Bridging gaps in corneal ulcer management: Can photoactivated chromophore for infectious keratitis–corneal collagen cross-linking delay or replace therapeutic keratoplasty?

Abstract

The retrospective study by Edwar et al reinforces the role of therapeutic penetrating keratoplasty (PK) as a vital intervention in severe, treatment-resistant infectious keratitis. In advanced cases—often complicated by trauma, delayed presentation, and corneal perforation—PK restores globe integrity and provides limited visual recovery. However, its application is constrained by graft-related complications and donor shortages, particularly in low-resource settings. These limitations highlight the need for earlier, globe-sparing strategies to prevent progression and reduce surgical demand. Photoactivated chromophore for infectious keratitis–corneal collagen cross-linking (PACK-CXL) has emerged as a promising adjunct or alternative. With both antimicrobial and tissue-stabilizing effects, PACK-CXL may control infection and preserve corneal structure in earlier stages. A layered treatment framework that incorporates PACK-CXL as an initial intervention and reserves PK for refractory cases may help improve clinical outcomes. Further studies are needed to define their best use in practice.

Key Words: Infectious keratitis; Photoactivated chromophore for infectious keratitis-corneal collagen cross-linking; Corneal ulcer; Therapeutic keratoplasty; Cross-linking therapy

Core Tip: Infectious keratitis remains a major cause of corneal blindness, particularly in low-resource settings where delayed presentation and limited access to donor tissue challenge effective management. This editorial highlights the potential of photoactivated chromophore for infectious keratitis–corneal collagen cross-linking (PACK-CXL) as an adjunct or alternative to therapeutic penetrating keratoplasty (PK). With both antimicrobial and tissue-stabilizing properties, PACK-CXL offers a globe-sparing approach that may reduce the need for PK. Integrating PACK-CXL into a stratified treatment algorithm based on ulcer severity and etiology could improve outcomes and expand access to vision-saving care.

INTRODUCTION

Corneal blindness remains a significant global health challenge, particularly in developing regions where infectious keratitis is a leading cause of visual impairment[1]. According to the World Health Organization, corneal opacities, including those from infectious keratitis, account for approximately 4% of global blindness, disproportionately affecting low-resource regions where access to timely interventions is limited[2]. The retrospective study by Edwar et al[3] underscores the heavy burden of infectious corneal ulcers in Indonesia, where ocular trauma is the primary risk factor, and therapeutic penetrating keratoplasty (PK) is often a last resort to preserve globe integrity. Severe corneal ulcers, often precipitated by trauma or microbial infection, can progress to perforation, necessitating PK to restore ocular integrity[1]. While PK is effective in managing advanced cases, it is fraught with challenges, including high rates of postoperative complications such as graft rejection and secondary glaucoma, as well as limited donor tissue availability in resource-constrained settings. These barriers exacerbate visual morbidity, especially where delayed presentation and inadequate early interventions are common[4]. Additionally, PK reduces cost burden as it is now sparingly considered as a highly cost-effective method[5,6].

This sobering reality underscores the need for earlier, globe-sparing alternatives to halt disease progression before irreversible damage. Photoactivated chromophore for infectious keratitis–corneal collagen cross-linking (PACK-CXL) has emerged as a promising strategy[7]. By leveraging riboflavin-mediated photochemical reactions activated by ultraviolet-A (UVA) light, PACK-CXL provides antimicrobial and anti-collagenolytic effects, enhancing corneal biomechanical stability and impairing microbial viability[8]. Growing evidence supports its efficacy in bacterial and, to a lesser extent, in selected fungal cases, even as a standalone treatment modality for the former[9]. Its role is noteworthy in infections refractory to medical therapy due to underlying antibiotic resistance[10], especially in cases that pose significant clinical risk yet do not immediately warrant PK.

This editorial explores the role of PACK-CXL in a stratified treatment framework for infectious keratitis, evaluates its potential, and advocates for its integration into clinical algorithms based on disease severity and etiology.

