In November 2022, the California Department of Public Health reported that the United States (US) Centers for Disease Control and Prevention (CDC) was requesting information regarding cases via their Epidemic Information Exchange network [1]. On 20-Jan-2023, the American Association of Ophthalmology issued a statement advising that the CDC was investigating the outbreak [2].

Los Angeles County, California, US

The source of the VIM-GES-CRPA outbreak is suspected to be ‘Ezricare Artificial Tears’ eyedrops [4]. These eyedrops (marketed also under the brand name ‘Delsam Pharma’), are an over-the-counter (OTC) preservative-free eyedrop, manufactured in Chennai, India, by Global Pharma Healthcare, and sold in popular stores including Walmart and Amazon [5,6]. Laboratory testing by the CDC of opened eyedrop bottles identified the presence of VIM-GES-CRPA matching the outbreak strain, with ongoing testing to determine whether bottles were contaminated during manufacturing or after opening [4]. A nationwide recall of the eyedrops was issued on 2-Feb-2023 [7]. On 21-Feb-2023, another OTC product, ‘Delsam Pharma’s Artificial Eye Ointment’ was also recalled due to potential contamination [7].

The earliest date of specimen collection was 17-May-2022 [8]. The delay between outbreak onset and first official report may have been due to the sporadic, widespread nature of cases.

Ongoing

As of 14-Mar-2023, 16 US states have reported cases: California, Colorado, Connecticut, Florida, Illinois, North Carolina, New Jersey, New Mexico, New York, Nevada, Pennsylvania, South Dakota, Texas, Utah, Washington, Wisconsin [4].

68 cases as of 14-Mar-2023 [4]

P. aeruginosa eye infections can cause [9]:

• Discomfort, pain
• Redness
• Mucopurulent discharge
• Photophobia
• Conjunctival, eyelid or corneal oedema
• Reduced visual acuity

• Fever
• Lymphadenopathy
• Joint pain
• Systemic inflammation
• Maculopapular pruritic rash
• Diarrhoea
• Wound/burn infections (local tenderness, swelling, purulent discharge)
• Lung infections (pneumonia, severe coughing, congestion)
• Ear infections (otalgia, otorrhea)

P. aeruginosa is an opportunistic pathogen commonly found in the environment, including in soil and water [11]. Nosocomial infections are common, with P. aeruginosa causing an estimated 7.1-7.3% of healthcare-associated infections and 23% of ICU-acquired infections [12]. P. aeruginosa causes 10% of all ventilator-associated pneumonia and catheter-associated urinary tract infections (UTIs) [12]. Transmission may occur via direct contact with contaminated hands, surfaces, or equipment, or ingestion of contaminated water or food, particularly raw vegetables [13,14]. Aerosol transmission is also possible [11].

Ocular infections may cause systematic effects, as bacteria can enter the nasal cavity via the tear ducts, and then disseminate to the lungs and other sites via the bloodstream [15].

Limited demographic information is available. However, it is known that twenty-five cases occurred across five nursing homes in Connecticut, and six cases occurred in Davis County, Utah [16]. Three cases have died, including a man from Washington [4,16]. Demographic information is lacking for the remaining cases.

During the current outbreak, the case fatality rate is 4.41% [4].

P. aeruginosa eye infections can lead rapidly to permanent vision loss or blindness, due to scarring following corneal ulceration or severe inflammation [17,18]. P. aeruginosa keratitis is challenging to manage, with poor prognosis if untreated [17]. Progression to endophthalmitis is rare, but visual outcomes are very poor, potentially requiring evisceration or enucleation [18,19]. During the current outbreak, at least eight cases experienced permanent vision loss, and four cases required enucleation [16].

Systemic P. aeruginosa infections can cause respiratory complications, UTIs, endocarditis, meningitis, septicaemia, and death [20]. A 30-day mortality rate of 33.8-36.7% has been reported for patients with P. aeruginosa bacteraemia [21,22].

Several measures assist with preventing P. aeruginosa infections and reducing nosocomial transmission risk [13,23]:

• Maintaining hand hygiene
• Environmental cleaning
• Sterilising shared medical equipment
• Ensuring water quality and cleanliness of water reservoirs
• Performing quality assurance of medical products

P. aeruginosa is often resistant to many antibiotics, including carbapenems [3]. Some carbapenem-resistant strains produce carbapenemases, with VIM and GES being respectively the first and second most common P. aeruginosa carbapenemases globally [24,25].

Due to this widespread carbapenem resistance, combination therapy is commonly used to increase treatment efficacy [26]. However, during this outbreak, susceptibility testing indicated that VIM-GES-CRPA isolates were resistant to many antimicrobials and combination drugs, though three isolates demonstrated susceptibility to cefiderocol [4]. Cefiderocol is a cephalosporin that overcomes Gram-negative resistance mechanisms by acting as a siderophore to transport across the outer cell membrane, after which it inhibits cell wall synthesis [27].

