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Newer carbapenems for urinary tract infections
International Journal of Antimicrobial Agents 24S (2004) S35–S38
Newer carbapenems for urinary tract infections Tetsuro Matsumoto∗ , Tetsuro Muratani Department of Urology, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
Abstract Four carbapenems have been available clinically in Japan. These are imipenem/cilastatin (IMIP/CS) and panipenem/ betamipron (PANI/BP) of the older compounds and newer carbapenems such as biapem (BIAP) and meropenem (MERO). The latter compounds are relatively stable to dehydropeptidase-1 (DHP-1) and have been reported to have higher antimicrobial activities compared to the earlier carbapenems. The antimicrobial activity of these four carbapenems against fresh urinary isolates showed high activities against Enterobacteriacae such as Serratia marcescens, Enterobacter cloacae, Citrobacter freundii and Escherichia coli containing the class C--lactamase- and extended spectrum -lactamase (ESBL)-producing strains compared to piperacillin (PIPC) and ceftazidime (CTAZ). Against Pseudomonas aeruginosa, the carbapenems, with the exception of panipenem showed strong antimicrobial activities compared to PIPC and CTAZ. High activities were also seen against Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis, but methicillin-resistant strains were not affected. The first generation carbapenems showed better activity against E. faecalis than newer carbapenems. All four carbapenems were similar in clinical effectiveness in double blind trials for complicated urinary tract infections (UTIs). However, PANI/BP is less effective in UTIs caused by P. aeruginosa than IMIP/CS. MERO showed better eradication rate of P. aeruginosa than IMIP/CS. Retrospective analysis of treated cases using carbapenems showed a rapid defervescence in the treatment of febrile complicated UTIs, which were mainly caused by mixed infection of Gram-negative and Gram-positive bacteria, especially those involving P. aeruginosa and E. faecalis. © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Carbapenems; Urinary tract infection; Imipenem/cilastatin; Panipenem/betamipron; Meropenem; Biapenem
1. Introduction Carbapenems have a broad spectrum, strong antimicrobial activity and less affinity to -lactamases than other -lactam antibiotics. Carbapenem antibiotics have been developed during the last three decades. Thienamycin was first discovered in 1976. It had a wide antibiotic-spectrum and also highly active against bacteria. It was however poorly stable in vitro and in vivo, and showed toxicity to the kidneys and central nervous system [1]. The first generation carbapenem includes imipenem/cilastatin (IMIP/CS) and panipenem/betamipron (PANI/BP), which are used in the combined form with inhibitors, because they are unstable to dehydropeptidase-1 (DHP-1) and exhibit nephrotoxicity [2]. Newer carbapenems such as meropenem (MERO) and biapenem (BIAP) have been developed recently. They are relatively stable to DHP-1 and reported to have higher
∗
Corresponding author. Tel.: +81-93-691-7446; fax: +81-93-603-8724. E-mail address: [email protected] (T. Matsumoto).
antimicrobial activities against bacteria including Pseudomonas aeruginosa than the first generation carbapenems [3–5]. We describe the characteristics of newer carbapenems against urinary tract infections (UTIs) compared to the first generation carbapenems and other antibiotics.
2. Antimicrobial activities of carbapenems against fresh urinary isolates The minimal inhibition concentrations (MICs) were determined by the two-fold serial agar dilution method as described by NCCLS [6]. Antibiotics tested were IMIP, PANI, MERO, BIAP, piperacillin (PIPC), ampicillin (AMPC) and ceftazidime (CTAZ). 2.1. Gram-negative bacteria All four carbapenems showed higher activities against Enterobacteriacae such as Serratia marcescens, Enterobacter cloacae, Citrobacter freundii and Escherichia coli than PIPC and CTAZ. A low rate of resistant strains of
0924-8579/$ – see front matter © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2004.03.001
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Fig. 1. Antibacterial susceptibility of Ps aeruginosa against carbapenems—UOEH hospital (1998–1999) (䊏) susceptible; ( ) intermediate; ( ) resistant.