PATHOPHYSIOLOGIC BASIS AND MECHANISM OF ACTION

As mentioned, PACK-CXL harnesses riboflavin, a photosensitizing chromophore, activated by UVA light to produce reactive oxygen species (ROS) that exert robust antimicrobial effects[1,11]. Richoz et al[12] demonstrated that this photochemical reaction eliminates over 90% of Pseudomonas aeruginosa and Staphylococcus aureus (S. aureus) compared to controls. The ROS disrupt microbial cell membranes and DNA, reducing viability across bacteria, fungi, and protozoa, with particularly strong efficacy against bacterial pathogens[11]. Simultaneously, PACK-CXL strengthens corneal stromal integrity by forming covalent bonds between collagen fibers, enhancing biomechanical stability and resistance to proteolytic enzymes that degrade corneal tissue[7]. This dual antimicrobial and anti-collagenolytic action decelerates or even halts microbial proliferation and corneal melting, preserving ocular structure in infectious keratitis[13].

Preclinical studies underscore the efficacy of PACK-CXL in controlled settings, with diverse protocols tailored to specific pathogens. Kowalska et al[11] reviewed 133 studies testing pathogens like Streptococcus pneumoniae, Aspergillus fumigatus, and Acanthamoeba species, using in vitro pathogen suspensions (e.g., in 12- or 96-well plates) and in vivo rabbit models of bacterial and fungal keratitis. These studies reported significant reductions in colony-forming units (CFUs), with endpoints like “bacterial elimination (CFU/Ml)” and “fungal growth inhibition” confirming efficacy in superficial infections[11]. For instance, Tal et al[14] found that PACK-CXL monotherapy in a rabbit model of S. aureus keratitis reduced corneal infiltrate size and scarring more effectively than antibiotic treatment, highlighting its potential as a standalone therapy for bacterial ulcers. However, inconsistent reporting of pathogen loads and antimicrobial resistance profiles often complicates cross-study comparisons. Tissue-stabilizing effects have been assessed through endpoints like resistance to enzymatic digestion, measured by corneal opacity or stromal integrity, reinforcing the role of PACK-CXL in preventing ulcer progression[11].

Despite its promise, the efficacy of PACK-CXL is constrained by UVA light penetration and riboflavin diffusion, typically limited to the anterior 200–300 µm of the cornea[14]. This makes it most effective for early-stage, superficial ulcers, particularly bacterial ones. Deeper stromal infections, such as those caused by Acanthamoeba or fungi like Fusarium, often located in the posterior cornea, may respond poorly due to inadequate penetration, and UVA exposure in these cases risks endothelial damage or inflammation[14]. Kowalska et al[11] noted significant heterogeneity in preclinical endpoints, with “corneal opacity/clouding” used in 16 of 29 in vivo records for infectious keratitis scoring, highlighting the need for standardized outcome measures to enhance translational potential.

This depth limitation is particularly consequential in fungal and protozoal keratitis, where the pathogens often invade the deeper stroma early in infection. Fungal species such as Fusarium and Aspergillus germinate within the corneal layers and express immunostimulatory β-glucans and α-mannans, which are recognized by pattern-recognition receptors like Dectin-1 and Dectin-2 on resident macrophages, initiating the Syk–CARD9–NF-κB inflammatory cascade. This leads to pronounced IL-1β production, neutrophil recruitment, and stromal tissue damage. Simultaneously, Toll-like receptors (e.g., TLR2 and TLR4) respond to fungal ligands and amplify this cascade, with upregulation of interleukin (IL)-6, tumor necrosis factor-alpha, and IL-17 further intensifying corneal inflammation[15]. However, due to the limited anterior penetration of PACK-CXL, ROS and collagen cross-linking effects fail to reach deep-seated fungal hyphae, reducing therapeutic efficacy[16]. A similar challenge exists in Acanthamoeba keratitis, where the protozoa secrete cytolytic proteases (e.g., MIP-133) and can encyst deep within the cornea. Although TLR4 and downstream MyD88/NF-κB signaling are activated, contributing to cytokine release and immune recruitment, the encysted forms resist both immune clearance and oxidative damage. Moreover, Acanthamoeba often coexists with bacterial endosymbionts, further complicating immune responses and treatment outcomes. In contrast, bacterial keratitis typically involves superficial colonization by pathogens such as S. aureus and Pseudomonas aeruginosa, which express lipoteichoic acid, peptidoglycan, or flagellin recognized by TLR2, TLR4, and TLR5[15]. These interactions initiate robust but more spatially confined immune responses and are more readily modulated by the anteriorly focused ROS-mediated microbicidal activity of PACK-CXL. Experimental models support this discrepancy: Cross-linked corneas exhibit localized inflammation, preserved architecture, and resistance to enzymatic degradation, while untreated controls display deep infiltration and melting[17]. Furthermore, recent data show that PACK-CXL inhibits interlamellar cell movement and alters stromal remodeling, further enhancing structural resistance in the anterior cornea[17]. Thus, microbial tropism, depth of invasion, and immune activation profiles collectively determine the differential efficacy of PACK-CXL across pathogen classes.

