The role of carbapenems in initial therapy for serious Gram-negative infections

The treatment of patients with serious Gram-negative infections must be both prompt and correct. Numerous studies have demonstrated that mortality risk is significantly increased when the initial antibiotic regimen does not adequately cover the infecting pathogen. Furthermore, changing to an appropriate regimen once culture results are available does not reduce this risk. Therefore, one must empirically treat serious infections with a regimen that covers likely pathogens. Selecting such a regimen is complicated by the increasing prevalence of resistance to commonly used antibiotics. Moreover, multidrug-resistant pathogens, once limited to hospital-acquired infections, are increasingly being detected in community-acquired infections, especially those involving the urinary and gastrointestinal tracts or in immunocompromised patients. Consequently, the initial antibiotic regimen must have a broad spectrum of activity that includes potential resistant pathogens, as indicated by the local antibiogram. Many multidrug-resistant pathogens remain susceptible to carbapenems despite increasing worldwide antibiotic resistance. This article reviews the role played by carbapenems in the initial treatment of serious Gram-negative infections and the potential effect of emerging resistance on this role.


Introduction
Appropriate antibiotic therapy for any given circumstance requires consideration of three factors: the pathogen, the timing, and the patient, including the site of infection. The role of the pathogen is clearly understood. Treatment must be directed at the pathogens potentially responsible for the patient's illness, and this treatment must take into consideration local resistance factors for these pathogens. In serious bacterial infections such as bacteremia and ventilatorassociated pneumonia (VAP), antibiotic resistance is the most important risk factor for therapeutic failure [1,2]. In a prospective, multicenter evaluation [2], 19% of Klebsiella pneumoniae bacteremias were caused by organisms that produced extended-spectrum β-lactamase (ESBL). Twenty-four per cent of these patients died within 14 days of the first positive blood culture. The single greatest risk factor for mortality was failure to use an antibiotic with in vitro activity against the isolate during the initial 5 days (odds ratio 10.7, 95% confidence interval 2.2 to 57.0; P = 0.001).
Although less often appreciated than the pathogen, the significance of therapeutic timing is equally important. In the study described above, reduced mortality was associated not only with appropriate antimicrobial therapy but also with the initiation of this therapy early in the course of the disease process. Likewise, several evaluations of both VAP (Figure 1) [3][4][5][6] and septicemia ( Figure 2) [7][8][9][10] have demonstrated that inadequate initial antibiotic therapy was associated with increased mortality risk. In one evaluation [11], 73% of patients with VAP received an initial empiric antibiotic regimen that was inappropriate for their infection based on subsequent culture results. In multivariate analysis, this inappropriate antibiotic selection was a significant and independent risk factor for in-hospital mortality (odds ratio 3.28, 95% confidence interval 2.12 to 5.06; P = 0.006). In another evaluation of patients with VAP [5], inappropriate initial antibiotic therapy was associated with a 2.4-fold increase in mortality risk (95% confidence interval 1.5-fold to 5.0-fold). Furthermore, changing from inappropriate to appropriate therapy once culture results were available did not reduce this risk significantly. Consequently, in order to reduce mortality, it is essential that the initial antibiotic regimen appropriately cover likely pathogens [8,12]. Therefore, the initial 12 to 24 hours of therapy is not a time to be concerned with restricting antibiotics.
Patient status also influences the prognosis and therefore the treatment approach. Patients with prolonged hospitalization, prior antibiotic use, or higher Acute Physiology and Chronic