Enterobacteriaceae to these carbapenems was observed. Against P. aeruginosa, these carbapenems showed higher antimicrobial activity than PIPC and CTAZ, with the exception of PANI. When the NCCLS breakpoint criteria of susceptible, intermediate, and resistance was used (4, 8 and 16 mg/l for carbapenems; 16, 32–64, and 128 mg/l for PIPC; 8, 16, and 32 mg/l for CTAZ), 70–80% of P. aeruginosa in urinary isolates were covered by IMIP, MERO and BIAP (Fig. 1). Only 22% of strains were susceptible to PANI. The main mechanism of resistance to CTAZ and PIPC may be the hyper-production of chromosomal class C -lactamase. Thirty to forty percent of urinary isolates of E. cloacae and C. freundii are resistant to CTAZ or PIPC in Japan [7]. Carbapenems are known to be stable to this type of -lactamase. On the other hand, extended spectrum -lactamase (ESBL)-producing E. coli have been increasing in our region. The carbapenems tested were the most active parenteral -lactams against these E. coli (Fig. 2). From these results, MERO, BIAP and IMIP are considered suitable antibiotics in the treatment of complicated UTIs caused by Gram-negative bacteria including P. aeruginosa.
Fig. 3. Antibacterial susceptibility of E. faecalis (n=49) to ampicillin and carbapenems—UOEH hospital (1998–1999). (䊏) susceptible; ( ) intermediate; ( ) resistant.
However, PANI is not recommended in the treatment of UTIs caused by P. aeruginosa, because of its poorer activity compared to ceftazidime or piperacillin. 2.2. Gram-positive bacteria Ampicillin is known to be the most active antimicrobial against Enterococcus faecalis. The four carbapenems also showed high activity against E. faecalis similar to that as ampicillin. The susceptibility of these strains to these carbapenems were: MERO—77%, BIAP—75%, IMIP—98% and PANI—92% (Fig. 3). Carbapenems did not show good activity to E. faecium, similar to that as ampicillin. The incidence of resistance of E. faecium to carbapenems range from 65 to 85%. Carbapenems showed good activity against methicillin-sensitive Staphylococcus aureus (MSSA); there were no resistant strains. Carbapenems also have better activity against Staphylococcus epidermidis than ceftazidime. These carbapenems had no antimicrobial activity against methicillin-resistant strains of S. aureus and S. epidermidis. There were 20–30% resistance seen in S. epidermidis strains. From these results, carbapenems are suitable for the treatment of complicated UTIs caused by Gram-positive bacteria such as E. faecalis, S. aureus and S. epidermidis except for methicillin-resistant strains. IMIP and PANI were more active against E. faecalis than MERO and BIAP.
3. Clinical studies of newer carbapenems in Japan
Fig. 2. Antibacterial susceptibility of ESBL- producing E. coli (n = 74) against parenteral -lactams from Kitakyushu area (2000–2001) (䊏) imipenem; (䊐) meropenem; (䊉) ceftazidime; (䊊) piperacillin/tazobactam; (䉬) aztreonam; (䉫) cefpirome; (䉱) ampicillin/sulbactam; () cefoperazone/sulbactam; ( ) cefotaxime.
