Determining the best course of treatment for bacterial infections can be a daunting task, especially in the age of multidrug-resistant organisms.

Staphylococcus aureus, one of the six pathogens with growing multidrug resistant virulence. These six bacteria are responsible for two-thirds of all healthcare-associated infections.">

Perhaps the most well known multidrug resistant organism is methicillin resistant Staphylococcus aureus (MRSA). A survey conducted at 97 hospitals showed the rate of MRSA in diabetic foot infections to have almost doubled between 2003 and 2007, and these numbers have surely increased since then.1

Recently, there has been a rise of Gram-negative, multidrug-resistant organisms that have caught many physicians off guard. Gram-negative organisms have now evolved from multidrug resistance (resistance to three or more classes of antimicrobials) to extreme drug resistance (susceptibility to two or fewer classes of antimicrobials) to pan-drug resistance (diminished susceptibility to all classes of antimicrobials).2

These organisms are proliferating at an alarming rate both here and abroad. Antibiotic resistance is a worldwide threat. In a 2011 study in India, researchers collected samples from 102 patients with diabetic foot infections.3 Authors found that 45 percent of patients tested positive for multidrug resistant organisms, 68.5 percent of which had extended spectrum beta-lactamases (ESBLs) producing Gram-negative organisms and 43.2 percent with MRSA.

As podiatric physicians, we must be aware of such organisms as they severely limit our treatment options and may ultimately lead to higher rates of morbidity and mortality.

What Are The ‘ESKAPE’ Pathogens?

We have focused on organisms that podiatric physicians are most likely to encounter in their patient population. The term “ESKAPE” pathogens has come to encompass the six pathogens with growing multidrug resistant virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter, Pseudomonas aeruginosa and Enterobacter.4

According to the latest data from the Centers for Disease Control and Prevention, the six ESKAPE bacteria are responsible for two-thirds of all healthcare-associated infections.4

While each of these organisms has unique mechanistic actions, the common foundation is resistance to antibiotics clinicians previously used to treat them. There are several mechanisms of resistance including: mutations occurring in target enzymes; enzymatic deactivation of the drug; gene acquisition; bypassing the target; prevention of drug access to the target; and lastly via biofilms with dormant “persister” cells.5,6 Two target enzymes play a key role in the ESKAPE pathogens’ ability to become drug resistant, specifically when it comes to Gram negative organisms.

What You Should Know About Extended Spectrum Beta-Lactamases

Named for their ability to hydrolyze extended spectrum cephalosporins, ESBLs first surfaced in Germany in 1983.6 E. coli and Klebsiella pneumoniae remain the most common ESBL producers. However, ESBL production may also occur with Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii, Citrobacter freundii, Serratia marcescens and Enterobacter cloacae.

The incidence of ESBL producing organisms is increasing worldwide. In a diabetic foot infection study from India, 44.7 percent of gram negative aerobes cultured were ESBL-positive.7 In a study by Dent and colleagues, nearly 47 percent of surgical patients had evidence of multidrug resistant A. baumannii in their amputation sites and chronic diabetic ulcers.8 Some of the infections persisted for months.

Although ESBLs hydrolyze cephalosporins and monobactams such as aztreonam (Azactam, Bristol-Myers Squibb), they do not generally affect cephamycins such as cefoxitin (Mefoxin, Merck) and cefotetan (Cefotan, AstraZeneca) or carbapenems such as meropenem (Merrem, AstraZeneca), imipenem (Primaxin, Merck) or ertapenem (Invanz, Merck). Some strains may also be hyper-producers of beta-lactamase, limiting the usefulness of beta-lactam/beta lactamase inhibitor compounds. In an age of increasing resistance, it is more important than ever that antibiotic choice be guided by culture results.

According to a study by Jadhav and co-workers, over one-half of the ESBL-producing colonies of E. coli were resistant to ciprofloxacin (Cipro, Bayer), implying resistance to all the currently available fluoroquinolones.9 Treatment options are therefore limited. One may consider carbapenems reasonable therapeutic options although tigecycline (Tygacil, Pfizer) may also prove useful.

