The use of Aprokam® (cefuroxime sodium) in the management of post-operative infectious risk in pediatric cataract surgery

doi:10.21203/rs.3.rs-4199069/v1

Purpose: to describe the safety and efficacy of the intracameral use of cefuroxime sodium (Aprokam®) during congenital cataract surgery to prevent endophthalmitis.

Design: monocentric, prospective, observational pilot study.

Methods:

Setting: San Giuseppe Hospital, University of Milan, Milan, Italy.

Study population: pediatric patients with a mean age of 21.4 ± 40.52 weeks with congenital cataracts. 65 eyes from 65 patients, i.e. only one eye for each patient was included in the study. At the end of the surgery, patients received the administration of intracameral Aprokam. The efficacy endpoint was assessed by excluding postoperative intra-ocular infections, while the safety endpoint was assessed by recording vital signs (body temperature, heart rate, blood pressure, respiratory rate) and local effects (corneal edema, toxic anterior segment syndrome, presence of cells or fibrin formation in anterior chamber, intraocular pressure, conjunctival hyperemia) after the administration of the substance.

Results: Aprokam intracameral administration at the end of the cataract surgery prevented the occurrence of intraocular infection in all of our patients. Among the analyzed systemic parameters, breath frequency was the only one showing a statistically significant increase after the drug delivery (∆(post-pre) 0.4 breaths/minute ± 1.74; p = 0.022). Regarding the local adverse effects, a statistically significant increase of intraocular pressure has been detected from the first week (∆7days-1day: 0.9 mmHg ± 2.28, p = 0.042), and remained constantly elevated in the first month. The presence of conjunctival hyperemia noticed in the first week after surgery showed a significant decrease over time, with a statistically significant reduction after one month (8 cases vs 0, p = 0.009).

Conclusions: intracameral administration of Aprokam in pediatric cataract surgery, for the prevention of post-operative endophthalmitis, has been demonstrated to be safe and effective. It may be considered suitable for an optimal post-operative management of intra-ocular post-operative infections in congenital cataract surgery.

Pediatric cataract stands as one of the leading causes of childhood blindness globally. Congenital cataract affects approximately 3 out of every 10,000 newborns, with two-thirds of cases being bilateral and responsible for 7.4–15.3% of pediatric blindness instances [1, 2].

Surgical intervention for congenital cataract involves phacoemulsification, with or without intraocular lens (IOL) implantation, constituting a highly intricate procedure demanding meticulous postoperative monitoring to ensure its success and minimize the risk of complications [3]. Potential complications include aphakic glaucoma, amblyopia, retinal detachment, intraocular lens displacement, and endophthalmitis, with the latter being deemed a medical emergency. Effective prevention methods for endophthalmitis have been in practice for several years, primarily employing antibiotic drugs [4]. In recent times, the incidence of endophthalmitis has substantially decreased in regions where intracameral injection has been adopted as a standard post-cataract prophylaxis method.

Cefuroxime sodium (Aprokam®), an antibiotic belonging to the class of beta-lactam antibiotics (second generation cephalosporin), exhibits potent efficacy against Gram-negative bacteria commonly associated with postoperative endophthalmitis. Aprokam, approved by the European Medicines Agency (EMA), is a commercial product containing 50 mg of cefuroxime powder for solution, designed for intracameral injection following cataract surgery [5].

To assess the efficacy of intracameral cefuroxime in preventing endophthalmitis, the European Society of Cataract and Refractive Surgeons conducted a comprehensive randomized clinical trial across nine European countries. Published in 2007, the results unequivocally demonstrated significant clinical benefits. Patients receiving an intracameral injection of 1 mg of cefuroxime at the conclusion of cataract surgery experienced a five-fold reduction in postoperative endophthalmitis incidence [6].

Despite its inclusion in guidelines for adult patients, intracameral cefuroxime administration has yet to find a place in guidelines for pediatric patients. This study aims to establish the safety and efficacy of intracameral cefuroxime administration in pediatric cases.

This prospective, observational study was conducted at San Giuseppe Hospital, Milan, with approval from the local Medical Ethics Committees. Written informed consent was obtained from the parent or legal guardian of each child participating in the research after explaining the nature and purpose of the study. We included patients afflicted by visually significant pediatric cataracts. In cases of bilateral cataracts, only the first eye undergoing surgery was included in the study. Exclusion criteria comprised clinically significant cardiovascular, respiratory, gastrointestinal, hematological, endocrine, or neurological conditions that could escalate surgical risks, presence of microphthalmos, persistent fetal vasculature, post-traumatic cataract, history of previous ocular surgery, concurrent ocular medication that might influence the study results, and reported hypersensitivity to any of the active substances used in the study.

Surgery was performed by a specialized surgeon (P.N.). At the end of the procedure, each patient received a single intracameral injection of 0.1 ml of Aprokam [7].