This is the first VIM-GES-CRPA outbreak reported in the US and globally; no other confirmed or suspected outbreaks have been documented. However, several genomic analysis studies have identified the co-expression of VIM and GES genes, of differing variants, in isolated cases in several countries [28-33] (Table 1).

This outbreak is the first detection of a CRPA strain harbouring both VIM and GES genes in the US. Genomic analyses demonstrate that such a combination is rare; one review study in the Arab region found that co-expression of either VIM or GES genes often occurs with genes for oxacillinases (OXA) instead [36]. The large number of cases is therefore alarming, as carbapenemase-producing strains are still uncommon in the US (though their prevalence may be under-reported) [24]. The association of cases with eyedrops, rather than nosocomial infection in healthcare settings, is also unusual. The lack of an obvious common transmission event could have hindered investigation efforts, as cases occurred over several months, across different locations, and with various clinical presentations [16]. This may explain the delay in official reporting and subsequent recall initiation, by which time 55 cases and one death had already occurred [7]. This outbreak also demonstrates the difficulty in identifying and linking cases linked to OTC medical products, which is concerning given the virulence of VIM-GES-CRPA.

Antimicrobial resistance (AMR) is growing rapidly worldwide [37], with alarming healthcare implications. AMR occurs when pathogens adapt to no longer respond to previously effective medications [38]. This causes serious illnesses that require lengthier, costlier and more intensive care to treat, with vulnerable populations (e.g. the very young, the elderly) especially likely to experience increased morbidity and mortality [39,40]. The emergence of increasingly resistant pathogens, such as dual- (or even multi-) carbapenemase-producing bacteria, like VIM-GES-CRPA during the current outbreak, is therefore extremely concerning.

Unfortunately, there is limited data regarding global VIM-GES-CRPA prevalence, and although isolated confirmed cases have occurred in several countries, there is likely underreporting [28-33]. Ezricare eyedrops were marketed in the US [41], however, the outbreak source could be certain eyedrop ingredients or manufacturing equipment. Therefore, additional VIM-GES-CRPA cases could occur elsewhere, as Global Pharma Healthcare exports to over 30 countries [42].

Increased surveillance is thus urgently needed, yet is often ignored and under-resourced [43]. The current VIM-GES-CRPA outbreak highlights the challenges of identifying novel strains of resistant pathogens, linking cases, and pinpointing outbreak sources. There is therefore a need for surveillance systems that can identify novel or concerning resistant pathogens, gather data on antimicrobial use, provide early disease warnings, and support outbreak management. Efforts to establish a global AMR surveillance system have only occurred relatively recently, with the World Health Organization (WHO) launching the Global Antimicrobial Resistance and Use Surveillance System (GLASS) in 2015 [44]. By the end of 2021, 109 countries and two territories and areas were enrolled in GLASS for AMR surveillance, with only 33 of these also involved in antimicrobial consumption surveillance [44]. Thus, greater efforts to encourage enrolment by nations and expand both antimicrobial resistance and consumption surveillance are required. Surveillance is also an important biosecurity consideration, as knowledge of AMR mechanisms could be used in genetic engineering of pathogens for biocrime and bioterrorism [45]. Genomic and disease surveillance are therefore critical for monitoring AMR and ensuring public health.

Improving laboratory diagnostic capacity is another crucial aspect of antimicrobial stewardship and AMR surveillance. Timely, accurate diagnoses help guide clinical decision-making and optimise the use of existing medications [43]. Whole-genome sequencing was used in the current outbreak to show that cases were closely related, with 37 linked to four healthcare facilities, and assisted with epidemiological investigations [4]. However, not all laboratories have sufficient resources for susceptibility testing or whole-genome sequencing [46], particularly in lower-resource settings. Thus, some cases during the current VIM-GES-CRPA outbreak may not have been captured by laboratory surveillance. Efforts to combat AMR must therefore improve access to confirmatory testing services and ensure appropriate testing policies and resources.

Urgent action is needed to address AMR. This includes expanding disease surveillance, enhancing rapid pathogen detection and identification measures, and improving guidance on clinical prevention and management. This outbreak should provide yet another warning for public health authorities and governments that cross-disciplinary, co-ordinated efforts are needed to bolster AMR surveillance globally and address the multi-faceted causes that have contributed to its spread.

• How can public awareness of AMR be improved within communities and industries?
• How can genomic and disease surveillance systems be used more effectively in conjunction to provide early warning of AMR in pathogens and cases of disease?
• How can laboratory testing be strengthened to ensure rapid pathogen identification with efficient, equitable use of resources?
• How might laboratory testing referral pathways be strengthened to encourage, and improve access to, confirmatory testing?
• How can countries avoid importing novel strains of resistant pathogens (e.g. in medical products, food, livestock, etc.)?
• How can the identification and linkage of cases during outbreaks associated with OTC products be improved?
• Should the purchase and use of OTC products be regulated more stringently? How?
• Are current quality assurance measures for OTC products sufficient? How might they be strengthened?