Current status on antimicrobial resistance in keratitis

Microbial keratitis is a major cause of corneal blindness globally. In South Asia, and especially in India, the burden of infectious keratitis is very high, which makes the challenge huge.[1,2] Timely initiation of effective antimicrobial therapy directly affects the visual outcome. Emergence and increase in antimicrobial resistance (AMR) among common pathogens have decreased the options of empirical treatment, which has a direct corelation with therapeutic failures, need for surgical intervention, increased patient morbidity, and healthcare costs. There is a need to have an updated understanding of bacterial and fungal antimicrobial resistance, and applying the knowledge for making evidence-based decisions for treating microbial keratitis. Reasons for AMR Among the many reasons of AMR identified, the most important ones which can be addressed with proper understanding of pathogens, their behavior, virulence factors, and resistance profile are worthy of attention of ophthalmologists. These include: a) indiscriminate use of antimicrobials, which may be due to over-the-counter availability, overprophylaxis during procedures, or overtreatment; b) emergence of new pathogens like Candida auris, Pythium insidiosum, and others, whose treatment options are limited; c) emerging virulence factors in the pathogens, for example, a rise in biofilm formation attributes in bacteria and yeasts, hypervirulent Klebsiella pneumoniae, etc.; d) delayed/inadequate microbiological diagnosis, which leads to an increase in hit and trials of all available antimicrobial options; and e) increasing interventions in the form of contact lens use, steroid use, advanced surgeries and procedures, and so on.[1] AMR in Keratitis – A Global Crisis A rise in AMR has bearing at all levels of ophthalmic care. In the patient, it leads to refractory course, complications, and recurrences despite surgical intervention, thus affecting the quality of life adversely. At the level of healthcare facilities, there is expenditure of time, energy, reputation, and cost, which could otherwise be used for more productive patient care. At the global community level, it is causing depletion in armamentarium against pathogens causing keratitis. Such concerns have prompted researchers throughout the world to keep abreast with the current spectra of pathogens causing infectious keratitis and their resistance patterns. The pathogen prevalence and distribution vary geographically and temporally across the world, and antibacterial and antifungal resistance patterns also show marked variation in different denominators. In bacterial keratitis, some of the pathogens like Staphylococci and Pseudomonas aeruginosa are uniformly present among the most common etiological agents, while some others like Corynebacterium sp., Streptococci, and Enterobacterales show marked regional variation. In developed countries like Switzerland, Australia, USA, and England, most of the microbial keratitis cases have bacterial etiology; mycotic keratitis is rare. In these countries, though the resistance to methicillin in Staphylococci and fluroquinolones in all bacteria is rising, it is less than most parts of the world.[3–7] In bacterial keratitis studies from China, Mexico, Romania, and Egypt, moderate (30%–50%) resistance is seen against methicillin, protein synthesis inhibitors, and fluroquinolones. From Mexico, 25% resistance to polymixin in Pseudomonas has also been reported. A large compilation of 26 years data from the Republic of Korea has reported a rise in methiciliin resistance (from 47% to 53%) in Staphylococci and an increase in vancomycin-resistant Enterococci (from 0% to 26.1%) over the years.[8–12] In all studies across the world, methicillin-resistant Staphylococci also show increased resistance to other groups of antibacterials, thus limiting treatment options; susceptibility to vancomycin, however, is maintained in all geographical regions.[3–12] Most of the developed countries have Candida as the most common or one of the most common pathogens in mycotic keratitis.[3,5] The most common fungal pathogen reported from Mexico is Fusarium, and Fusarium and Candida from Romania.[9,10] An Egyptian study has reported Aspergillus sp. to be the most common fungal isolate and 10% resistance to voriconazole among the isolates.[11] While these studies highlight the regional trends in microbial keratitis, there is recent meta-analysis of 42 studies from 21 countries, and an excellent review elucidating the worldwide trends in pathogen prevalence and resistance patterns, and approaches to guide the way forward.