News | Taj Pharma Colistin Colistimethate sodium injection : Antibiotic resistance optometrytimes (UBM Medica, LLC, a UBM company.)

A most unwelcome guest—a superbug called mcr-1 positive—arrived in the United States in May 2016.¹ That event, along with the increasing threat of Zika virus, has brought microbes to the forefront of our thinking.

The current dilemma we face is that we have no viable treatments for many of these new microbes. Mcr-1 positive is a superbug, which means it has resistance to not just one class of drugs but several drug classes. The new superbug is resistant to even what is called our last line of defense, the antibiotic Colistin (colistimethate sodium, Taj Pharmaceuticals).

Microbial antibiotic resistance is the ability of microbes to survive the effects of drug compounds formulated to eradicate them.

As a background, microbes have inhabited the earth for billions of years and may be the earliest life forms on the planet. They have the capacity to survive in the most extreme environments. The success of microorganism survival is due to their remarkable adaptability. Having the flexibility to change under stressful external environmental conditions, antibiotic exposure for example, ensures microbial survival.

Antibiotic resistance is a natural phenomenon. During antibiotic challenge in the course of bacterial generations, those bacteria that are weak or sensitive to the drug will perish, and those resistant will continue to thrive and multiply. For example, bacteria which have undergone random genetic mutation that provides genetic material to encode for antibiotic resistance will continue to populate. This natural selection process ensures genetic survival.

Different genetic mutations encode for different resistance mechanisms in bacteria. Some bacteria have genetic material that encodes for enzymes that deactivate the challenging antibiotic. Others remove landing sites for the antibiotic so that it is unable to exert its therapeutic effect. Bacteria can close membrane ports, blocking antibiotic access into the cell, and yet others develop pumps to pump the offending antibiotic out of the cell.

When bacteria possess the genome to encode for resistance, they can pass it on vertically to subsequent generations or horizontally to its contemporaries through different mechanisms. Via transformation, bacteria incorporate free-floating DNA strands from their environment. In transduction, bacterial DNA is moved from one bacterium to another by a virus; in bacterial conjugation, direct cell-to-cell contact allows for bacterial DNA sharing or gene swapping,² as seen with mcr-1 positive.

Staphylococcus aureus is recognized as having expert flexibility in the face of challenge. In the early 1960s, S. aureus was first recognized as being resistant to the favored antibiotic of the time, methicillin, and now we have methicillin-resistant S. aureus, or MRSA.³ S. aureus has been discovered in Egyptian mummies, and MRSA was first found in 1961 in the U.K.

Entering the 21^st century, S. aureus and other bacterial groups have become resistant to methacillin and other classes of antibiotics, including the fluoroquinolones.⁴

Current rising and alarming levels of multi-class antibiotic resistance of groups of bacteria are thought to be due to increased selective pressure from the overuse of antibiotics in medicine, agriculture, and veterinary medicine. Bacterial exposure to antibiotics in these settings generates microbial resistance that is transferred and spread through person-to-person contact, food, water, and other sources.

The Centers for Disease Control (CDC) estimated in 2015 over two million infections in the U.S. were due to antibiotic-resistant organisms that culminated in over 23,000 deaths.⁵

In May 2015, the World Health Assembly adopted the global action plan on antimicrobial resistance. One of the five strategic objectives of the action plan is to strengthen the evidence base through enhanced global surveillance and research in antibiotic resistance. The Global Antimicrobial Resistance Surveillance System (GLASS) is being launched to support a standardized approach to the collection, analysis, and sharing of data on antimicrobial resistance at a global level in order to inform decision-making; drive local, national, and regional action; and provide the evidence base for action and advocacy. GLASS aims to combine clinical, laboratory, and epidemiological data on pathogens that pose the greatest threats to global health.⁶

Antibiotic resistance is present in eye care as well. One bug all too familiar to us is Pseudomonas aeruginosa. It causes keratitis and subsequent corneal ulcers and infiltrates. We see Pseudomonas infections related to contact lenses. There is a new species of Pseudomonas called multidrug-resistant Pseudomonas aeruginosa or MDR-PA.^7-10

MDR-PA is a superbug showing resistance to several antibiotics. When compared to Pseudomonas, MDR-PA is more virulent and results in poorer treatment outcomes.⁷Corneal perforation, cyanoacrylate glue, and keratoplasty are more commonly required with MDR-PA vs. Pseudomonas.

Contact lens wearers are not immune to antibiotic resistance. The rising tide of resistance can be seen in several cases of Pseudomonas ulcers related to contact lens wear.⁶Because most ulcers are caused by Pseudomonas, MDR-PA is more common that you may think. Studies have shown the root cause of many antibiotic treatment failures is resistance.^7-10

In many cases, the initial regimen of antibiotics proved to be ineffective. Changing initial regimens from time to time is recommended as a step toward reducing resistance in Pseudomonas.⁸ Going outside the normal antibiotic realm for eye care is another option. As mentioned before, Colistin has been shown to be effective against superbugs, even those in eye care. But as already mentioned, new superbugs are resistant to Colistin.¹ In one case, the dosing regimen was topical Colistin 0.19% every hour. It took 28 days of treatment to finally resolve. The scar remained even after one year of follow-up.¹⁰

Specifically related to eye care, the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study is the only ongoing nationwide antibiotic resistance surveillance program specific to ocular pathogens.¹¹ The ARMOR study reported resistance rates and trends among common ocular isolates collected during 2009-2013. Clinical centers across the U.S. submitted ocular isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. A total of 3,237 ocular isolates were collected from 72 centers.

