Treatment of MDR gram-negative infections: A review of combination regimens

Issue: December 2016

ByKati Shihadeh, PharmD, BCIDP

ByLana T. Al-Omar, PharmD

The rise of multidrug-resistant gram-negative infections in health care settings is a major area of concern. In 2013, the CDC estimated that the annual direct health care cost of infections caused by resistant bacteria was as high as $20 billion. Not only are these infections associated with higher hospital costs, but of particular concern is the impact on morbidity and mortality rates. Therefore, it is important to address which combination therapies have the best data for the treatment of resistant gram-negative infections.

Kati Shihadeh

Lana T. Al-Omar

Combination therapy for critically ill patients at risk for infection with multidrug-resistant (MDR) pathogens increases the likelihood of adequate initial therapy. Moreover, several studies have shown that mortality rates are higher in patients who receive initial inappropriate empiric therapy for severe gram-negative infections, despite changing therapy directed by antibiotic susceptibilities. Data regarding the benefit of continuing combination therapy once susceptibilities are known, however, are lacking. For most patients, a single agent that is susceptible to an isolated pathogen is appropriate.

Empiric coverage for resistant gram-negative organisms usually consists of a broad-spectrum beta-lactam and an aminoglycoside or fluoroquinolone. Beta-lactams are active against a broad range of bacterial pathogens and have been the cornerstone for treatment of serious gram-negative infections for years. In vitro models have demonstrated that the addition of a beta-lactam to an aminoglycoside can elicit synergy by enhancing the uptake of the aminoglycoside, thus eradicating infections more quickly.

Although clinical evidence for the use of combination therapy with beta-lactams and aminoglycosides for gram-negative infections is conflicting, several retrospective analyses have shown that combination empiric therapy targeting gram-negative pathogens is associated with greater initial appropriate therapy and clinical response compared with monotherapy with a beta-lactam. Moreover, combination therapy with a beta-lactam and a fluoroquinolone has shown reductions in 28-day all-cause mortality compared with beta-lactam monotherapy. Nevertheless, the optimal choice of empiric antibiotics will depend on local resistance patterns in addition to individual factors such as recent antibiotic use and prolonged hospitalization.

Treatment of carbapenem-resistant Enterobacteriaceae

There is approximately a 50% mortality rate associated with carbapenem-resistant Enterobacteriaceae (CRE) bacteremia. Of the estimated 140,000 nosocomial Enterobacteriaceae infections that occur annually in the United States, approximately 9,300 cases are caused by CRE. These pathogens have the capability to hydrolyze almost all beta-lactam antibiotics and are unaffected by most beta-lactamase inhibitors. Unfortunately, treatment options for CRE infections are limited, largely due to their broad resistance to most beta-lactam antibiotics and other antibiotic classes such as aminoglycosides and fluoroquinolones. For treatment of CRE bacteremia, combination therapy with at least two drugs that display in vitro activity against the isolate has shown to improve survival and is therefore preferred over monotherapy.

To date, no randomized controlled trials have studied the effect of antimicrobial treatments on clinical outcomes in patients infected with CRE. Some pharmacokinetic data suggest that high-dose carbapenems (meropenem 6,000 mg/day administered as an extended or continuous infusion) have a high probability of target attainment up to a minimum inhibitory concentration (MIC) of 8 g/mL to 16 g/mL. Treatment efficacy also depends on MIC. However, clinical data assessing the efficacy of carbapenems for the treatment of CRE infections are limited.

Mortality rates of patients receiving a carbapenem-containing regimen compared with those receiving noncarbapenem regimens for the treatment of carbapenemase-producing Klebsiella pneumoniae are lower (12% [3/26 patients] vs. 41% [46/112 patients], respectively; P = .006). However, mortality rates with carbapenem monotherapy appear to be high, whereas combination therapy with a carbapenem appear to have the lowest mortality rates for the treatment of carbapenemase-producing Enterobacteriaceae.

Colistin and polymyxin B have the most in vitro activity against CRE. However, toxicities, primarily nephrotoxicity, may limit their use. Furthermore, the ideal dosages of colistin and polymyxin B are largely unknown, especially in patients with renal failure or those who are critically ill. Moreover, high doses of colistin are required to treat resistant gram-negative infections, which may also lead to further dose-related adverse effects, including worsening renal function. Evidence, however, demonstrates that these agents can decrease mortality in patients infected with CRE, and their use is frequently warranted as part of a combination regimen.

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Tigecycline, a bacteriostatic agent that inhibits protein synthesis by binding to the 30S ribosomal subunit of bacteria, is frequently included in a combination regimen, although resistance to tigecycline is increasing. Evidence has demonstrated its efficacy for the treatment of CRE infections. For instance, in 22 ICU patients without comorbidities, a regimen of tigecycline plus colistin or gentamicin was effective at treating 24 of 26 Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infections.

Aminoglycosides are also used in combination regimens to treat CRE infections, especially in patients with urinary tract infections. Several studies have shown success rates with aminoglycoside combination therapy, and in a review of 20 clinical trials conducted by Tzouvelekis and colleagues, the combination of an aminoglycoside and a carbapenem was associated with the lowest mortality rate (11.1%) for the treatment of CRE infections.

Treatment of MDR Pseudomonas aeruginosa

To increase the likelihood of providing activity against MDR Pseudomonas aeruginosa, the use of two antipseudomonal agents is often recommended. However, due to the lack of randomized controlled trials comparing different antibiotic regimens, it is difficult to conclude which regimens are the most effective at treating MDR Pseudomonas. Empiric therapy should be guided by the institution’s antibiogram and the individual’s underlying risk factors for resistance.

Certain antibiotics, such as imipenem, are more prone to developing resistance during therapy, which can lead to treatment failure. For example, in three controlled studies, resistance to imipenem was reported more frequently when compared with ceftazidime, ciprofloxacin or piperacillin/tazobactam.

Moreover, enhanced in vitro activity against highly resistant P. aeruginosa has been shown with the following combinations: a fluoroquinolone with either ceftazidime or cefepime, polymyxin B with rifampin, ceftazidime with colistin, clarithromycin with tobramycin, and colistin with rifampin. Once susceptibilities are known, therapy should be narrowed to one active antibiotic to reduce the incidence of superinfection and adverse effects.

Conclusion

Treating suspected resistant gram-negative infections is best accomplished by using combination antimicrobial therapy initially. This will not only increase the likelihood that at least one agent will provide coverage against the infectious pathogen, but evidence suggests that it can significantly improve survival rates. Selection of an empiric combination regimen should take the institution’s antibiogram and available evidence in the literature into account.

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For more information:
Lana T. Al-Omar, PharmD, is a pharmacy practice resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.

Disclosures: Al-Omar and Shihadeh report no relevant financial disclosures.