Three studies of randomised, double-blind equivalence trial for complicated UTIs were performed with newer carbapenems in Japan. Randomised, double-blind trial of PANI/BP compared to IMIP/CS was performed in 1992. The dose of carbapenems used was 500 mg twice daily and the treatment duration was for 5 days. Evaluation of clinical effectiveness was examined 1 day after completion of treatment. Overall clinical effectiveness rate and the microbiological effect of PANI/BP and IMIP/CS groups were almost equal (79.1 and 77.3%; 91.1 and 93.3% respectively). However, the eradication rate
T. Matsumoto, T. Muratani / International Journal of Antimicrobial Agents 24S (2004) S35–S38
of P. aeruginosa was less in the PANI/BP group than in the IMIP/CS group (66.7 and 85.2%), but the difference was not statistically significant [8]. Randomised, double-blind study of MERO compared to IMIP/CS was also performed in 1992. The treatment dose was 500 mg twice daily and the duration of administration was also 5 days. Clinical effectiveness rate was equivalent in the two groups (87.2 and 81.1%). The microbiological effect was almost similar in the MERO group (87.4%) and the IMIP/CS group (87.7%). Eradication rate of P. aeruginosa was however better in the MERO group (73.7%) than in the IMIP/CS group (66.7%), but was not statistically significant [9]. Randomised, double-blind study was also performed using 300 mg twice daily of BIAP and 500 mg twice daily of IMIP/CS in year 2000. The overall effectiveness rates of BIAP and IMIP/CS were 94.7 and 93.4%, respectively. The microbiological effect was also equivalent in both groups (95.0 and 94.4%) [10]. The clinical effectiveness rate and the microbiological effect of carbapenems such as PANI/BP, BIAP and MERO were equivalent to that of IMIP/CS. The microbiological effect against P. aeruginosa of PANI/BP was less than IMIP/CS group. On the contrary, eradication rate of P. aeruginosa was better in MERO group than that of IMIP/CS group. Thus, MERO is the most active antibiotic against P. aeruginosa.
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Fig. 4. The clinical course (shown by body temperature) of eight patients with complicated pyelonephritis or urosepsis treated by carbapenems. All patients were treated with meropenem except Pt 7 by PANI/BP and Pt 8 by IMIP/CS. (䊏) Patient 1: complicated pyelonephritis, P. aeruginosa and E. faecalis, 8 days treatment; (䊐) patient 2: complicated pyelonephritis, E. faecalis, 3 days treatment; (䊉) patient 3: complicated pyelonephritis, E. coli and E. faecalis, 8 days treatment; (䊊) patient 4: Urosepsis, E. intermedius, 5 days treatment; (䉬) patient 5: complicated pyelonephritis, P. aeruginosa, 5 days treatment; (䉫) patient 6: complicated pyelonephritis, E. coli, P. stuartii and E. faecalis, 8 days treatment; (䉱) patient 7: complicated pyelonephritis, C. koseri, P. aeruginosa and E. faecium, 9 days treatment (PANI/BP); () patient 8: complicated pyelonephritis, P. aeruginosa and E. faecalis, 5 days treatment (IMIP/CS).
febrile complicated UTIs, even if there is polymicrobial infection caused by P. aeruginosa and E. faecalis.
4. Clinical summary of the cases of complicated UTIs 5. Discussion In the clinic, complicated UTIs are caused by various species of bacteria. Three main species of bacteria isolated from complicated UTIs in our hospital were E. coli, P. aeruginosa and E. faecalis. The incidence of antibiotic resistance in P. aeruginosa was 20 to 35% to third generation cephalosporins, 35% to piperacillin, 40 to 50% to fluoroquinolones and 8 to 10% to aminoglycosides. About 15% were resistant to carbapenems such as IMIP and MERO in our hospital. Mixed or polymicrobial infection by Gram-negative and Gram-positive bacteria is a serious concern in the treatment of complicated UTIs. Mixed infections that include P. aeruginosa was observed in 25% of complicated UTIs. Carbapenem antibiotics is believed to be a good candidate for the treatment of UTIs caused by mixed infections that include P. aeruginosa. The clinical summary of febrile UTIs cases with or without septic state, which were treated by carbapenems in our hospital is presented in Fig. 4. Almost all cases were caused by monomicrobial or polymicrobial infection containing P. aeruginosa and enterococci. Defervescence was rapid when carbapenems were used initially in the treatment of febrile complicated UTIs. All patients were cured after the treatment with carbapenems. Carbapenems may therefore be used as the first choice of antibiotics in the treatment of
