ReviewDual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?
Introduction
Despite our best efforts, antibiotic resistance continues to be a pressing public health concern. Evidence shows that the only way to stay ahead of the resistance curve is to follow the best infection control practices, use antibiotics prudently, and bring new agents to market (World Health Organization (WHO), 2001, World Health Organization (WHO), 2012). From a drug development perspective, there has been an impressive response to combat infections due to resistant Gram-positive pathogens. Since 2000, 7 antibiotics were approved with activity against infections due to methicillin-resistant Staphylococcus aureus (Boucher et al., 2009, Liu et al., 2011). This is in stark contrast to the Gram-negative antibiotic landscape. Over the past 15 years, only 3 antibiotics (doripenem, ertapenem, and tigecycline) with expanded Gram-negative activity have been approved by the US Food and Drug Administration, and none are considered chemically novel compounds (Boucher et al., 2009). The dismal progress in expanding our antibiotic armamentarium is further exacerbated by the rising rate of resistance among key Gram-negative pathogens (Anonymous, 2004, Master et al., 2011, Nordmann et al., 2011, Spellberg et al., 2011). Not only are we observing increases in resistance to frequently encountered Gram-negative pathogens like Pseudomonas aeruginosa and Klebsiella pneumoniae, but we are also witnessing a rise in the number of multidrug-resistant (MDR) strains. In certain areas of the world, pan-drug–resistant Gram-negative infections are becoming commonplace and forcing healthcare providers to use older, previously used antibiotics such as colistin (Bradford et al., 2004, Falagas and Bliziotis, 2007, Falagas and Kasiakou, 2005, Nicasio et al., 2008, Nordmann et al., 2011, Urban et al., 2008).
Growing resistance rates, combined with a diminishing arsenal of safe and effective antimicrobial agents, have created an impetus to utilize existing antimicrobial agents in innovative ways for invasive Gram-negative infections. One therapeutic approach that is often employed in practice is combination therapy involving the use of agents from different antibiotic classes. Such therapy is advocated by the Infectious Diseases Society of America guidelines for treatment of many serious Gram-negative infections (Baddour et al., 2005, Freifeld et al., 2011, Mandell et al., 2007, Mermel et al., 2009, Osmon et al., 2013, Tunkel et al., 2004). The 2 most frequently recommended combinations are a beta-lactam with an aminoglycoside or a fluoroquinolone. While often employed in clinical practice, evidence supporting the enhanced efficacy of dual-agent therapy is limited, and there are concerns due to the potential risk for toxicity and unintended ecologic sequelae (Paul et al., 2003, Paul et al., 2004, Safdar et al., 2004, Tamma et al., 2012, Traugott et al., 2011).
The discouraging outcomes with these aforementioned combinations have served as a catalyst for investigations into alternative combination therapies for Gram-negative infections. One combination approach that was heavily studied in the 1980s but later abandoned is dual beta-lactam therapy. Overall, in vitro, animal, and human data were largely positive, but perceived need for this combination therapy was low due to the high success and susceptibility rates with single beta-lactam agents (DeJace and Klastersky, 1986, Gutmann et al., 1986). However, the rising resistance rates, lack of new agents, and limited success of current combination approaches have created an impetus to re-investigate the existing literature on currently available beta-lactam combinations for the treatment of Gram-negative infections. In light of the near availability of potent beta-lactamase inhibitors, which neutralize the effect of common beta-lactamases like molecular class A K. pneumoniae carbapenemases (KPCs), dual beta-lactam combination therapy may offer a mechanism to improve outcomes among patients with serious Gram-negative infections (Bush, 2012, Crandon and Nicolau, 2013, Sader et al., 2013, Zhanel et al., 2013). The purpose of this review is to evaluate the existing in vitro, in vivo, and clinical literature for the use of dual beta-lactam combinations to treat Gram-negative infections.
Section snippets
Methods
An extensive PubMed search was completed in order to acquire all relevant literature on in vitro, in vivo, and clinical data pertaining to dual beta-lactam therapy against P. aeruginosa or Enterobacteriaceae spp. Any articles written in English and relevant to the topic at hand were reviewed for inclusion in this article. Upon identification, all of the articles underwent cross-referencing to ensure that all relevant articles were included in this review. Although a number of articles evaluated
Expanded spectrum of activity
The advantages of combining antibiotics for the empiric treatment of bacterial infections have been well described in the literature. First, administering two antibiotics versus a single agent will increase the likelihood of adequate coverage for potential pathogens causing the infection. Given the increased mortality associated with delays in appropriate therapy (Bodey et al., 1985, Chamot et al., 2003, Garnacho-Montero et al., 2007, Heyland et al., 2008, Hilf et al., 1989, Ibrahim et al., 2000
In vitro data on dual beta-lactam therapy
The methodologies and specific definitions for synergy, additivity, indifference, and antagonism for each in vitro study that tested for synergy against P. aeruginosa or Enterobacteriaceae spp. with 2 beta-lactams are listed in Table 2, Table 3. Most of these studies used broth or agar dilution or the checkerboard method to test for synergy (Anderson et al., 1981, Baltimore et al., 1976, Bosso et al., 1990, Bosso et al., 1991, Buesing and Jorgensen, 1984, Chattopadhyay and Hall, 1979, Chen et
In vitro pharmacodynamic (PD) and in vivo efficacy data on dual beta-lactam therapy
Similar to in vitro synergy studies, most in vitro PD studies and in vivo efficacy analyses evaluating dual beta-lactam therapy were conducted in the 1970s and 1980s (Table 4). Many of the beta-lactams that were tested are no longer available or commonly used, but favorable results were observed in most of the analyses. For example, mecillinam was frequently studied in combination with other beta-lactams and was commonly found to enhance activity against Enterobacteriaceae (Anderson et al., 1981
Clinical data
Clinical or microbiological responses in patients treated with dual beta-lactam therapy are shown in Table 5, Table 6, Table 7. The majority of studies were conducted in febrile neutropenic patients (n = 14). Other analyses consisted of cancer patients with or without neutropenia (n = 4), critically ill patients with nosocomial pneumonia (n = 1), or patients with mixed soft tissue infections (n = 1). Dual beta-lactam therapy was compared to mono beta-lactam therapy in 5 studies (Table 5) and to
Application/discussion
Overall, the collective results from the dual beta-lactam studies were largely favorable and suggest that dual beta-lactam therapy is just as effective as combinations consisting of a beta-lactam with an aminoglycoside (De Jongh et al., 1986, Fainstein et al., 1984, Feld et al., 1985, Joshi et al., 1993, Klastersky et al., 1975, Middleman et al., 1972, Rotstein et al., 1988, Schimpff et al., 1976, Schimpff et al., 1978, Torres et al., 1989, Winston et al., 1984). Furthermore, the data support
Future directions
While we observed supportive findings with dual beta-lactam therapy, there are a number of important considerations for future investigations into this potentially valuable combination. First, few studies have evaluated combinations comprising newer agents. Only 1 analysis evaluated the in vitro synergy of the newest beta-lactam on the market, ceftaroline (Vidaillac et al., 2009). The minimal data on carbapenems used in combination with other beta-lactams generally supported their use as
Conclusions
Overall, in vitro, animal and human data were generally promising for dual beta-lactam therapy. At a minimum, the collective findings suggest that beta-lactam combinations produce a synergistic effect versus Gram-negative pathogens that sometimes rivals that of aminoglycoside or fluoroquinolone combination therapy. In certain situations, the data suggest that dual beta-lactam therapy confers better outcomes with less toxicity than beta-lactam-aminoglycoside combination regimens. However, more
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