Methicillin resistance was found among 42.2 percent of S. aureus isolates. Note that this MRSA resistance level increased from 29.5 percent in 2000 and 41.6 percent in 2005.¹²Methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones, aminoglycosides, or macrolides. Multidrug resistance to at least three additional antibiotic classes was found in 86 percent of MR S. aureus isolates. Staphylococcal isolates from elderly patients were more likely to be MR, as were S. aureus isolates obtained from the southern United States. Although methicillin resistance among staphylococci in ocular isolates did not increase during the five-year study period, overall levels of multi-drug resistance is of serious concern.

These findings are consistent with resistance trends reported for nonocular staphylococcal isolates.¹¹ Continued surveillance of ocular isolates provides critical information to guide selection of topical antibacterials used for empirical management of ocular infections.

Clinicians should remain vigilant for patients at heightened risk for ocular MRSA colonization/infection. Risk factors include increasing age, increasing healthcare exposure, systemic disease, pre-existing ocular surface disorder,¹³ and long-term use of antibiotics or steroids.

Preventing antibiotic resistance

Several strategies have been laid out to combat resistance. A comprehensive strategy goes beyond just the prescriber. It encompasses education to the public, farming guidelines, and political and research goals.

For the prescriber, better diagnostics are needed to differentiate among causes of infection. Not every red eye is bacterial and should be treated appropriately. Differentials are needed among bacterial, viral, and allergic conjunctivitis. Lab testing is very helpful in targeting the proper antibiotics to use. Indiscriminately using broad-spectrum antibiotics contributes to the resistance profile. Hygiene, hand-washing, and disinfection are very important practices to instill and continue to instill. Much of the transmission can be attributed to poor hygienic procedures.¹⁴ Also mentioned previously are changing initial regimens periodically and using antibiotics outside the norm when needed.

For our patients and the public, education on proper use is important. Instructing patients to follow the prescription as directed needs constant review. The rationale for taking the antibiotic for the full course, instead of “saving” the pills for a later time needs emphasis. Using antibiotics on a chronic basis nullifies its anti-microbial abilities. There are exceptions—some antibiotics (such as doxycycline) are purposely prescribed for chronic use for anti-inflammatory, not anti-microbial, effects. Again, hand washing and hygiene are important guidelines to reinforce for patients and the public.¹⁴

Strategies with regard to political policy and research and new antibiotics need to be discovered. Politicians can aid simplification of the complicated requirements for new drug approvals. Tax breaks and financial incentives can be offered for new antibiotic drug discoveries. Researchers can create better ways to monitor antibiotic resistance and identify new drug targets. Finally, use of antibiotics in farming and cattle/poultry raising can be reduced or modified.¹⁴

Perhaps we got it all wrong. One expert opines we should take the bacterium’s point of view. Actually, by numerical count, 90 percent of the cells in our bodies are bacteria. There are an estimated 100 trillion bacterial cells in your gut.¹⁵ The bacteria need to develop resistance just to survive. And sometimes bacteria have a reason to hurt you. One example is surgery—the first thing that happens is placing the patient on an IV drip. The drip deprives bacteria of their nutrients. Their sustenance is disappearing and causes a general panic. The bacteria become defensive, speed up reproduction and gene acquisition, and produce toxins that makes their host even sicker. Resistance is part of their natural process.¹⁵

Antibiotic resistance is real. Practitioners should maintain a level of suspicion for resistant organisms, especially in more aggressive infections or those lacking improvement with standard therapies. Consider antibiotic usage only when necessary and in concert with local antibiograms. (An antibiogram is an overall profile of antimicrobial susceptibility testing results of a specific microorganism to a battery of antimicrobial drug). Finally, carefully consider antibiotic selection based on the patient’s medical history and previous antibiotic exposure.

2. Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Available at: http://www.ncbi.nlm.nih.gov/books/NBK7627/. Accessed 8/27/16.

4. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003 May;111(9):1265-73.

7. Vazirani J, Wurity S, Ali MH. Multidrug-Resistant Pseudomonas aeruginosa Keratitis: Risk Factors, Clinical Characteristics, and Outcomes.

8. Mohammadpour M, Mohajernezhadfard Z, Khodabande A, Vahedi P. Antibiotic Susceptibility Patterns of Pseudomonas Corneal Ulcers in Contact Lens Wearers. Middle East Afr J Ophthalmol. 2011 Jul-Sep; 18(3):228-231.

9. Chatterjee S, Agrawal D.Multi-drug resistant Pseudomonas aeruginosa keratitis and its effective treatment with topical colistimethate. Indian J Ophthalmol. 2016 Feb; 64(2): 153-157.

10. Seo MH, Na YH, Lee DH, Kim JH. A Case of Successful Treatment Using Topical Colistin in Multidrug-resistant Pseudomonas aeruginosa Bacterial Ulcer. J Korean Ophthalmol Soc. 2016 Aug;57(8):1307-1311.

Antibiotic Resistance Among Ocular Pathogens in the United States: Five-Year Results From the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study. JAMA Ophthalmol. 2015 Dec;133(12):1445-54.

12. Asbell PA, Sahm DF, Shaw M, Draghi DC, Brown NP. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg. 2008 May;34(5):814-8.

13. Shanmuganathan VA, Armstrong M, Buller A, Tullo AB. External ocular infections due to methicillin-resistant Staphylococcus aureus (MRSA). Eye (Lond). 2005 Mar;19(3):284-91.

14. Lee C-R, Cho IH, Jeong BC, Lee SH. Strategies to Minimize Antibiotic Resistance. Int J Environ Res Public Health. 2013 Sep; 10(9):4274-4305.

Katherine M. Mastrota, MS, OD, FAAO
Clinical director of Omni Center for Dry Eye Specialty Care in New York City

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