Battling endophthalmitis: New bugs, new technologies, new drugs

This article was reviewed by Harry W. Flynn Jr, MD

In many instances, the word “new” can imply good, improved, or progressive, which are all positive attributes. When it is used in conjunction with bacteria, however, it could translate to the description of new drug-resistant microorganisms. 

Endophthalmitis, one of the most feared diagnoses in ophthalmology, is often associated with cataract surgery (acute-onset postoperative endophthalmitis) and is caused by coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus species, and gram-negative bacteria.

Delayed-onset pseudophakic endophthalmitis is caused by Cutibacterium acnes (formerly called Propionibacterium acnes), coagulase-negative staphylococci, and fungi. Conjunctival filtering bleb-associated endophthalmitis results from Streptococcus species, Haemophilus influenzae, and Staphylococcus species. 

“This classification by etiology allows clinicians to predict the most likely causative organisms,” according to Harry W. Flynn Jr., MD, the J. Donald M. Gass Distinguished Chair and professor of ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, during his delivery of the Jones/Smolin lecture.

Less common causes of endophthalmitis are posttraumatic cases (open globe injuries) caused by Bacillus species and Staphylococcus species; keratitis-associated cases caused by Pseudomonas and Staphylococcus; intravitreal injection–associated cases from Staphylococcus and Streptococcus; and endogenous cases from Candida species, S aureus, and gram-negative species.

Coagulase-negative staphylococci, the most common cause of endophthalmitis after cataract surgery, can be resistant to antibiotics. 

According to Dr. Flynn, a fairly consistent rate of moxifloxacin resistance (about 30% to 40%) has been observed at the Bascom Palmer Eye Institute from 1995 through 2018. He added that moxifloxacin is widely used as an intracameral antibiotic during cataract surgery but it provides inconsistent coverage for coagulase-negative staphylococci. 

Challenges in endophthalmitis prophylaxis
Dr. Flynn said he has encountered a number of cases that were resistant to intracameral moxifloxacin but responded to vancomycin, which is the primary weapon for treating endophthalmitis. However, it is important to recognize that the minimum inhibitory concentration (MIC)90 rates for vancomycin are increasing.

Dr. Flynn also reported on 36 cases in the United States (1 referred to Bascom Palmer) and 23 in Europe. He described a case of hemorrhagic occlusive retinal vasculitis following cataract surgery in which intracameral vancomycin was used. 

“This is an immune-mediated response to vancomycin that can cause this disease 7 to 10 days after cataract surgery,” he explained. “This can be a devastating delayed-onset complication.” 

Dr. Flynn recounted the case of a patient in whom this complication developed 10 days after the first cataract surgery but who had undergone the second cataract surgery seven days after the first. The patient developed bilateral disease and hand motion vision in both eyes. At this point, vancomycin is no longer recommended as a prophylactic intracameral antibiotic.

Cefuroxime, an antibiotic used mostly in Europe, requires preparation at a compounding pharmacy in the United States. Dr. Flynn cited a report of 8 patients with endophthalmitis from Fusarium solani caused by contaminated intracameral cefuroxime solution used during cataract surgery. 

Following vitrectomy with or without silicone oil and systemic antifungal therapy, the patients’ final visual acuities ranged from 20/100 to light perception.

Antimicrobial challengesCandida auris is a relatively new pathogen that is resistant to multiple antifungal agents. Worldwide outbreaks have been documented, and the Centers for Disease Control and Prevention has placed it on the list of Antibiotic Resistance Threats in the United States report. 

In the latest case in New York, a patient with immunosuppression developed endophthalmitis resulting from C auris and Pseudomonas and ultimately underwent enucleation. A multicenter study in India showed that resistance genes are prevalent in C auris; the pathogen can be resistant to multiple drugs. Moreover, 13% of organisms were multi-azole resistant and 8% were resistant to amphotericin B.

Achromobacter xylosoxidans, formerly referred to as Alcaligenes xylosoxidans, is a gram-negative motile rod that in culture resembles Pseudomonas. This pathogen, which may cause delayed-onset endophthalmitis after cataract surgery, responds to ceftazidime and imipenem.