The first generation carbapenems, IMP/CS and PANI/BP, and newer carbapenems, MERO and BIAP are clinically available in Japan. Carbapenems have a broad and a very high antimicrobial activity. The broad antimicrobial spectrum and the pharmacological profiles of the carbapenems are useful in the treatment of complicated UTIs, especially of febrile complicated UTIs. Carbapenems are superior to cephalosporins or penicillins in Gram-negative bacteria including class C -lactamase and ESBL producers. In Japan, Class C -lactamase- and ESBL-producing Gram-negative bacteria have been increasingly found in isolates from complicated UTIs. Stability to these -lactamases is one reason why carbapenems are useful in the treatment of complicated UTIs. In addition, carbapenems also have good antimicrobial activity against E. faecalis. As E. faecalis have been increasing in causing complicated UTIs, carbapenems could be one of the best antibiotics in the treatment of polymicrobial infection caused by Gram-positive and Gram-negative bacteria. In our clinical studies, IMIP/CS, PANI/BP, MERO and BIAP are equally good in the treatment of complicated UTIs. Newer carbapenems are superior against Gram-negative bacteria including P. aeruginosa than first generation carbapenems. However, PANI/BP is not suitable in the treatment of
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UTIs caused by P. aeruginosa because of the poor antimicrobial activity. The antimicrobial effect of newer carbapenems such as MERO and BIAP against E. faecalis is not greater than the first generation carbapenems. Newer carbapenems are therefore recommended in the treatment of febrile complicated UTIs caused by Gram-negative bacteria or polymicrobial infection by P. aeruginosa and other bacteria except for E. faecalis. In Japan, the incidence of carbapenem-resistant bacteria are low but gradually increasing. A metallo--lactamase, which is able to hydrolyse carbapenems and causing carbapenem resistance has been observed in isolates from complicated UTIs [11]. Other causes of carbapenem resistance relate to permeation of the compound into the bacterial cell, involving a loss of the outer membrane protein, and efflux mechanisms of drugs [12]. Five to eight percent of P. aeruginosa isolated from complicated UTIs are resistant to IMIP, MERO and BIAP. Surveillance of carbapenem resistance in clinical isolates should therefore be continued. Many carbapenems currently being development are mostly parenteral compounds. The superior features of these carbapenems are having anti-MRSA activity, having potent activity to P. aeruginosa, and being a longer active compound. In addition, two oral carbapenems have been tried in clinical study. These have potent antibacterial activity and broad antimicrobial spectrum except against P. aeruginosa. Oral carbapenems however, may not achieve high concentrations in blood [13,14]. We hope to have more potent and safe carbapenems in the future. References [1] Kahan FM, Kropp H, Sundelof JG, et al. Thienamycin: development of imipenem-cilastatin. J Antimicrob Chemother 1983;12(Suppl D):1–25.
[2] Shimada J, Kawahara Y. Overview of a new carbapenem, panipenem/betamipron. Drugs Exp Clin Res 1994;20:241–5. [3] Ubukata K, Hikida M, Yoshida M, et al. In vitro activity of LJC10627, a new carbapenem antibiotic with high stability to dehydropeptidase I. Antimicrob Agents Chemother 1990;34:994–1000. [4] Perry CM, Ibbotson T. Biapenem. Drugs 2002;62:2221–34. [5] Sunagawa M, Matsumura H, Inoue T, et al. A novel carbapenem antibiotic, SM-7338 structure-activity relationships. J Antibiot 1990;43:519–32. [6] National Committee for Clinical Laboratory Standards: M7-A5. Methods for dilution: antimicrobial susceptibility tests for bacteria that grow aerobically approved standard. 5th ed., M-100-S11. Wayne, PA: National Committee for Clinical Laboratory Standards; 2000. [7] Kumazawa J, Matsumoto T. Epidemiology of microbial resistance today. In: Naber KG, Pechere JC, Kumazawa J, Khoury S, Gerberding JL, Schaffer AJ, editors. Nosocomial and Health Care Associated Infections in Urology. 