A notable challenge to today’s podiatric physician has been that of Acinetobacter. The resistance mechanism of Acinetobacter baumannii has been so efficient that it has extended into the hospital-associated strains of the Enterobacteriaceae family such as Klebsiella, E. coli and Enterobacter.10 With even greater healthcare implications, clinicians have discovered Gram-negative, multidrug-resistant organisms in relatively healthy patients outside hospitals.11 Examples include urinary tract infections caused by E. coli that are resistant to trimethoprim/sulfamethoxazole (Bactrim, Roche) and fluoroquinolones, and produce extended beta-lactamases.11

Key Insights On Klebsiella Pneumoniae Carbapenemases

Another enzyme to note is Klebsiella pneumoniae carbapenemase. Originally isolated in Klebsiella pneumoniae, these organisms confer resistance not only to carbapenems but to penicillin, cephalosporins and monobactams. Although most commonly seen in K. pneumoniae, Klebsiella pneumoniae carbapenemases have also been reported in in K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp. and P. aeruginosa.11

Treatment options are limited and include tigecycline and colistin. Colistin (also known as polymyxin E) is an interesting antibiotic that has enjoyed a re-emergence in recent years to treat infections caused by Gram-negative organisms. Aminoglycosides, when C&S shows susceptibility, may be adjunct therapies.

Bratu and colleagues studied Klebsiella pneumoniae carbapenemase producing K. pneumoniae in bacteremic patients in New York City.12 Results showed that several of the isolates were not only resistant to carbapenems but were also resistant to colistin. As noted previously in recent literature, colistin has long been heralded as the “last resort” antibiotic therapy for Gram-negative infections.12

What The Literature Reveals About Declining Treatment Options

Traditional antibiotic therapies for Gram-negative bacterial infections have included the carbapenems. However, their effectiveness has been steadily declining.13 Bacterial production of beta-lactamases, a.k.a. carbapenemases, is the driving force behind this. Carbapenemases are enzymes that render the beta-lactam ring (the core of the antibiotic structure) completely incompetent.14 Even more worrisome is the ability to transfer this type of resistance between Gram-negative organisms.

Tigecycline is the first of a novel class of broad-spectrum antibiotics, the glycylcyclines, for the parenteral treatment of adult patients with complicated skin and soft-tissue infections. Of particular importance is the drug’s activity against ESBL- and Klebsiella pneumoniae carbapenemase-producing Gram negatives.2

Physicians are now resorting to drastic measures and re-prescribing previously used antibiotics that fell out of use due to serious adverse events.

An example of this is colistin, a polymyxin antibiotic discovered in the 1940s and specifically used for Gram-negative infections.15 It works by competitively displacing divalent cations (Mg and Ca), which disrupts the outer membrane and creates leakage leading to cell lysis and subsequent cell death. Colistin has a narrow antibacterial spectrum but offers activity against multidrug resistant, Gram-negative organisms.15 Unfortunately, it carries with it a high risk of nephrotoxicity and neurotoxicity.

A 2010 study by Lim and colleagues looked at the growing rate of resistance of Gram-negative bacteria to colistin.15 They state that while the mechanism of resistance is poorly understood, it is clear that cases of resistance are growing in numbers. The authors note that it is imperative that one optimizes dosing of colistin. Suboptimal dosing in patients may generate resistance in a number of antibiotic treatments.

What About Future Directions With Antibiotics?

Crane and colleagues recently studied the efficacy of the use of local colistin impregnated beads versus parenteral colistin in soft tissue infection in mice.16 While the authors noted that the parenteral colistin failed to have a measureable effectiveness on the infection, the impregnated beads were significant in reducing it. Further study in human models is necessary to evaluate the effective treatment of common podiatric conditions such as chronic osteomyelitis, chronic diabetic wounds and post-surgical infections.

As with most areas of medicine and science, up-to-date research will allow clinicians to stay ahead of the multidrug resistance curve. Currently, a compound known as avibactam (Cerexa), which is in phase III clinical trials, provides promise in the fight against multidrug-resistant organisms especially when researchers combine it with cephalosporins such as ceftazidime (Fortaz, GlaxoSmithKline) and ceftaroline (Teflaro, Forest Laboratories). One in vitro study showed that avibactam inhibited 100 percent of the Klebsiella pneumoniae carbapenemase producing K. pneumoniae and ESBL producing E. coli.17

In Conclusion

It is imperative that physicians are aware of the new class of multidrug-resistant organisms, the ESKAPE pathogens, which include Gram-negative organisms. The object of this review was to highlight the most common organisms that are causing such problems, mechanisms of action in regard to ESBLs and Klebsiella pneumoniae carbapenemases, and current treatment options. By emphasizing judicious use of antibiotic regimens based on culture and sensitivity reports, physicians can help prevent the creation of resistant organisms.

Dr. Perez is a first-year resident at the New York College of Podiatric Medicine Residency Program.

Ms. Attanasio is a third-year student at the New York College of Podiatric Medicine.

Dr. Khan is an Associate Professor at the New York College of Podiatric Medicine. He is an attending in the Surgery Department at Metropolitan Hospital in New York City.

References

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