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 ventilator-associated pneumonia (VAP), antibiotic resistance is the most important risk factor for therapeutic failure 12. 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) 3456 and septicemia (Figure 2) 78910 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 812. 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 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 1516. 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.

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.

Antibiotic resistance is a function of drug exposure and can be acquired through numerous mechanisms 192021. 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. 222324.

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) 32333435363738. 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 both decreased permeability and increased efflux 2539. As a result, in vitro resistance selection occurs less frequently with newer carbapenems than with imipenem 4041. Whether this will translate into a clinically meaningful difference has not been shown.

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 ESBL-producing 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 ESBL-producing 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 ESBL-producing 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 424344. As a result, carbapenems may play an increasingly important role in the empiric emergency room treatment of serious community-acquired infections, particularly those involving the urinary and gastrointestinal tracts or in immunocompromised patients. Urinary tract infections caused by E. coli resistant to trimethoprim-sulfamethoxazole and fluoroquinolones are no longer uncommon 42. In fact, a surveillance study conducted in 2006 reported a 20% rate of trimethoprim-sulfamethoxazole resistance in community-acquired urinary tract infections in North America, and many of these organisms were also resistant to cephalosporins 42.

Another potentially increased role for carbapenems is their use in combination with aminoglycosides, cefepime, polymyxins, and/or rifampin in the treatment of MDR or pan-drug resistant Gram-negative pathogens. As discussed above, reduced permeability through the outer membrane is one of the principal means by which Gram-negative pathogens acquire resistance to carbapenems. Polymyxins increase outer membrane permeability in these organisms, enhancing carbapenem penetration 45, but their use clinically still awaits controlled clinical studies. Numerous studies have demonstrated the in vitro and clinical efficacy of combination therapy against MDR pathogens, although some organisms were not susceptible to the drugs when tested individually (Table 3) 45464748. For example, Yoon and colleagues 45 evaluated eight isolates of Acinetobacter baumannii that were resistant to imipenem alone. However, the combination of imipenem with subinhibitory concentrations of polymyxin B was bactericidal against seven of these isolates. The combination of imipenem with polymyxin B and rifampin was bactericidal against all eight isolates within 24 hours (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 4549. 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.

Finally, the future development of β-lactamase inhibitors and/or efflux inhibitors may enhance and extend the utility of the carbapenem class. Both Gram-positive and Gram-negative organisms can express multidrug efflux pumps, and almost all antibiotics are susceptible to the effects of these pumps 50. When they are used in combination with antimicrobial agents, inhibitors of these pumps should reverse resistance, enhancing the potency and expanding the spectrum of activity of antimicrobial agents while decreasing the emergence of new resistance 50. The development of clinically useful efflux inhibitors has proven to be problematic. However, one candidate (MP-601,205; Mpex Pharmaceuticals, San Diego, CA, USA) is undergoing phase I clinical trials for the treatment of P. aeruginosa infections 50. Likewise, the development of inhibitors of AmpC, KPC, or metallo-β-lactamases may extend the life span of this class, but progress has been slow 51.

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 ESBL-producing 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.

ESBL = extended-spectrum β-lactamase; KBC = Klebsiella pneumoniae carbapenemase; MDR = multidrug-resistant; VAP = ventilator-associated pneumonia.

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