THE CASE FOR PACK-CXL INTEGRATION

Edwar et al[3] conducted a retrospective study of patients undergoing PK for infectious keratitis at a tertiary hospital in Jakarta from 2018 to 2020. Most patients (77.8%) had trauma-related corneal ulcers, predominantly central (89.9%) and large (> 6 mm in 41.4%), with 41.4% perforated at presentation. Microbial growth was detected in one-third of the cases, with Staphylococcus epidermidis emerging as the most frequently identified organism. Due to donor shortages, 58.6% of patients received periosteal grafts as a temporary measure before PK. Despite anatomical success, clinical outcomes were suboptimal. Average visual acuity showed a slight improvement, decreasing from 2.50 to 2.04 LogMAR; however, just 20 patients reached a visual acuity of 0.40 LogMAR or better. Adverse events were frequently observed, with secondary glaucoma occurring in 26.3% of cases, graft failure in 18.2%, and graft rejection in 13.1%, aligning with trends reported in international literature[13]. These results reflect advanced disease at presentation and inherent limitations of PK, such as postoperative complications and reliance on donor tissue[18]. Ozbek-Uzman et al[19] noted similar graft failure rates in infections not managed with adjunctive therapies like PACK-CXL. The frequent use of periosteal grafts highlights systemic donor tissue shortages, a challenge echoed globally[20]. Delayed intervention often exacerbates stromal degradation, increasing visual morbidity and reinforcing the need for earlier, conservative strategies to reduce PK dependence.

The findings by Edwar et al highlight that many patients undergo PK only after significant disease progression and failed medical therapy[3]. In contrast, PACK-CXL can be applied earlier, with demonstrated efficacy in bacterial and select fungal keratitis[9,10]. The metanalysis of 46 studies including four randomized controlled trials (RCTs) conducted by Ting et al showed that adjunctive PACK-CXL with standard antimicrobial therapy (SAT) significantly reduced the mean time to complete corneal healing by 7.44 days (95%CI: -10.71 to -4.16) compared to SAT alone, with notable benefits in bacterial keratitis[21]. For instance, Bamdad et al[22] reported faster healing in bacterial ulcers treated with PACK-CXL plus SAT[20], while Kasetsuwan et al[23] observed quicker resolution of stromal infiltrates at 7 days (-5.49 mm², 95%CI: -7.44 to -3.54) in bacterial and fungal cases. Non-RCT data further indicate an 84.8% complete healing rate for bacterial keratitis (78/92 cases) and 73.5% for fungal keratitis (36/49 cases), though only 1.1% and 6.1% of these cases, respectively, required additional amniotic membrane transplantation. Adjunctive PACK-CXL also lowers perforation risk and enhances visual outcomes by stabilizing corneal structure, as evidenced by the RCT performed by Said et al[24], which noted reduced infiltrate sizes and preserved corneal integrity. This strengthens corneal stiffness, halting enzymatic stromal melting, a critical factor in preventing ulcer progression[24]. However, efficacy in fungal infections is less consistent, with Uddaraju et al[25] reporting variable outcomes in fungal keratitis[25], and PACK-CXL is contraindicated in herpetic cases due to risks of viral reactivation[26].

Adjunctive PACK-CXL outperforms SAT alone by reducing re-epithelialization time, lowering perforation risk, and improving visual outcomes[24,27]. It also enhances corneal stiffness, halting enzymatic stromal melting[28]. Meta-analyses report healing rates above 85% in bacterial keratitis, though efficacy in fungal and protozoal infections is less consistent, and it is contraindicated in herpetic cases[29]. The use of accelerated PACK-CXL protocols at the slit lamp enables treatment in outpatient settings, making it a practical option for scale-up in areas with limited healthcare resources[12]. Delaying PK addresses the challenges of donor shortages and postoperative complications, making it a valuable tool for cases like those reported by Edwar et al[3].

A STRATIFIED TREATMENT ALGORITHM FOR CORNEAL ULCER MANAGEMENT

A stepwise treatment approach allows for the strategic application of PACK-CXL in infectious keratitis, adapting its use based on ulcer depth, clinical severity, and the underlying microbial cause. This targeted strategy aims to promote faster resolution while minimizing the need for PK.

