UPDATE Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum b-lactamases (ESBLs) D. L. Paterson Infectious Disease Section, Instituto per I Trapianti Terapie as Alta Specializzazione, Palermo, Italy and Infectious Disease Division, University of Pittsburgh Medical Center, Pittsburgh, USA Extended-spectrum b-lactamase (ESBL)-producing organisms are a global problem. No randomized controlled trials have ever been performed to guide optimal treatment. However, in vitro studies and observational studies strongly suggest that carbapenems (imipenem or meropenem) should be regarded as drugs of choice for serious infections due to ESBL-producing organisms. Other b-lactam antibiotics (cefepime, b-lactam/b-lactamase inhibitor combinations) are not suitable as ¢rst-line therapy.The increasing frequency of the association between quinolone resistance and ESBL production have greatly limited the role of this class of antibiotic against ESBL producers. Keywords ESBL, extended-spectrum beta-lactamase, beta-lactamase, carbapenems, cephadosporins,
Klebsiella Accepted 17 May 2000
Clin Microbiol Infect 2000: 6: 460^463
INTRODUCTION Extended-spectrum b-lactamases (ESBLs) are plasmidmediated b-lactamases which have the ability to hydrolyze blactam antibiotics containing an oxyimino group (e.g. ceftazidime, ceftriaxone, cefotaxime or aztreonam). They have been most commonly found in Klebsiella pneumoniae, but are being increasingly found also in Escherichia coli, Proteus mirabilis and other members of the Enterobacteriaceae. In contrast to the inducible, chromosomally encoded b-lactamases produced by organisms such as Enterobacter cloacae, the ESBLs are usually susceptible to inactivation by compounds such as clavulanic acid. In addition, the cephamycins (e.g. cefoxitin and cefotetan) are stable to hydrolysis by the ESBLs. The vast majority of ESBLs are derivatives of TEM-1 (the common plasmid-mediated b-lactamase of organisms such as Escherichia coli) or SHV-1 (the common chromosomally mediated b-lactamase of K. pneumoniae). TEM-1 and SHV-1 can inactivate ampicillin but not the third-generation cephalosporins; mutations in the genes encoding TEM-1 or SHV-1 extend the spectrum of activity of the b-lactamase so that inactivation of third-generation cephalosporins and aztreonam occurs. In many South American countries and in eastern Corresponding author and reprint requests: D. L. Paterson, Infectious Disease Section, Istituto per I Trapianti e Terapie ad Alta Specializzazione, Piazza Sett'Angeli, 10, 90134 Palermo, Italy Tel: +39 335 564 1485 Fax: +39 091 666 8148 E-mail:
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Europe, ESBLs of non-TEM and non-SHV lineage (e.g. CTX-M-1 to CTX-M- 6) are also prominent. TEM and SHV derivatives are found in every inhabited continent, but nonTEM, non-SHV ESBLs (e.g. the newly described VEB-1 and GES-1 ESBLs) are notable at the present time for the limited geographic locations in which they have been isolated [1, 2]. Infections with ESBL-producing organisms are usually hospital-acquired, especially in intensive care units. Nursing homes may also be a reservoir [3]. Given the ecologic niche of K. pneumoniae and other Enterobacteriaceae in the gastrointestinal tract, it is not surprising that common infections with ESBL-producing organisms include urinary tract infections, peritonitis, cholangitis and intra-abdominal abscesses. However, given the propensity for Gram-negative bacilli to colonize the upper respiratory tract and skin of seriously ill hospitalized patients, ESBL-producing organisms are also a common cause of nosocomial pneumonia and central venous line-related bacteremia. In hospitalized patients who have had neurosurgical procedures, ESBL producers may also cause meningitis. On the other hand, it must be noted that for every patient with a signi¢cant infection with an ESBL-producing organism, there are at least two patients with skin, urinary tract or respiratory tract colonization, which does not require speci¢c antimicrobial therapy. Identi¢cation of the colonized patient is important, however, since these patients serve as a source of infection for other patients in conditions where handwashing and other basic infection control precautions are suboptimal [4, 5].