1st ed. UK: Plymbridge Distributors Ltd.; 2001. p. 61–6. [8] Kumazawa J, Matsumoto T, Kumamoto E, et al. Phase III comparative clinical trial of panipenem/betamipron (PAPM/BP) with imipenem/cilastatin sodium (IPM/CS) for the treatment of complicated urinary tract infections. Nishinihon J Urol 1992;54:254–71. [9] Kumazawa J, Matsumoto T, Tanaka M, et al. Clinical study of meropenem for complicated urinary tract infection—double blind comparative study comparing to imipenem/cilastatin. Nishinihon J Urol 1992;54:954–69. [10] Kawada Y, Deguchi T, Tsukamoto T, et al. Comparative study of biapenem and imipenem/cilastatin for complicated urinary tract infection. Chemotherapy 2000;48:218–32. [11] Hirakata Y, Yamaguchi T, Nakano M, et al. Clinical and bacteriological characteristics of IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa. Clin Infect Dis 2003;37:26–32. [12] Pai H, Kim J, Kim J, et al. Carbapenem resistance mechanisms in Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 2001;45:480–4. [13] Sakagawa E, Otsuki M, Oh T, et al. In-vitro and in-vivo antibacterial ˆ activities of CS834, a new oral carbapenem. J Antimicrob Chemother 1998;42:427–37. [14] Miyazaki S, Hosoyama T, Furuya N, et al. In vitro and in vivo antibacterial activities of L-084, a novel oral carbapenem, against causative organisms of respiratory tract infections. Antimicrob Agents Chemother 2001;45:203–7.
Newer carbapenems for urinary tract infections Tetsuro Matsumoto∗ , Tetsuro Muratani Department of Urology, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
Abstract Four carbapenems have been available clinically in Japan. These are imipenem/cilastatin (IMIP/CS) and panipenem/ betamipron (PANI/BP) of the older compounds and newer carbapenems such as biapem (BIAP) and meropenem (MERO). The latter compounds are relatively stable to dehydropeptidase-1 (DHP-1) and have been reported to have higher antimicrobial activities compared to the earlier carbapenems. The antimicrobial activity of these four carbapenems against fresh urinary isolates showed high activities against Enterobacteriacae such as Serratia marcescens, Enterobacter cloacae, Citrobacter freundii and Escherichia coli containing the class C--lactamase- and extended spectrum -lactamase (ESBL)-producing strains compared to piperacillin (PIPC) and ceftazidime (CTAZ). Against Pseudomonas aeruginosa, the carbapenems, with the exception of panipenem showed strong antimicrobial activities compared to PIPC and CTAZ. High activities were also seen against Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis, but methicillin-resistant strains were not affected. The first generation carbapenems showed better activity against E. faecalis than newer carbapenems. All four carbapenems were similar in clinical effectiveness in double blind trials for complicated urinary tract infections (UTIs). However, PANI/BP is less effective in UTIs caused by P. aeruginosa than IMIP/CS. MERO showed better eradication rate of P. aeruginosa than IMIP/CS. Retrospective analysis of treated cases using carbapenems showed a rapid defervescence in the treatment of febrile complicated UTIs, which were mainly caused by mixed infection of Gram-negative and Gram-positive bacteria, especially those involving P. aeruginosa and E. faecalis. © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Carbapenems; Urinary tract infection; Imipenem/cilastatin; Panipenem/betamipron; Meropenem; Biapenem
1. Introduction Carbapenems have a broad spectrum, strong antimicrobial activity and less affinity to -lactamases than other -lactam antibiotics. Carbapenem antibiotics have been developed during the last three decades. Thienamycin was first discovered in 1976. It had a wide antibiotic-spectrum and also highly active against bacteria. It was however poorly stable in vitro and in vivo, and showed toxicity to the kidneys and central nervous system [1]. The first generation carbapenem includes imipenem/cilastatin (IMIP/CS) and panipenem/betamipron (PANI/BP), which are used in the combined form with inhibitors, because they are unstable to dehydropeptidase-1 (DHP-1) and exhibit nephrotoxicity [2]. Newer carbapenems such as meropenem (MERO) and biapenem (BIAP) have been developed recently. They are relatively stable to DHP-1 and reported to have higher
∗
Corresponding author. Tel.: +81-93-691-7446; fax: +81-93-603-8724. E-mail address: [email protected] (T. Matsumoto).
antimicrobial activities against bacteria including Pseudomonas aeruginosa than the first generation carbapenems [3–5]. We describe the characteristics of newer carbapenems against urinary tract infections (UTIs) compared to the first generation carbapenems and other antibiotics.