C acnes can cause delayed-onset progressive indolent inflammation after cataract surgery. 

According to Dr. Flynn, removing the intraocular lens may be the best way to eliminate the infection. 

Fortunately, the visual outcomes are generally good. C acnes has been associated with resistance genes; the mutants S101L and S101W are always associated with high resistance. He described a patient with C acnes endophthalmitis who underwent 2 failed vitrectomies.

Later, removal of the entire capsular bag and intraocular lens resulted in elimination of the infection and postoperative vision of 20/25 with an aphakic contact lens.

Pseudomonas aeruginosa, a decades-old pathogen responsible for keratitis and endophthalmitis, is often treated by pars plana vitrectomy and silicone oil infusion. Dr. Flynn pointed out that some eyes can be salvaged, but best-corrected vision may be 20/200 or worse in many eyes.

Methicillin-resistant S aureus has also been associated with specific resistance genes. The pathogen is resistant to all fourth-generation fluoroquinolones. 

The eyes can be successfully treated in most cases, but the visual outcomes are often poor. Methicillin-sensitive S aureus has a much better visual prognosis.

Trichosporon asahii endophthalmitis can be devastating in patients who are immunocompromised. 

Dr. Flynn recounted the case of a 37-year-old patient undergoing chemotherapy for acute lymphoblastic leukemia who developed pneumonia and fungemia. His vision decreased and vitreous debris and a subretinal lesion were seen in the right eye.

Following 67 intravitreal voriconazole injections over 1 year and systemic micafungin and voriconazole administration, his final vision was 20/20 in the right eye at 1 year.

The patient was managed by Royce Chen, MD, the Helen and Martin Kimmel Assistant Professor of Ophthalmology at Columbia University Medical Center and attending ophthalmologist at the New York-Presbyterian Hospital.
 

New technology
Polymerase chain reaction (PCR) is an example of molecular technology that has evolved into a more clinically useful tool with increased sensitivity and specificity, rapid identification of etiologic agents, and detection of new and emerging pathogens. 

According to Flynn, classic PCR technology had nonuniform standards, few commercial kits available, required skilled personnel, and was expensive. Next-generation sequencing, he noted, is more advanced technology utilizing both PCR and whole genome sequencing to identify pathogens causing ocular infections by using microbial DNA in vitreous specimens. 

“We are now able to more rapidly and specifically identify the correct causative organism,” he said.

Next-generation sequencing has been reported to identify specific microbes rapidly in twice as many patients compared with traditional cultures (88% vs 44%, respectively). This technology may be very helpful in culture-negative cases in which delayed diagnoses may result in poor visual outcomes.

Antifungal therapies
Since 2000, numerous antifungal therapies have been introduced. Flynn and colleagues compared old and new antifungals against 17 Candida isolates. 

“We found that voriconazole was still the top antifungal agent with an MIC90 of 0.03 µg/mL followed by amphotericin B with an MIC90 of 0.12 µg/mL. In very severe fungal endophthalmitis cases, I use both agents,” he explained.

When Dr. Flynn and his colleagues undertook an extensive analysis of 47 exogenous fungal endophthalmitis isolates (mold and yeast) and susceptibilities to antifungal agents spanning a 20-year period, they found that voriconazole remained the most potent against these pathogens. 

“Intravitreal voriconazole appeared to provide the broadest spectrum of antifungal coverage and may be considered for empiric therapy of endophthalmitis caused by yeast and most are molds (exception fusarium),” the investigators reported (Am J Ophthalmol 2015;159:257-64). Importantly, voriconazole is also the least toxic, Dr. Flynn pointed out.

Antibiotic therapies
Coagulase-negative staphylococci are the main offender after cataract surgery and most ocular surgeries. With the methicillin-resistant form, vancomycin has a good MIC90 at 2 µg/mL; besifloxacin has an MIC90 of 4 µg/mL, indicating borderline resistance. Moxifloxacin is low on the effectiveness list with an MIC90 of 32 µg/mL.