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Paterson Treatment of severe infections caused by Enterobacteriaceae producing ESBLs
THERAPY OF BACTEREMIA AND OTHER SERIOUS INFECTIONS WITH ESBL-PRODUCING ORGANISMS No randomized controlled trials on therapy of infections with ESBL-producing organisms have ever been performed, and nor does it seem likely that such studies will be performed in the near future. Therefore, recommendations for optimal therapy of infections with ESBL-producing organisms are based on studies of in vitro e¡ectiveness of antimicrobial agents, small case series and large prospective observational studies (Table 1).
In vitro studies In vitro, the carbapenems (imipenem and meropenem) and the cephamycins have the most consistent activity against ESBL-producing organisms, given their stability to hydrolysis by ESBLs. Indeed, published reports of carbapenem resistance in organisms such as K. pneumoniae are exceedingly rare [6, 7]. The plasmids harboring genes encoding ESBLs frequently also contain genes encoding mechanisms of resistance to aminoglycosides and trimethoprim ^ sulfamethoxazole. Although there has been only one report of plasmid-mediated quinolone resistance in K. pneumoniae [8], there is a strong association between quinolone resistance and ESBL production [9, 10]. The reason for this association is not well understood, although it must be noted that patients with infections with ESBL producers and patients with quinolone-resistant isolates frequently share heavy prior antibiotic use (of both third-generation cephalosporins and quinolones) [9]. Combinations of b-lactam antibiotics with b-lactamase inhibitors are usually active in vitro against organisms possessing a single ESBL. However, in vitro resistance of ESBL-producing isolates to such combinations is increasing alarmingly; in a study of isolates from 35 intensive care units in western and southern Europe, the percentage of ESBL-producing isolates resistant
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to piperacillin ^ tazobactam rose from 31% in 1994 to 63% in 1997/1998 [10, 11]. Cephalosporins Di¡erent ESBLs vary in their ability to hydrolyze di¡erent third-generation cephalosporins. Therefore, although an ESBL-producing organism may have a ceftazidime MIC of >256 mg/L, the MIC for ceftriaxone or cefotaxime may be less than 16 mg/L (i.e. within the susceptible range, using current NCCLS criteria) [12]. However, clinical outcome is poor when third-generation cephalosporins are used to treat infections with ESBL-producing organisms, even in the presence of apparent `susceptibility' [13^16]. Third-generation cephalosporins should not be used to treat serious infections with ESBL-producing organisms. Even though cefepime exhibits more stability to hydrolysis by ESBLs than the third-generation cephalosporins, positive clinical results with the use of cefepime have not been forthcoming [1, 17]. In common with third-generation cephalosporins, MICs for cefepime rise substantially when the inoculum of infecting organisms rises. In vitro synergy may be achievable between cefepime and amikacin against ESBLproducing organisms [17]. Cefepime should not be used as ¢rst-line therapy against ESBL-producing organisms; when it is used, it should be used in high dosage, preferably in combination with an aminoglycoside. Based on in vitro studies, the cephamycins appear an attractive option for use against ESBL-producing organisms. However, published clinical experience with these drugs is almost completely lacking.The only reports describe in vivo selection of porin-de¢cient mutants during therapy [18^20]. In addition, combined cephamycin and carbapenem resistance in K. pneumoniae has been observed in the setting of widespread cephamycin use in response to an outbreak of infection with ESBL-producing organisms [6]. Until positive published clinical experience with cephamycins appears, these drugs must be regarded as second-line therapy for infections with
Table 1 Treatment recommendations for infections caused by organisms producing extended-spectrum b-lactamases (ESBLs) Type of infection
First-line therapy
Second-line therapy
Bacteremia Nosocomial pneumonia Intra-abdominal infection Urinary tract infection Meningitis
Carbapenema (imipenem or meropenem) Carbapenem (imipenem or meropenem) Carbapenema (imipenem or meropenem) Cipro¯oxacin Meropenema
Cipro¯oxacin Cipro¯oxacin Cipro¯oxacin Amoxycillin±clavulanate Addition of polymyxin B
a
Removal of central venous lines, drainage of collections and removal of neurosurgical hardware is important for optimal outcome of these infections.