The role of carbapenems in initial therapy for serious Gram-negative infections
Health Evaluation II scores are more likely to be infected with resistant organisms [1]. In addition, mortality risk has been shown to correlate significantly and independently with Acute Physiology and Chronic Health Evaluation II score [8]. Excepting critically ill patients with short life expectancies, the detrimental effect of inadequate initial antibiotic coverage increases with increasing severity of disease [12].
Although the initial antibiotic regimen should be broad enough to cover likely pathogens, this regimen should be rapidly de-escalated after 48 to 72 hours, with subsequent antibiotic therapy determined by culture results and clinical course. In a prospective evaluation of patients with VAP [13] the use of broad initial coverage with a combination of imipenem, ciprofloxacin, and vancomycin, with modification after 24 to 48 hours, significantly increased the prevalence of adequate initial coverage (94% versus 48%; P < 0.01), reduced the duration of therapy (9 days versus 15 days; P < 0.001), and decreased recurrences (8% versus 24%; P = 0.03). A prospective randomized trial of intensive care unit patients with pulmonary infiltrates [14] evaluated the effects of a protocol of de-escalation of antibiotic therapy after 3 days, based on clinical status. This protocol resulted in a shorter duration of treatment (mean 3 days versus 10 days; P < 0.0001), a lower cost of antibiotic therapy (mean $259 versus $640; P < 0.0001), and reduced prevalence of resistance and/or superinfection (15% versus 35%; P = 0.017) compared with 'standard' therapy. However, there was no significant effect on mortality (0% for de-escalation versus 7% for standard therapy; P > 0.05).
Optimal dosing is a critical component of antibiotic therapy, regardless of type or class of agent employed. In patients with serious bacterial infections, the use of maximum tolerable antibiotic doses improves therapeutic outcomes and may prevent the development of resistance [15,16]. Bactericidal rather than bacteriostatic agents may be preferred, because these agents may curtail the development of resistance. As Stratton so concisely stated, 'Dead bugs don't mutate' [17]. However, even when bactericidal agents are used, the administered dose must be sufficient to achieve bactericidal activity. In a Monte Carlo simulation, the probability of achieving bactericidal activity against representative pathogens of nosocomial pneumonia (excluding methicillin-resistant Staphylococcus aureus) increased from 67.9% to 92.5% when the ceftazidime dose was doubled from 3 to 6 g/day, from 90.3% to 95.0% when the cefepime dose was doubled from 2 to 4 g/day, and from 12.0% to 54.7% when the ciprofloxacin dose was increased by 50% from 800 to 1,200 mg/day [18]. In the same study the probability of achieving bactericidal activity for a typical carbapenem regimen was approximately 98%, illustrating the potency of this class against Gram-negative infections.
Considering the therapeutic principles summarized above, this article reviews the rationale for carbapenem use in the initial therapy of serious bacterial infections that are potentially caused by Gram-negative pathogens. It also explores the potential effects of emerging resistance on carbapenem use.

Carbapenem resistance mechanisms
Activity against many multidrug-resistant (MDR) pathogens is among the main advantages of using carbapenems in patients with serious Gram-negative infections. Consequently, the future utility of carbapenems depends, to a great extent, on controlling the development of resistance to this class. Adequate versus inadequate initial antibiotic therapy: intensive care unit (ICU)-acquired pneumonia and ventilator-associated pneumonia (VAP). Shown is the mortality risk associated with adequate versus inadequate initial antibiotic therapy in patients with ICU-acquired pneumonia [3] or VAP [4][5][6].

Figure 2
Adequate versus inadequate initial antibiotic therapy: bacteremia and severe sepsis/early septic shock. Shown is the mortality risk associated with adequate versus inadequate initial antibiotic therapy in patients with bacteremia [8][9][10] or severe sepsis/early septic shock [7].
Antibiotic resistance is a function of drug exposure and can be acquired through numerous mechanisms [19][20][21]. Resistance to carbapenems in particular is produced through three mechanisms: reduced permeability, efflux, and synthesis of carbapenem β-lactamases.
Reduced permeability is the major mechanism by which Pseudomonas aeruginosa acquires resistance to carbapenems in the Western hemisphere. To be effective against Gram-negative organisms, carbapenems must enter the periplasmic space. Downregulation of porin channels in the outer lipopolysaccharide membrane effectively reduces this entry. Recent data suggest that reduced permeability, in combination with certain β-lactamases, may also play a role in resistance acquisition by Klebsiella, Enterobacter, and Acinetobacter spp. [22][23][24].