 In an ongoing study at Bascom Palmer of 45 Staphylococcus isolates, vancomycin was 100% effective. A new fluoroquinolone, delafloxacin, had a low MIC90 (0.98 µg/mL), which Flynn believes will be receiving a great deal of attention in the future, but the drug is not yet commercially available.  

The current first-line intravitreal agents for managing endophthalmitis are the following:

For gram-positive organisms:

> vancomycin 1 mg/0.1 mL

For gram-negative organisms:

>vceftazidime 2.25 mg/0.1 mL or 

>vamikacin 0.4 mg/0.1 mL

For fungi:

> voriconazole 5-10 µg/0.1 mL and/or 

> amphotericin B 50-100 µg/0.1 mL

Dr. Flynn enumerated the cascade of events leading to antibiotic resistance and gave credit to Dan Jones, MD, for his work in this area.  

“Environmental factors influence microbial evolution,” he said. “These factors include antibiotics used in agriculture and environmental changes due to many other local issues.”

Related:

Dr. Flynn added that these changing environmental factors allow emergence and evolution of new infectious agents. 

“These new microbes result in use of increased prophylactic antibiotics during surgery as well as use in general medicine,” he said. “The altered environmental pool of organisms and in turn allows for selection of intrinsically resistant organisms and eventually evolution of more resistant strains, which then forces the use of more antibiotics.”

 In addition, the increased use of broad-spectrum antibiotics causes ocular surface microbiome changes or dysbiosis. 

“Obviously, we have a lot to learn about the use of antibiotics prophylactically and in choosing the right drugs for specific infections,” he concluded. 

Harry W. Flynn Jr, MD
e: hflynn@med.miami.edu
Dr. Flynn has no financial interest in any aspect of this report. Dr. Flynn recognizes Dr. Darlene Miller for her assistance in preparing this article.

References:

Flynn HW Jr, Batra NR, Schwartz SG, Grzybowski A. Endophthalmitis in Clinical Practice. Springer; 2018.

Shirodkar AR, Pathengay A, Flynn HW Jr, et al. Delayed- versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012;153:391-398.e2. PMID: 22030353.

Villegas VM, Emanuelli A, Flynn HW Jr, et al. Endophthalmitis caused by Achromobacter xylosoxidans after cataract surgery. Retina. 2014. 34(3):583-586. PMID: 24150240.

Sridhar J, Flynn HW Jr, Kuriyan AE, et al. Endogenous fungal endophthalmitis: risk factors, clinical features, and treatment outcomes in mold and yeast infections. J Ophthalmic Inflamm Infect. 2013,3:60. PMID: 24053550.

Banker TP, McClellan AJ, Wilson BD, et al. Culture-positive endophthalmitis after open globe injuries with and without retained intraocular foreign bodies. OSLI Retina. 2017;48:632-637. PMID: 28810038.

Scofield-Kaplan SM, Chen RWS, Flynn HW Jr, et al. Recalcitrant endogenous Trichosporon endophthalmitis in 2 immunocompromised patients. Ophthalmol Retina. 2018;7:746-748. PMID: 30364523.

Hong BK, Lee CS, Van Gelder RN, Garg SJ. Emerging techniques for pathogen discovery in endophthalmitis. Curr Opin Ophthalmol. 2015;26:221-225.

Miller D, Chang JS, Flynn HW Jr, Alfonso EC. Comparative in vitro susceptibility of besifloxacin and seven comparators against ciprofloxacin- and methicillin-susceptible/nonsusceptible staphylococci. J Ocul Pharmacol Ther. 2013;29:339-344. PMID: 23289847.

Fan KC, Lin J, Yannuzzi NA, Al-Khersan H, et al. In vitro susceptibilities of methicillin-susceptible and resistant staphylococci to traditional antibiotics compared to a novel fluoroquinolone. J Ophthalmic Inflamm Infect. 2020;10:9. PMID:32103368.

Silva RA, Sridhar J, Miller D, Wykoff CC, Flynn HW Jr. Exogenous fungal endophthalmitis:  an analysis of isolates and susceptibilities to antifungal agents over a 20-year period (1990-2010). Am J Ophthalmol. 2015;159:257-264. PMID:25449001.