The efficacy of the drug was assessed by monitoring potential signs of ocular infection (such as cells or fibrin formation in the anterior chamber, hypopyon, corneal or conjunctival edema, conjunctival injection, and fever) on postoperative days 1, 7, and 30. Safety was evaluated by recording vital signs (body temperature, heart rate, blood pressure, and respiratory rate) both before and after substance injection. Local effects, including corneal edema, toxic anterior segment syndrome, cell or fibrin formation in the anterior chamber, and intraocular pressure, were also assessed on postoperative days 1, 7, and 30. Additionally, conjunctival hyperemia was graded on a scale of 0 to 2: 0 for absence of hyperemia, 1 for mild hyperemia of conjunctival vessels, and 2 for diffuse hyperemia of conjunctival vessels.

The efficacy endpoint was defined as the attainment of adequate prophylaxis against intraocular infections. The safety endpoint encompassed the stability and tolerability of systemic and local effects following drug administration.

STATISTICS

Continuous variables were summarized as mean with standard deviation and median with range; categorical data were expressed with frequency and percentage.

A Wilcoxon Signed Rank Test was performed to determine if there was a statistically significant difference in continuous variables before and after the surgery.

Cochran's Q-test and post-hoc McNemar test for pairwise comparisons were applied to determine whether the difference in the proportions of the presence of each local effect changed significantly over time. Friedman's test was employed to calculate differences in continuous variables over time, and Wilcoxon signed-rank tests were used for post-hoc tests with an adjusted alpha level. A p value of < 0.05 was taken to indicate statistical significance.

Sixty-five eyes of 65 patients with visually significant pediatric cataracts were enrolled. Mean age at the time of surgery was 21.4 ± 40.52 weeks.

As for safety endopoints (table 1), only respiratory rate showed a statistically significant increase pre and post injection (∆(post-pre) 0.4 ± 1.74; p = 0.022).

Table 1: Systemic effects of cefuroxime.
	Pre injection	Post injection	∆_(post-pre)	p*
Heart rate	133.2 ± 13.42 133.0 (100.0 - 158.0)	133.2 ± 13.32 134.0 (100.0 - 161.0)	0.0 ± 2.58 0.0 (-6.0 - 8.0)	0.77
Systolic blood pressure	95.7 ± 5.04 94.0 (88.0 - 111.0)	93.3 ± 9.70 94.0 (58.0 - 106.0)	-2.4 ± 8.78 0.0 (-38.0 - 3.0)	0.09
Diastolic blood pressure	59.5 ± 4.24 58.0 (52.0 - 70.0)	59.5 ± 4.32 58.0 (52.0 - 71.0)	0.0 ± 1.17 0.0 (-3.0 - 3.0)	0.99
Respiratory rate	40.3 ± 5.34 41.0 (27.0 - 52.0)	40.7 ± 5.36 41.0 (28.0 - 54.0)	0.4 ± 1.74 1.0 (-5.0 - 8.0)	0.022
Body temperature	36.8 ± 0.52 36.6 (36.2 - 37.7)	36.9 ± 0.54 36.6 (36.2 - 37.7)	.03 ±.27 0.0 (-1.1 - 1.1)	0.46
*Wilcoxon signed rank test

Regarding the local effects of Aprokam (table 2), a statistically significant increase in intraocular pressure in the first month after surgery was observed (p = 0.002). A pairwise comparison showed that the increase was already detected in the first week, with significant differences between day 1 and day 7 (∆7days-1day: 0.9 ± 2.28, p = 0.042), while between the first week and the first month the trend remained constant (∆1 month-7days: -0.1± 1.20, p = 0.99).

At 1 month, the difference already found in the first week was confirmed (∆1 month-1day: 0.8 ± 1.83, p = 0.022).

The presence of conjunctival hyperemia showed a statistically significant decrease over time (p = 0.012). The reduction was statistically significant only one month after the surgery compared to day 1 (8 cases vs 0, p = 0.009).

Table 2: Local effects of cefuroxime.