Carbapenem β β-lactamases
Synthesis of β-lactamases by Gram-negative bacilli has become increasingly important in the development of resistance to carbapenems. Four classes of β-lactamases can produce carbapenem resistance (Table 1). Traditionally, carbapenemasemediated resistance, particularly in Pseudomonas and Acinetobacter spp., was due to the synthesis of class-B metallo-β-lactamases. Although widely scattered throughout the world, bacteria possessing genes for metallo-β-lactamases have not yet penetrated North America to any great extent. Thus, carbapenems could be used with relatively little concern about β-lactamase induced resistance. However, the recent emergence of carbapenem-resistant organisms utilizing other classes of β-lactamase has altered this presumption. A chromosomal 'AmpC-like' β-lactamase that can be transferred from one organism to another via plasmids has been recognized in Klebsiella, Enterobacter, Pseudomonas, and Acinetobacter spp., which utilize this mechanism in combination with a permeability defect to create carbapenem resistance [25]. In addition, an increasing number of organisms, most notably Acinetobacter spp., can produce oxacillinase enzymes that inactivate carbapenems [26]. Finally, in 2001, Yigit and colleagues [27] reported isolation of a K. pneumoniae strain that possessed a novel plasmidencoded class A β-lactamase (K. pneumoniae carbapenemase [KPC]-1), which conferred resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam [27]. Several other KPCs have been identified since. Furthermore, this class of enzymes is no longer limited to Klebsiella but also has recently been found in Escherichia coli, Salmonella enterica, Citrobacter freundii, Serratia marcescens, and P. aeruginosa [28,29].

Emergence of resistance in P. aeruginosa
In a cohort evaluation of hospitalized patients, the likelihood of emergence of antibiotic-resistant P. aeruginosa was greatest in patients treated with imipenem (hazard ratio 2.8; P = 0.02), followed by piperacillin (hazard ratio 1.7; P = 0.3), ciprofloxacin (hazard ratio 0.8; P = 0.6), and ceftazidime (hazard ratio 0.7; P = 0.4) [30]. Similarly, in an open, prospective evaluation of intensive care unit patients, the risk for emergence of resistance was greatest in patients treated with imipenem (hazard ratio 6.0, 95% confidence interval 2.8 to 13.2; P < 0.0001), followed by piperacillin-tazobactam (hazard ratio 3.8, 95% confidence interval 1.2 to 11.8; P = 0.018) and ceftazidime (hazard ratio 1.1, 95% confidence interval 0.3 to 3.9; P = 0.85) [31]. Likewise, cumulative data from studies of patients with P. aeruginosa pneumonia who were treated with imipenem suggest a high rate of emergence of resistance during therapy (Table 2) [32-38]. Fear of central nervous system toxicity has caused many clinicians to limit their dosing of imipenem to 2 g/day, even in the presence of normal renal function. The use of maximum doses of antibiotic may limit the development of resistance, particularly that which is mediated by chromosomal mechanisms.
Decreased permeability is sufficient for the acquisition of resistance to imipenem by P. aeruginosa. In contrast, the acquisition of resistance to newer carbapenems requires Available online http://ccforum.com/content/12/S4/S5

Future role of carbapenems
The future role of carbapenems will be governed by local resistance patterns. Carbapenems are currently indicated for the initial treatment of serious infections potentially caused by MDR bacteria. They will retain this indication, whereas the prevalence of resistance due to the production of ESBLs exceeds that of resistance due to the production of KPCs and metallo-β-carbapenemases. Infections caused by ESBLproducing organisms are an increasing problem worldwide. For example, the prevalence of K. pneumoniae producing ESBLs has reached 50% in parts of Europe, and similar high rates have been observed in Asia and Central and South America [2]. Several groups have reported a reduction in mortality after the early initiation of carbapenem therapy for ESBL-producing organisms. In one evaluation [2] the 14-day mortality rate in patients with bacteremia caused by ESBLproducing K. pneumoniae was 5% in patients who received a carbapenem early, as compared with 64% in patients whose initial antibiotic regimen did not adequately cover ESBLproducing organisms.
Although ESBL-producing organisms are typically thought of as being hospital-acquired, these organisms have moved beyond the hospital setting, and their prevalence in community-acquired infections is also on the rise   Figure 3) [45].
Furthermore, when the infecting organism is susceptible to the antibiotic(s) being administered, adding an additional agent may improve efficacy. In a randomized evaluation of 121 patients with bacteremia due to P. aeruginosa that was susceptible to β-lactams and aminoglycosides [46], the addition of rifampin to standard β-lactam plus aminoglycoside therapy was associated with improvement in bacteriologic cure rate compared with standard therapy (P = 0.018). The potential beneficial effect of combination therapy may depend on the prevalent mechanisms of resistance. For example, adding polymyxin to carbapenem therapy should have a positive effect against resistant Gram-negative pathogens when the carbapenem resistance mechanism is reduced permeability. This may not occur if the resistance mechanism is carbapenemase production [45,49]. However, there are no clinical data demonstrating that adding polymyxin to carbapenem therapy has a positive effect. Suboptimal dosing is a contributing factor to poor outcomes and the emergence of resistance. Thus, antibiotics used in combination should not be administered in reduced doses.

