and MRSE: methicillin-resistant coagulase-negative staphylococci. a Numbers of isolates. Table 3 Distribution of minimal inhibitory concentrations (MIC) in mg/l of linezolid against uropathogens Pathogen MIC in (mg/l) Total a MSSA MRSA MSSE MRSE E. faecalis E. faecium Total Cumulative total Cumulative percentage MSSA: methicillin-susceptible S. aureus, MRSA: methicillin-resistant S. aureus, MSSE: methicillin-susceptible coagulase-negative staphylococci and MRSE: methicillin-resistant coagulase-negative staphylococci. a Numbers of isolates. ruption of cell membrane permeability, reducing synthesis of lipoteichoic acids, and the disruption of the transmembrane electrochemical gradient [18]. Daptomycin is administered intravenously and has a serum half-life averaging 8.5 h. The compound is approximately 90% bound to serum proteins and 80% is excreted in urine, 66% as the active drug [19,20]. Dose adjustment in patients with renal impairment may therefore be necessary. The pharmacodynamic parameter that predicts outcome best, is the AUC/MIC ratio [21]. We tested the MICs of daptomycin against Gram-positive uropathogens (Table 2). The MIC distribution of daptomycin for all Gram-positive uropathogens tested were in the range of 0.12 and 2 mg/l, indicating that all strains are susceptible to daptomycin. The methicillin susceptible or resistant S. aureus, coagulase negative staphylococci as well as enterococcal strains showed about the same MIC range, indicating that the activity is independent of methicillin susceptibility. According to in vitro activity, daptomycin may then be considered a promising antibacterial agent for the treatment of complicated UTI caused by Gram-positive pathogens Linezolid Linezolid is the first oxazolidinone agent that has been launched in clinical practice. It interferes with an early step in the protein synthesis process [22]. Linezolid is rapidly and extensively absorbed after oral dosing with an absolute bioavailability of about 100%. Its serum half-life is about 6.4 h and the protein binding approximately 31% [11]. Comparable with the daptomycin study, the MIC distribution of linezolid for all Gram-positive uropathogens tested was in the range of 0.25 and 2 mg/l (Table 3), indicating that all strains were susceptible to linezolid [23]. To assess if linezolid is also suitable for the treatment of UTI, we measured plasma and urine concentration and urinary bactericidal titers (UBTs) in volunteers following the administration of 600 mg linezolid versus 500 mg ciprofloxacin [24]. The mean maximum plasma concentration (13.1 mg/l) was more than five times higher than that after an oral dose of 500 mg ciprofloxacin (2.46 mg/l). The median cumulative renal excretion (parent drug) of linezolid (44%) was equal to that of ciprofloxacin (43%). Fig. 1. Median concentrations of linezolid (600 mg) and ciprofloxacin (500 mg) in urine of 12 healthy volunteers.

4 S42 F.M.E. Wagenlehner, K.G. Naber / International Journal of Antimicrobial Agents 24S (2004) S39 S43 The median concentrations of linezolid (600 mg) and ciprofloxacin (500 mg) in the urine of 12 healthy volunteers is shown in Fig. 1. The UBTs, i.e. the highest two-fold dilution of urine that is bactericidal (antibiotic free urine as diluent), were determined for a reference strain and five Gram-positive clinical uropathogens. The organisms had the following MICs for linezolid/ciprofloxacin: S. aureus ATCC 27278, 2/0.25 mg/l; S. aureus (MSSA), 1/16 mg/l; S. aureus (MRSA), 2/64 mg/l; S. saprophyticus (MSSE), 1/0.25; Enterococcus faecalis, 2/1 and E. faecium, 2/1. The median UBTs measured within the first 6 h for linezolid were 1:96 for the two enterococcal strains and between 1:128 and 1:256 for the four staphylococcal strains. The median UBTs for ciprofloxacin were 1:64 for the two enterococcal strains, between 1:384 and 1:512 for the two ciprofloxacin susceptible and 1 (bactericidal activity of undiluted urine only) and 1:2 for the two resistant staphylococcal strains. The areas under the UBT time-curve (AUBT) showed no statistically significant (P <0.05) dif- ferences between linezolid and ciprofloxacin, except for the two ciprofloxacin resistant staphylococcal strains which showed to be in favour of linezolid. For linezolid there were no statistically significant differences of UBTs or AUBTs regarding ciprofloxacin-susceptible and resistant strains. The median reciprocal UBTs of linezolid (600 mg) and ciprofloxacin (500 mg) for S. aureus ATCC and five clinical uropathogens in 12 volunteers tested are shown in Fig. 2. With an oral dose of 600 mg linezolid twice daily, urinary bactericidal activity against Gram-positive uropathogens, regardless of their methicillin and fluoroquinolone resistance, can be expected throughout the complete therapeutic interval. Thus, the urinary bactericidal activity of linezolid and ciprofloxacin were comparable against susceptible strains, whereas linezolid also exhibited the same bactericidal activity against ciprofloxacin-resistant strains [6]. Linezolid should therefore also be tested for empiric treatment of complicated UTI due to Gram-positive uropathogens in an appropriate clinical trial. Fig. 2. Median reciprocal UBTs of linezolid (LIN) (600 mg) and ciprofloxacin (CIP) (500 mg) for S. aureus ATCC and five clinical uropathogens in 12 volunteers tested.

5 F.M.E. Wagenlehner, K.G. Naber / International Journal of Antimicrobial Agents 24S (2004) S39 S43 S43 4. Conclusion Gram-positive pathogens may become more important in causing complicated UTIs. There are new potential drugs for the treatment of UTIs caused by Gram-positive uropathogens. These compounds exhibit good activity in urine and are active against otherwise resistant Gram-positive bacteria. However, there have already been reports on the emergence of enterococcal strains, resistant to linezolid, in patients all over the world [25,26]. The emergence of resistance to antimicrobial agents among previously susceptible organisms continues to be an important obstacle to the successful treatment of infection. The health and economic impact of this cannot be overlooked since it results in more and longer hospitalisation, longer therapy and higher mortality. We therefore need to be very cautious and use these new compounds prudently to conserve its activity in the future. 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