Early-stage ulcers (superficial, bacterial, or culture-negative)

Initiate treatment: Administer intensive topical antibiotics guided by local antibiograms to target common bacterial pathogens, such as Staphylococcus or Pseudomonas spp., ensuring broad-spectrum coverage[19]. If no clinical improvement (e.g., reduced epithelial defect or infiltrate) is observed within 48–72 hours, apply PACK-CXL using accelerated protocols.

Rationale: Early intervention leverages the antimicrobial effects of PACK-CXL, driven by UV-A light and riboflavin-generated ROS, to halt progression and reduce stromal damage.

Moderate ulcers (stromal infiltration ≤ 300 µm, resistant bacterial)

Combined therapy: Integrate PACK-CXL with continued topical antibiotics to accelerate re-epithelialization and minimize perforation risk in cases with resistant bacterial strains or slow response to SAT. In a study by Achiron et al[27], patients with culture-confirmed bacterial keratitis who received PACK-CXL in combination with antibiotics showed significantly faster re-epithelialization (mean difference: 9.6 days, P = 0.004), improved visual acuity outcomes, and fewer clinic visits (mean reduction: 4.8 visits, P = 0.007) compared to those receiving antibiotics alone. No patients treated with PACK-CXL required tectonic keratoplasty, whereas one-third of those receiving antibiotics alone, ultimately did require this procedure[27]. Knyazer et al[30] supported these findings in a retrospective cohort study of 70 patients with moderate presumed bacterial keratitis. Those treated with PACK-CXL plus antibiotics re-epithelialized significantly faster (9.3 ± 6.0 days vs 16.0 ± 12.7 days, P = 0.01) and were less likely to undergo emergency keratoplasty (0% vs 19.4%, P = 0.006). Nearly half of the PACK-CXL group healed within 6 days compared to only 6.5% in the control group (P < 0.001)[30].

Monitoring: Regular slit-lamp examinations are critical to assess re-epithelialization and ensure no progression to deeper stromal involvement.

Advanced ulcers (deep stromal involvement > 300 µm, fungal, or protozoal)

The use of PACK-CXL in advanced infectious keratitis should be individualized, based on clinical judgment and risk-benefit considerations. Bamdad et al[22] reported partial success with PACK-CXL in refractory fungal keratitis, with epithelial healing averaging 14.3 days and stromal improvement in 22.5 days among responders, though over half required corneal transplantation[31]. Wei et al[32], in a randomized trial of 41 patients, demonstrated that CXL combined with antifungal therapy significantly reduced ulcer size, treatment duration, and medication burden compared to antifungal therapy alone. Said et al[24] highlighted the role of PACK-CXL in preventing complications in advanced keratitis with corneal melting: While healing times were comparable to controls, no perforations occurred in the CXL group vs three in the control group[23]. Conversely, Atia et al[33] and Price et al[34] advised caution in deep fungal ulcers or herpetic keratitis due to risks such as recurrence or perforation, noting that the cytotoxic depth of standard CXL may limit its safety in deep stromal infections[24,34]. If corneal integrity is compromised (e.g., impending perforation), proceed to PK or therapeutic keratoplasty, prioritizing anatomical stability over conservative measures.

Post-keratoplasty infections (infected corneal grafts or suture-related microbial keratitis)

In cases of graft infections unresponsive to antibiotics, PACK-CXL may serve as a beneficial adjunctive treatment. Ozbek-Uzman et al[19] retrospectively evaluated 40 eyes and found that combining PACK-CXL with medical therapy shortened healing time (median 23.5 days vs 34 days, P = 0.02) and was associated with a lower graft failure rate (27.8% vs 54.5%) compared to medical therapy alone[19]. Although some differences did not reach statistical significance, a trend toward improved epithelialization and infiltrate resolution was observed. PACK-CXL does not replace the need for immunosuppression, and careful follow-up remains essential to monitor graft rejection.

This adaptable framework guides clinicians on the optimal timing, settings, and indications for PACK-CXL, balancing efficacy with safety across infectious keratitis stages. Future refinements may incorporate biomarkers (e.g., cytokine profiles) or pathogen-specific protocols to further personalize treatment, potentially improving outcomes in fungal and protozoal cases.