Target pathogens
The majority of ESBL-producing enteric Gram-negative bacilli are susceptible to carbapenem therapy and, because of coresistance, few other good treatment options remain for many of these organisms [2,42,52]. In an evaluation of 312 ESBLproducing Gram-negative bacilli recovered from patients at a single urban teaching hospital [53], 75% were found to be resistant to gentamicin, 70% to trimethoprim-sulfamethoxa-zole, 59% to ciprofloxacin, 40% to piperacillin-tazobactam, 11% to amikacin, and 0% to imipenem. Likewise, in an evaluation of 34 isolates of piperacillin-resistant P. aeruginosa recovered from patients with VAP [21], 94% were also resistant to ticarcillin-clavulanic acid, 91% to ticarcillin, 88% to piperacillin-tazobactam, 71% to ciprofloxacin, 62% to ceftazidime, 59% to imipenem, and 50% to amikacin. Because co-resistances will vary among institutions, knowledge of the local antibiogram is crucial in selecting appropriate antimicrobial therapy for the target pathogen. Carbapenems are effective in the treatment of susceptible MDR Acinetobacter spp., with or without the addition of a second active agent [52]. They are effective in the treatment of susceptible P. aeruginosa when combined with a second agent [13]. When used for this indication, follow-up cultures are essential in order to detect the emergence of resistant Pseudomonas. A recent meta-analysis of 12 randomized controlled clinical trials of therapy for hospital-acquired pneumonia in immunocompetent adults [54] showed equivalence between carbapenems, fluoroquinolones, and βlactams, alone or in combination with aminoglycosides. However, among a subset of patients with pneumonia due to P. aeruginosa, carbapenem therapy was associated with lower treatment success and pathogen eradication than fluoroquinolones and β-lactams.  single greatest predictor of survival in patients who develop septic shock. In their study, a 1-hour delay in the initiation of effective antibiotic therapy significantly increased in-hospital mortality risk compared with initiation of such therapy within the first hour (odds ratio 1.67, 95% confidence interval 1.12 to 2.48). Furthermore, this mortality risk continued to increase for each additional hour of delay. During the initial 6-hour period, overall survival fell by 7.6% for every hour that the initiation of effective antibiotic therapy was delayed. Our aggressive protocol is continuously updated as local susceptibility patterns change. As yet, there are no controlled clinical trial data to show that our current regimen is more effective than others.

Conclusion
Achieving optimal results against serious bacterial infections requires immediate, intensive antimicrobial therapy. Early treatment should employ potent broad-spectrum agents in order to increase the probability that this initial therapy will be appropriate for the infecting pathogen. Carbapenems, often in combination with other agents, remain a mainstay of this early therapy in patients with serious hospital-acquired infection. Further evolution of community-acquired ESBLproducing organisms may broaden this indication to include initial emergency room treatment of selected serious infections. Initial empiric therapy should be re-evaluated and adjusted once data from bacteriologic studies become available. De-escalation to narrow-spectrum agents and the use of short-course therapy, if appropriate for the infecting pathogen, may help to limit the emergence of resistance. However, short-term therapy should not be used against nonfermenters such as P. aeruginosa. Finally, the pharmacodynamics of antibiotics employed should always be considered in order to achieve maximum dosing and the best possible outcome. Such strategies may prolong the useful life span of this valuable class of antibiotics.

Competing interests
James J Rahal receives grant and/or research support from Ortho McNeil, Wyeth, and Hemispherx Biopharma.