2. Antimicrobial activities of carbapenems against fresh urinary isolates The minimal inhibition concentrations (MICs) were determined by the two-fold serial agar dilution method as described by NCCLS [6]. Antibiotics tested were IMIP, PANI, MERO, BIAP, piperacillin (PIPC), ampicillin (AMPC) and ceftazidime (CTAZ). 2.1. Gram-negative bacteria All four carbapenems showed higher activities against Enterobacteriacae such as Serratia marcescens, Enterobacter cloacae, Citrobacter freundii and Escherichia coli than PIPC and CTAZ. A low rate of resistant strains of
0924-8579/$ – see front matter © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2004.03.001
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T. Matsumoto, T. Muratani / International Journal of Antimicrobial Agents 24S (2004) S35–S38
Fig. 1. Antibacterial susceptibility of Ps aeruginosa against carbapenems—UOEH hospital (1998–1999) (䊏) susceptible; ( ) intermediate; ( ) resistant.
Enterobacteriaceae to these carbapenems was observed. Against P. aeruginosa, these carbapenems showed higher antimicrobial activity than PIPC and CTAZ, with the exception of PANI. When the NCCLS breakpoint criteria of susceptible, intermediate, and resistance was used (4, 8 and 16 mg/l for carbapenems; 16, 32–64, and 128 mg/l for PIPC; 8, 16, and 32 mg/l for CTAZ), 70–80% of P. aeruginosa in urinary isolates were covered by IMIP, MERO and BIAP (Fig. 1). Only 22% of strains were susceptible to PANI. The main mechanism of resistance to CTAZ and PIPC may be the hyper-production of chromosomal class C -lactamase. Thirty to forty percent of urinary isolates of E. cloacae and C. freundii are resistant to CTAZ or PIPC in Japan [7]. Carbapenems are known to be stable to this type of -lactamase. On the other hand, extended spectrum -lactamase (ESBL)-producing E. coli have been increasing in our region. The carbapenems tested were the most active parenteral -lactams against these E. coli (Fig. 2). From these results, MERO, BIAP and IMIP are considered suitable antibiotics in the treatment of complicated UTIs caused by Gram-negative bacteria including P. aeruginosa.
Fig. 3. Antibacterial susceptibility of E. faecalis (n=49) to ampicillin and carbapenems—UOEH hospital (1998–1999). (䊏) susceptible; ( ) intermediate; ( ) resistant.
However, PANI is not recommended in the treatment of UTIs caused by P. aeruginosa, because of its poorer activity compared to ceftazidime or piperacillin. 2.2. Gram-positive bacteria Ampicillin is known to be the most active antimicrobial against Enterococcus faecalis. The four carbapenems also showed high activity against E. faecalis similar to that as ampicillin. The susceptibility of these strains to these carbapenems were: MERO—77%, BIAP—75%, IMIP—98% and PANI—92% (Fig. 3). Carbapenems did not show good activity to E. faecium, similar to that as ampicillin. The incidence of resistance of E. faecium to carbapenems range from 65 to 85%. Carbapenems showed good activity against methicillin-sensitive Staphylococcus aureus (MSSA); there were no resistant strains. Carbapenems also have better activity against Staphylococcus epidermidis than ceftazidime. These carbapenems had no antimicrobial activity against methicillin-resistant strains of S. aureus and S. epidermidis. There were 20–30% resistance seen in S. epidermidis strains. From these results, carbapenems are suitable for the treatment of complicated UTIs caused by Gram-positive bacteria such as E. faecalis, S. aureus and S. epidermidis except for methicillin-resistant strains. IMIP and PANI were more active against E. faecalis than MERO and BIAP.