Recommendations for standardized PACK-CXL protocols

To address the current lack of standardized protocols for PACK-CXL, the following evidence-based parameters are presented to optimize UVA fluence, riboflavin formulation, and treatment duration according to pathogen type and ulcer depth (Table 1). Fluences ranging from 7.2 to 15.0 J/cm² have demonstrated enhanced antimicrobial efficacy, particularly in deeper or opaque stromal ulcers, while maintaining endothelial safety thresholds[7,35-37]. Use of a 0.1% hydroxypropyl methylcellulose-based riboflavin solution facilitates uniform stromal saturation, while accelerated protocols (e.g., 30 mW/cm²) offer reduced procedural time without compromising ROS generation[38,39]. In cases of Acanthamoeba keratitis, a sequential dual-chromophore strategy employing both riboflavin/UVA and rose bengal/green light has shown superior activity against resistant cystic forms[35]. These protocol parameters aim to harmonize PACK-CXL applications in clinical settings, enhance reproducibility, and inform future multicenter evaluations.

Table 1 Proposed standardized photoactivated chromophore for infectious keratitis–corneal collagen cross-linking protocols by pathogen type and ulcer depth.

Pathogen type	UVA exposure (fluence, intensity)	Riboflavin concentration	Treatment duration	Rationale/references
Bacterial Keratitis	7.2–10.0 J/cm² at 30 mW/cm² (4–5.5 minutes)	0.1% iso-osmolar with HPMC, applied every 2 minutes for 15–20 minutes	20–25 minutes (soak + irradiation)	Higher fluences achieve 97.50%–99.90% bacterial killing ratios for Staphylococcus aureus and Pseudomonas aeruginosa. Accelerated delivery is oxygen-independent, effective for ulcers < 300 μm[37,38]
Fungal Keratitis	7.2–15.0 J/cm² at 30 mW/cm² (4–8.3 minutes)	0.1% iso-osmolar with HPMC, applied every 2 minutes for 15–20 minutes	25–30 minutes (soak + irradiation)	Deeper ulcers (33%–67% stroma) require higher fluences due to ultraviolet absorption in opaque corneas. 7.2 J/cm² eradicated resistant cases[40,41]
Mixed bacterial/fungal	10.0 J/cm² at 30 mW/cm² (5.5 minutes)	0.1% iso-osmolar with HPMC, applied every 2 minutes for 15–20 minutes	25 minutes (soak + irradiation)	Broad-spectrum efficacy with high fluence targets both pathogens, with proven safety[39]
AK	Sequential: Riboflavin/UVA (7.2 J/cm² at 30 mW/cm², 4 minutes) + Rose bengal/green light (0.1–0.2 J/cm² at 532 nm, 15–30 second)	0.1% riboflavin (15–20 minutes soak) + 0.1% rose bengal (10 minutes soak)	35–45 minutes (dual soak + irradiation)	Dual-chromophore approach targets resistant AK cysts, leveraging complementary absorption spectra[42]
Ulcer depth adjustment	< 100 μm: 7.2 J/cm²; 100–300 μm: 10.0–15.0 J/cm²	As above	As above	Adjust fluence based on AS-OCT-measured depth to ensure ROS penetration in opaque ulcers[35]

AK: Acanthamoeba keratitis; AS-OCT: Anterior segment optical coherence tomography; ROS: Reactive oxygen species; HPMC: Hydroxypropyl methylcellulose; UVA: Ultraviolet-A.

Cost considerations of PK and PACK-CXL

As mentioned, PK is a resource-intensive intervention associated with substantial direct and indirect expenditures. Direct costs typically include surgical fees, anesthesia, hospital admission, donor tissue procurement, and the need for extensive postoperative care. Indirect costs further burden patients and healthcare systems, encompassing travel expenses, prolonged recovery periods, and complications such as graft failure or rejection[20]. In high-income countries, the average cost of corneal transplantation ranges from approximately $13000 to over $32500, factoring in the surgeon’s fees, operating theater time, and perioperative services[40-43]. In low-and middle-income countries, although nominal surgical costs are lower, the relative economic burden is often significantly greater[6]. This is largely due to limited surgical infrastructure, out-of-pocket payment models, and constrained healthcare budgets. Moreover, the chronic global shortage of donor corneal tissue further restricts access and delays treatment in many regions[20].

