Editor's Note: Artificial tears are substitutes that mimic the composition of natural tears, providing lubrication to the eyes and alleviating symptoms of dry eye, such as pain and burning. However, a recent study published in Clinical Infectious Diseases highlights a concerning public health event: an outbreak of carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) across multiple U.S. states, with the source traced back to commonly used artificial tears.
Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) is an emerging public health threat in the United States. These bacteria are typically highly resistant to treatment, and infections caused by CP-CRPA have higher mortality rates compared to non-CP-CRPA infections. In the U.S., only about 2% of clinical CRPA isolates carry carbapenemases (with higher rates in other countries), but outbreaks have been reported beyond individual healthcare facilities, including interstate outbreaks linked to medical tourism.
To effectively monitor and respond to CP-CRPA, the U.S. uses the Antimicrobial Resistance Laboratory Network (AR Lab Network) to collect CRPA isolates from clinical laboratories and test for carbapenem resistance mechanisms, supporting infection control and public health decisions. Since 2021, the Centers for Disease Control and Prevention (CDC) has prioritized whole-genome sequencing (WGS) of CP-CRPA isolates to better understand the molecular epidemiology of circulating strains and provide scientific evidence for local outbreak investigations.
In September 2022, during WGS analysis of a CP-CRPA outbreak in a post-acute care facility, researchers identified a strain with unique genetic characteristics—sequence type (ST) 1203, carrying the VIM variant blaVIM-80 and the GES variant blaGES-9. These variants had not previously been reported in U.S. isolates. Retrospective and prospective analyses of sequenced isolates from the AR Lab Network identified 30 isolates with similar genetic characteristics from five states, all from samples collected since May 2022. This article details the investigation into the source of this outbreak.
Preliminary Investigation
The investigation defined cases as U.S. patients from whom Pseudomonas aeruginosa ST1203 carrying the specific genes blaVIM-80 and blaGES-9 was first isolated from any specimen source between January 1, 2022, and May 15, 2023, and reported to the CDC.
In October 2022, the CDC issued a national alert requesting clinical laboratories to submit CRPA isolates that were non-susceptible to ceftazidime or cefepime to the AR Lab Network for testing of carbapenem resistance mechanisms and to report VIM-producing CRPA isolates to public health officials for further characterization.
The preliminary investigation included cases identified before November 2022. Researchers collected data on medical products used in the facilities where cases occurred and patient history, including any indwelling devices and medications. To hypothesize about the outbreak source, researchers conducted a 1:1 matched case-control study at a post-acute care facility. The control group consisted of patients who screened negative for CP-CRPA and had no clinical CRPA cultures, matched based on overlapping wards and admission dates. Information on medical products, procedures, and devices was collected from medical records.
Case Investigation
Data for all cases nationwide were collected using standardized case report forms, with interviews conducted with cases or their proxies when possible.
Given the limitations in tracking the specific brands of artificial tears used in healthcare facilities and the recall limitations for outpatient cases, researchers classified exposure to artificial tears using a tiered definition:
- Confirmed exposure: Patients or proxies recorded or reported use of the relevant brand of artificial tears in medical records.
- Probable exposure: (1) Patients received artificial tears in a healthcare facility that used both the relevant brand and other brands, but the specific brand used was not recorded; (2) Patients reported receiving a recall notice from a company or healthcare provider but could not recall the brand name, describing a product matching the relevant brand.
- Possible exposure: Patients received outpatient care at a facility that used the relevant brand during clinical treatment and/or provided the relevant brand to the patient, but the specific brand used was not recorded for each patient.
Traceback and Product Investigation
State and local health departments, along with the FDA, collected opened and unopened artificial tear products identified during epidemiologic investigations from patients’ homes, healthcare facilities, distribution centers, and pharmacies. The products were cultured for bacteria, and isolates were tested using WGS.
Preliminary Findings
The 1:1 matched case-control study revealed that exposure to sterile water was 15 times more likely in case patients than in controls (crude matched OR 15.0, 95% CI: 0.86–262.6; adjusted OR [aOR] not calculated). Exposure to artificial tears was 5 times more likely in case patients than in controls (crude matched OR 5.0, 95% CI: 1.1–22.8; aOR 4.7, 95% CI: 0.98–22.5, adjusted for mechanical ventilation).