3. Clinical studies of newer carbapenems in Japan
Fig. 2. Antibacterial susceptibility of ESBL- producing E. coli (n = 74) against parenteral -lactams from Kitakyushu area (2000–2001) (䊏) imipenem; (䊐) meropenem; (䊉) ceftazidime; (䊊) piperacillin/tazobactam; (䉬) aztreonam; (䉫) cefpirome; (䉱) ampicillin/sulbactam; () cefoperazone/sulbactam; ( ) cefotaxime.
Three studies of randomised, double-blind equivalence trial for complicated UTIs were performed with newer carbapenems in Japan. Randomised, double-blind trial of PANI/BP compared to IMIP/CS was performed in 1992. The dose of carbapenems used was 500 mg twice daily and the treatment duration was for 5 days. Evaluation of clinical effectiveness was examined 1 day after completion of treatment. Overall clinical effectiveness rate and the microbiological effect of PANI/BP and IMIP/CS groups were almost equal (79.1 and 77.3%; 91.1 and 93.3% respectively). However, the eradication rate
T. Matsumoto, T. Muratani / International Journal of Antimicrobial Agents 24S (2004) S35–S38
of P. aeruginosa was less in the PANI/BP group than in the IMIP/CS group (66.7 and 85.2%), but the difference was not statistically significant [8]. Randomised, double-blind study of MERO compared to IMIP/CS was also performed in 1992. The treatment dose was 500 mg twice daily and the duration of administration was also 5 days. Clinical effectiveness rate was equivalent in the two groups (87.2 and 81.1%). The microbiological effect was almost similar in the MERO group (87.4%) and the IMIP/CS group (87.7%). Eradication rate of P. aeruginosa was however better in the MERO group (73.7%) than in the IMIP/CS group (66.7%), but was not statistically significant [9]. Randomised, double-blind study was also performed using 300 mg twice daily of BIAP and 500 mg twice daily of IMIP/CS in year 2000. The overall effectiveness rates of BIAP and IMIP/CS were 94.7 and 93.4%, respectively. The microbiological effect was also equivalent in both groups (95.0 and 94.4%) [10]. The clinical effectiveness rate and the microbiological effect of carbapenems such as PANI/BP, BIAP and MERO were equivalent to that of IMIP/CS. The microbiological effect against P. aeruginosa of PANI/BP was less than IMIP/CS group. On the contrary, eradication rate of P. aeruginosa was better in MERO group than that of IMIP/CS group. Thus, MERO is the most active antibiotic against P. aeruginosa.
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Fig. 4. The clinical course (shown by body temperature) of eight patients with complicated pyelonephritis or urosepsis treated by carbapenems. All patients were treated with meropenem except Pt 7 by PANI/BP and Pt 8 by IMIP/CS. (䊏) Patient 1: complicated pyelonephritis, P. aeruginosa and E. faecalis, 8 days treatment; (䊐) patient 2: complicated pyelonephritis, E. faecalis, 3 days treatment; (䊉) patient 3: complicated pyelonephritis, E. coli and E. faecalis, 8 days treatment; (䊊) patient 4: Urosepsis, E. intermedius, 5 days treatment; (䉬) patient 5: complicated pyelonephritis, P. aeruginosa, 5 days treatment; (䉫) patient 6: complicated pyelonephritis, E. coli, P. stuartii and E. faecalis, 8 days treatment; (䉱) patient 7: complicated pyelonephritis, C. koseri, P. aeruginosa and E. faecium, 9 days treatment (PANI/BP); () patient 8: complicated pyelonephritis, P. aeruginosa and E. faecalis, 5 days treatment (IMIP/CS).
febrile complicated UTIs, even if there is polymicrobial infection caused by P. aeruginosa and E. faecalis.