[2,13] AMR in Keratitis – Indian Scenario Studies from various regions across the nation show variation in pathogen distribution. Staphylococci, Pseudomonas, Streptococci, and Enterobacterales are most common in North and Central India, while Eastern and Southern states also have Corynebacteria and Nocardia as common bacterial pathogens. Throughout the country, there are temporal changes in pathogen distribution and a gradual rise in resistance patterns.[14–17] Of note in bacterial keratitis, there is rising methicillin resistance among Staphylococci, resistance to fluroquinolones is increasing in Gram-positive as well as Gram-negative bacteria, and resistance to cephalosporins in Gram-negative bacteria is also on a rise. Vancomycin for Gram-positive bacteria, and carbapenems and polymixin-B for Gram negatives are good treatment options for refractory cases; however, some isolates resistant to these reserve drugs are also being reported. One large study from North India has reported high resistance against fluroquinolones, erythromycin, and cephalosporins and decreasing resistance against some antimicrobials like aminoglycosides, chloramphenicol, and trimethoprim-sulfamethoxazole. Such findings offer a ray of hope in the measures like antimicrobial cycling for keeping the available antimicrobials useful for longer times.[14] Mycotic keratitis is a huge challenge in the Indian subcontinent. Most common pathogens are filamentous fungi including Aspergillus, Fusarium, and dematiaceous fungi, and yeasts like Candida. The distribution and common species among these genera, however, vary in different parts of the country. Species diversity of moulds as well as yeasts is increasing in mycotic keratitis with more saprophytic, opportunistic, and emerging fungi causing keratitis cases. Studies from northern, southern, and eastern states have shown a general pattern of Aspergillus showing low minimum inhibitory concentrations (MICs) against azoles and Fusarium showing low MICs against natamycin. A trend of rising MICs against commonly used antifungals is seen in all fungi over the years.[18–23] Navigating the Way Forward Establishing and actively participating in antimicrobial stewardship is non-negotiable. Timely diagnosis for identification of pathogens and their susceptibility is vital for targeted management, so is having updates on the local pathogens and their resistance profile for near accurate empirical treatment. The importance of the right drug, to the right patient, in right dosage for right duration cannot be overemphasized. Microbiological diagnostics should be leveled up for identification of emerging and rare pathogens, as well as mixed infections, as such cases are refractory, leading to overuse of high-end antimicrobials. Standard operating procedures for limited periprocedure exposure of antimicrobials, and reviewing microbiology reports for de-escalation should be adhered to for avoiding unnecessary broad-spectrum antibiotics. Lastly, there should be continuous education and updates for young ophthalmologists as well as for patients emphasizing responsible use of antimicrobials. Regular audits should be conducted for steering through challenges and ensure stewardship.About the authorProf. (Dr.) Nishat Hussain Ahmed Dr. Nishat Hussain Ahmed completed her MBBS from Tirunelveli Medical College, Dr. MGR University, Tamil Nadu; and MD (Microbiology) from Grant Medical College, University of Mumbai, Maharashtra, in which she was conferred Gold Medal for her exceptional performance in MD exam. She worked as Senior Resident in Department of Microbiology, All India Institute of Medical Sciences, New Delhi for three years; and currently holds the position of Professor of Microbiology and Officer In-charge of Ocular Microbiology section at Dr. RP Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. She aims at working on a holistic approach for management, prevention and control of infectious diseases and has worked for around two decades for prevention, control and management of various infections. She has experience of 11 years in management of ocular infections; prevention and control of clusters and outbreaks of eye infections; and hospital infection prevention and control at ophthalmic centre. She has around 70 publications, more than 1000 citations, and has delivered numerous talks and presented papers, and received accolades at international and national platforms. Her notable research includes award-winning works on improving diagnosis of ocular pathogens especially uncommon and emerging ones, antimicrobial resistance, and infection control.