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Clinical Microbiology and Infection, Volume 6 Number 9, September 2000
ESBL-producing organisms. In general, cefotetan has lower MICs than cefoxitin, and should be used preferentially. b-Lactam/b b-lactamase inhibitor combinations As with the cephalosporins, combinations of b-lactam with b-lactamase inhibitor (e.g. ticarcillin ^ clavulanate or piperacillin ^ tazobactam) are also subject to rising MICs as inoculum rises. In addition, hyperproduction of b-lactamases or the combination of b-lactamase production and porin loss can also lead to reduction in activity of b-lactam/b-lactamase inhibitor combinations. Published clinical experience with use of these antibiotics for serious infections due to ESBLproducing organisms has been limited, but observed mortality rates have been > 50% [13, 21, 22]. Although the combination of cephalosporins and b-lactamase inhibitors is a theoretically attractive option, there is no published experience with this therapy, and it is possible that the same limitations will apply as seen with penicillins and b-lactamase inhibitors. Carbapenems Carbapenems should be regarded as the drugs of choice for serious infections with ESBL-producing organisms (Table 1). The basis for this statement is not just the almost uniform in vitro susceptibility but also increasingly extensive clinical experience. Published experience now amounts to more than 100 patients. Meyer [23], in his account of a prolonged outbreak of infections due to ESBL-producing organisms, was among the ¢rst to suggest that outcome was superior with imipenem. More recently, a large prospective, multicountry study of K. pneumoniae bacteremia has shown that mortality in patients with blood culture-positive, ESBL-producing organisms was less than 10% when patients received either imipenem or meropenem [13]. The choice between imipenem and meropenem is di¤cult. Published experience is greatest with imipenem, but MICs for meropenem are slightly lower than for imipenem. In vitro studies with a new carbapenem capable of once-daily administration show that it shares the excellent activity against ESBLproducing organisms of imipenem and meropenem [24]. Meropenem is the drug of choice in treatment of nosocomial meningitis due to ESBL-producing organisms, since it is likely to be less prone to neurologic side-e¡ects than imipenem in patients with underlying central nervous system (CNS) disease. Removal of neurosurgical hardware is mandatory in treatment of CNS shunt infections, and intrathecal polymyxin B should also be considered [25]. There is no evidence that combination therapy with a carbapenem and antibiotics of other classes is superior to use of a carbapenem alone. Synergy has been exhibited in some but
not all studies [17, 26]. However, anecdotal experience is that many clinicians use a combination of a carbapenem and an aminoglycoside such as amikacin in severely ill patients with documented infections due to ESBL-producing organisms.
Other drug classes The use of aminoglycosides for serious infections due to ESBL-producing organisms should probably be limited to combination therapy with b-lactam antibiotics. Quinolones may be regarded as the treatment of choice for less severe infections with ESBL-producing organisms, such as urinary tract infection. Unfortunately, increasing in vitro resistance to quinolones in isolates which are also ESBL producers [9, 10] will limit the role of these antibiotics in the treatment of infections due to ESBL-producing organisms in the future. In general, newer quinolones are unlikely to provide additional bene¢ts over cipro£oxacin. SUMMARY The detection in the clinical microbiology laboratory of ESBL production by Enterobacteriaceae is of great importance for at least three reasons. First, horizontal transfer of ESBL-producing organisms (often by the hands of medical and nursing sta¡) is a frequent occurrence but can be limited by use of contact isolation. Such isolation can be triggered by the designation of the organism as an ESBL producer. Second, serious infections with ESBL-producing organisms should not be treated with cephalosporins.Treatment failure has often been observed. Finally, a treatment of choice is emerging for such serious infections. Carbapenems (e.g. imipenem or meropenem) have been shown to be associated with the lowest mortality of any drug class when used against infections with ESBL-producing organisms. REFERENCES 1. Casellas JM. South America: a di¡erent continent, di¡erent ESBLs. JAntimicrob Chemother 1999; 44(suppl A): 16. 2. Poirel L, Le Thomas I, Naas Tet al. Biochemical sequence analyses of GES-1, a novel class A extended-spectrum beta-lactamase, and the Class 1 integron In52 from Klebsiella pneumoniae. Antimicrob Agents Chemother 2000; 44: 622^32. 3. Wiener J, Quinn JP, Bradford PA et al. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA 1999; 281: 517^23. 4. Pena C, Pujol M, Ardanuy C et al. Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended-spectrum beta-lactamases. Antimicrob Agents Chemother 1998; 42: 53^8. 5. Paterson DL, Yu VL. Extended-spectrum beta-lactamases: a call for improved detection and control. Clin Infect Dis 1999; 29: 1419^ 22.
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Paterson Treatment of severe infections caused by Enterobacteriaceae producing ESBLs
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