4. Clinical summary of the cases of complicated UTIs 5. Discussion In the clinic, complicated UTIs are caused by various species of bacteria. Three main species of bacteria isolated from complicated UTIs in our hospital were E. coli, P. aeruginosa and E. faecalis. The incidence of antibiotic resistance in P. aeruginosa was 20 to 35% to third generation cephalosporins, 35% to piperacillin, 40 to 50% to fluoroquinolones and 8 to 10% to aminoglycosides. About 15% were resistant to carbapenems such as IMIP and MERO in our hospital. Mixed or polymicrobial infection by Gram-negative and Gram-positive bacteria is a serious concern in the treatment of complicated UTIs. Mixed infections that include P. aeruginosa was observed in 25% of complicated UTIs. Carbapenem antibiotics is believed to be a good candidate for the treatment of UTIs caused by mixed infections that include P. aeruginosa. The clinical summary of febrile UTIs cases with or without septic state, which were treated by carbapenems in our hospital is presented in Fig. 4. Almost all cases were caused by monomicrobial or polymicrobial infection containing P. aeruginosa and enterococci. Defervescence was rapid when carbapenems were used initially in the treatment of febrile complicated UTIs. All patients were cured after the treatment with carbapenems. Carbapenems may therefore be used as the first choice of antibiotics in the treatment of
The first generation carbapenems, IMP/CS and PANI/BP, and newer carbapenems, MERO and BIAP are clinically available in Japan. Carbapenems have a broad and a very high antimicrobial activity. The broad antimicrobial spectrum and the pharmacological profiles of the carbapenems are useful in the treatment of complicated UTIs, especially of febrile complicated UTIs. Carbapenems are superior to cephalosporins or penicillins in Gram-negative bacteria including class C -lactamase and ESBL producers. In Japan, Class C -lactamase- and ESBL-producing Gram-negative bacteria have been increasingly found in isolates from complicated UTIs. Stability to these -lactamases is one reason why carbapenems are useful in the treatment of complicated UTIs. In addition, carbapenems also have good antimicrobial activity against E. faecalis. As E. faecalis have been increasing in causing complicated UTIs, carbapenems could be one of the best antibiotics in the treatment of polymicrobial infection caused by Gram-positive and Gram-negative bacteria. In our clinical studies, IMIP/CS, PANI/BP, MERO and BIAP are equally good in the treatment of complicated UTIs. Newer carbapenems are superior against Gram-negative bacteria including P. aeruginosa than first generation carbapenems. However, PANI/BP is not suitable in the treatment of
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UTIs caused by P. aeruginosa because of the poor antimicrobial activity. The antimicrobial effect of newer carbapenems such as MERO and BIAP against E. faecalis is not greater than the first generation carbapenems. Newer carbapenems are therefore recommended in the treatment of febrile complicated UTIs caused by Gram-negative bacteria or polymicrobial infection by P. aeruginosa and other bacteria except for E. faecalis. In Japan, the incidence of carbapenem-resistant bacteria are low but gradually increasing. A metallo--lactamase, which is able to hydrolyse carbapenems and causing carbapenem resistance has been observed in isolates from complicated UTIs [11]. Other causes of carbapenem resistance relate to permeation of the compound into the bacterial cell, involving a loss of the outer membrane protein, and efflux mechanisms of drugs [12]. Five to eight percent of P. aeruginosa isolated from complicated UTIs are resistant to IMIP, MERO and BIAP. Surveillance of carbapenem resistance in clinical isolates should therefore be continued. Many carbapenems currently being development are mostly parenteral compounds. The superior features of these carbapenems are having anti-MRSA activity, having potent activity to P. aeruginosa, and being a longer active compound. In addition, two oral carbapenems have been tried in clinical study. These have potent antibacterial activity and broad antimicrobial spectrum except against P. aeruginosa. Oral carbapenems however, may not achieve high concentrations in blood [13,14]. We hope to have more potent and safe carbapenems in the future. References [1] Kahan FM, Kropp H, Sundelof JG, et al. Thienamycin: development of imipenem-cilastatin. J Antimicrob Chemother 1983;12(Suppl D):1–25.
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