Further analysis found that only two of the four facilities reported cases involving the use of inhaled sterile water, with different brands reported in each. Cases in all four facilities used artificial tears, with at least two facilities reporting the use of six different artificial tear brands. Given these findings and the presence of ocular infections in two clusters, researchers focused their investigation on artificial tears.
Case Investigation
As of May 15, 2023, 81 patients were identified across 18 states. The median time from specimen collection to case confirmation was 43 days (range: 14–310 days). The isolates exhibited extensive drug resistance, with CDC antimicrobial susceptibility results showing five isolates were sensitive only to cefiderocol. Overall, 54 (67%) patients had clinical cultures from the eye (n=21, 39%), urinary tract (n=15, 28%), respiratory tract (n=13, 24%), blood (n=3, 5%), wounds (n=1, 2%), and ears (n=1, 2%). Surveillance cultures from rectal swabs (n=26) and sputum (n=1) identified 27 patients (33%).
Patients’ clinical characteristics and outcomes varied based on the source of the cultures:
- Among 50 patients with outbreak strains from clinical cultures, 42 (84%) had infections recorded in the case reports, including eye infections (n=21, 50%; keratitis without endophthalmitis, 12/21, 57%; keratitis progressing to endophthalmitis, 6/21, 28%; panophthalmitis, 2/21, 9.5%; unspecified ocular infection, 1/21, 5%), urinary tract infections (n=8, 19%), respiratory infections (n=9, 21%), bacteremia (n=3, 7%), and otitis media with osteoradionecrosis (n=1, 2%).
- Of the 39 patients with clinical cultures and outcome information, 4 (10%) died within 30 days of specimen collection. Among 18 patients with eye infections, 4 (22%) underwent enucleation.
An additional 14 patients experienced vision loss in the affected eye within 30 days of culture collection: 3 (23%) had moderate vision impairment (best corrected visual acuity [BCVA] ≤20/70 and >20/200), and 11 (77%) became legally blind (BCVA ≤20/200 or limited to hand motion or light perception).
Among the 27 patients identified through surveillance cultures, 6 (22%) later had the outbreak strain detected in clinical cultures (bloodstream: n=2; respiratory: n=3; urine: n=1), with a median time from surveillance culture to clinical culture of 152 days (range: 22–252 days).
Overall, 61 out of 70 patients (87%) reported using artificial tears. Of the 56 patients who provided brand information, 43 (77%) reported using Brand A, an over-the-counter (OTC) artificial tear product manufactured by Company Y, including 22 confirmed, 14 probable, and 7 possible exposures. One additional patient reported using a different artificial tear product from Company Y, Brand B.
Among the 22 patients who either did not report using artificial tears or reported using other brands, 12 (55%) had temporal and/or spatial overlap with other cases in healthcare facilities using Brand A, suggesting possible transmission within the facility.
Traceback and Product Investigation
Brands A and B are preservative-free artificial tear products manufactured by Company Y at the same location in India. These products are sold in multi-dose bottles and distributed to U.S. consumers via the internet and to healthcare facilities through medical product distributors.
The CDC and FDA tested opened (n=17) and unopened (n=18) bottles of Brand A artificial tears; each batch tested included 1–149 bottles. Pseudomonas aeruginosa ST1203 carrying blaVIM-80 and blaGES-9 was detected in samples from six opened batches, two unopened batches, and composite samples from two additional unopened batches of Brand A artificial tears. Among seven unopened batches of Brand B, bacteria were isolated from five batches (71%) from two different products: artificial tears (4 batches) and artificial ointment (1 batch), though Pseudomonas aeruginosa was not detected.
Phylogenetic analysis of 108 isolates from patients (n=81), opened (n=21), and unopened (n=6) bottles of Brand A found 0–110 single nucleotide polymorphism (SNP) differences across a 6.5 Mb (91.8%) clone framework. Most isolates (n=105) had 0–13 SNP differences; two 0-SNP clusters included isolates from patients in multiple states and from opened and unopened Brand A products. The outbreak isolates were distinctly different from other Pseudomonas aeruginosa ST1203 isolates from the U.S. and other countries.
Molecular epidemiology identified Brand A artificial tears as the source of a CP-CRPA outbreak across multiple U.S. states, highlighting regulatory gaps in the oversight of OTC product importers in the U.S. Additionally, the outbreak strain’s resistance to most antimicrobials limited treatment options, increasing public health risks. Therefore, improved regulatory measures and public health response capabilities are needed to effectively contain future outbreaks and reduce the spread of resistant strains among broader populations.