In contrast, PACK-CXL presents a more affordable and scalable therapeutic option, particularly in the early or moderate stages of infectious keratitis. PACK-CXL can be administered in outpatient settings and requires minimal consumables. Technological advances, such as slit-lamp mounted or portable PACK-CXL devices, have enabled its application in remote or resource-limited areas, thereby reducing dependence on hospital-based infrastructure[35]. As a single-session procedure, PACK-CXL also reduces the need for repeated clinical visits, minimizing travel-related expenses and loss of productivity—factors especially relevant in rural populations[44]. Furthermore, by effectively controlling infection and stabilizing the cornea early in the disease course, PACK-CXL may prevent progression to corneal perforation and thus obviate the need for PK. This preventive potential contributes to a lower long-term economic burden for both patients and health systems[22].

Although direct head-to-head cost-effectiveness analyses between PACK-CXL and PK remain limited, current evidence suggests notable differences[35]. PACK-CXL has been associated with shortened healing times, decreased dependency on pharmacologic therapy, and a lower incidence of severe complications—all of which translate into reduced aggregate costs[35]. Economic modeling from Canada evaluating corneal collagen cross-linking in keratoconus management demonstrated favorable cost-utility outcomes for CXL, with an incremental cost-effectiveness ratio of CAD 9090/QALY gained when compared with conventional management involving delayed PK. This analysis employed conservative assumptions that maximized the projected cost and risk profile of CXL, yet still found it to be cost-effective well below established Canadian and United States thresholds. While the indication in keratoconus differs from infectious keratitis, the economic rationale supports broader application of cross-linking in scenarios where it can delay or prevent the need for transplantation, particularly in resource-limited settings[43].

Limitations and practical considerations

The efficacy of PACK-CXL is pathogen-dependent, with robust evidence for bacterial keratitis but variable results in fungal, Acanthamoeba, and herpetic infections[29,35]. Deep stromal involvement reduces effectiveness due to limited UVA penetration, and aggressive enzymatic destruction may eventually necessitate PK[34]. Standardized protocols for different pathogens are lacking, and treatment response criteria vary across studies[44]. Logistical barriers, including device access and training, persist in low-resource settings. Despite improvements in treatment accessibility through slit-lamp mounted and portable PACK-CXL devices, widespread adoption remains contingent on sufficient resource availability and supportive infrastructure[7]. In this context, the potentiality of mobile eye care units, as demonstrated by Abdulhussein et al[45] for other ocular disease entities, such as age related macular disease or glaucoma, provides a compelling model for outreach delivery of PACK-CXL. Such units could probably be further equipped with portable cross-linking devices that would be able to be slit-lamp mounted. This model could not only bring care closer to remote populations, but also reduce the burden on tertiary centers and minimize delay in initiating appropriate and targeted therapy[46]. Clinicians also hesitate to omit antibiotics, favoring adjunctive use to address resistance and ulcer stage variability[47].

CONCLUSION

The study by Edwar et al[3] highlights the challenges of managing severe infectious keratitis, with high complication rates and limited visual gains underscoring the need for earlier interventions. PACK-CXL offers a practical, antimicrobial, and tissue-stabilizing alternative to delay or avoid PK. The ability to perform PACK-CXL in outpatient settings, along with its proven benefit in bacterial keratitis, supports its potential for broader use, especially in low-resource environments. Nonetheless, limitations persist, such as variable effectiveness depending on the pathogen, lack of standardized treatment protocols, and unequal access. While highly effective against bacterial infections, its role is limited in deep fungal or protozoal ulcers and is not recommended in herpetic keratitis. Timely application, appropriate ulcer depth, and adjunctive antibiotics are critical for success.

Advancing the integration of PACK-CXL into corneal ulcer management requires a multifaceted approach. Developing pathogen-specific protocols through high-quality RCT is essential to optimize treatment outcomes across bacterial, fungal, and protozoal etiologies. Refining patient selection criteria, particularly through imaging modalities like anterior segment optical coherence tomography, will enhance precision in assessing ulcer depth and ensuring effective cross-linking penetration. Improving the portability and affordability of PACK-CXL devices is critical to address the high burden of keratitis in resource-limited regions, where access to advanced ophthalmic care remains a challenge. Expanding clinical training programs for ophthalmologists will facilitate broader adoption of PACK-CXL techniques and improve decision-making in diverse clinical scenarios. Long-term studies are needed to evaluate recurrence rates, endothelial safety, and the impact on graft survival, providing a comprehensive understanding of the role of PACK-CXL in both primary and post-keratoplasty settings. These efforts will collectively transition PACK-CXL from a promising adjunct to a cornerstone of infectious keratitis management.