		One day post surgery	Seven days post surgery	One month post surgery	∆_(post-pre)	p*
Corneal edema	Absent	63 (96.9)	63 (96.9)	65 (100.0)		0.14
Corneal edema	Present	2 (3.1)	2 (3.1)	0 (0.0)		0.14
Toxic anterior segment Syndrome	Absent	65 (100.0)	63 (96.9)	65 (100.0)		0.14
Toxic anterior segment Syndrome	Present	0 (0.0)	2 (3.1)	0 (0.0)		0.14
Cell or fibrin formation in anterior chamber	Absent	65 (100.0)	63 (96.9)	65 (100.0)		0.14
Cell or fibrin formation in anterior chamber	Present	0 (0.0)	2 (3.1)	0 (0.0)		0.14
Intraocular pressure		11.3 ± 3.03 10.0 (6.0 - 18.0)	12.2 ± 3.86 11.0 (7.0 - 22.0)	12.1 ± 3.61 12.0 (7.0 - 20.0)	∆_(7days-1day): 0.9 ± 2.28 1.0 (-2.0 – 8-0) ∆_{(1 month-1day)}: 0.8 ± 1.83 0.0 (-3.0 – 6.0) ∆_{(1 month-7days)}: -0.1± 1.20 0.0 (-4.0 – 2.0)	0.002 Pairwise comparison: 1 day vs 7 days: 0.042 1 day vs 1 month: 0.022 7 days vs 1 month: 0.99
Macular edema	Absent	65 (100.0)	64 (98.5)	65 (100.0)		0.37
Macular edema	Present	0 (0.0)	1 (1.5)	0 (0.0)		0.37
Conjunctival hyperemia	Absent	57 (87.7)	62 (95.4)	65 (100.0)		0.012 Pairwise comparison: 1 day vs 7 days: 0.20 1 day vs 1 month: 0.009 7 days vs 1 month: 0.80
Conjunctival hyperemia	Present	8 (12.3)	3 (4.6)	0 (0.0)
* Friedman test/Cochran’s Q test

In our prospective observational study, we investigated the efficacy and safety of intracameral administration of Aprokam for pediatric cataract surgery, a practice that is still considered off-label for children. In pediatric patients, endophthalmitis more commonly presents with symptoms such as photophobia (50%) and pain (40.9%). The most prevalent clinical signs include conjunctival injection (36.4%) and hypopion (31.8%), although eyelid edema and fever have also been reported. Pain is rarely reported by pediatric patients, making diagnosis challenging and necessitating close post-operative monitoring [8].

In a study aimed at defining the incidence of post-operative endophthalmitis in pediatric cataract surgery, the overall rate was 0.376% out of a total of 2,390 surgeries. In 8 out of 9 cases, the mean duration between surgery and diagnosis was 2.5 days [9].

A recent survey was conducted to identify risk factors, diagnosis, and treatment of post-surgical endophthalmitis in pediatric cataracts. Most cases of endophthalmitis occurred in patients aged 2 to 4 years, with intraocular lens implantation in 59.1% of cases. The most commonly cultured organism was Staphylococcus Aureus (31.8%). Treatment typically involved a combination of intravitreal, systemic, and topical antibiotics (36.4%). The study concluded that endophthalmitis, though multifactorial and fortunately infrequent, can be limited through proper sterilization techniques, favorable environmental conditions, and the use of intracameral and subconjunctival antibiotics. Early postoperative evaluation, follow-up visits, and a high index of suspicion are crucial for timely recognition and treatment [10].

Additionally, suture management is vital as it represents a potential entry point for bacteria. Insufficient postoperative wound care significantly increases the risk of postoperative infection [11].

Our study achieved the efficacy endpoint—adequate prophylaxis to prevent infections—in all surgical procedures. Concerning safety, no side effects have been reported in the literature for intraocular cefuroxime injection, except for a very rare (< 1/10,000) anaphylactic reaction. Overdose cases have been described in the literature after incorrect dilution and unauthorized use of cefuroxime intended for systemic administration. However, when administered correctly, the drug is free from these risks.

In a recent study, complications arising from cefuroxime injection during phacoemulsification surgery included toxic anterior segment syndrome, serous retinal detachment with macular edema, retinal hemorrhagic infarction, and anaphylactic reactions. The first two complications can occur with both correct and incorrect dosages. Retinal hemorrhagic infarction was observed in cases with more than 50 mg of intracameral antibiotic injected into the anterior chamber. Anaphylactic shock was only reported in patients allergic to penicillin [12].

In our study, intracameral injection of cefuroxime was well tolerated by the patients. Vital parameters such as systolic and diastolic blood pressure, heart rate, and temperature remained stable before and after administration. Only respiratory rate showed a statistically significant increase between pre- and post-injection. These results align with previous clinical studies on intracameral antibiotics in adults, where no systemic adverse effects were reported.

In summary, prophylaxis with intracameral injection of cefuroxime (Aprokam), in conjunction with the management of other risk factors and proper asepsis during the procedure, contributes significantly to reducing the risk of post-operative endophthalmitis. While this is well-established for adults, in the case of pediatric patients, due to limited literature in this area, the optimal dose of Aprokam has not been firmly established. Pediatric surgeons have been using the drug off-label for many years in phacoemulsification procedures. Given the scarcity of resources available for conducting trials in children, it is imperative to prioritize efforts on safety and efficacy for agents used in this vulnerable population with high prevalence.

Our study demonstrates that intracameral injection of Aprokam during cataract surgery in children aged from 4 weeks to nearly 4 years old is safe and effective for the prophylaxis of ocular infections.

ACKNOWLEDGEMENT

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.

a. Funding/support: the authors did not receive any financial support from any public or private sources.

b. Financial disclosures: the authors have no financial conflict of interest in a product, method or material described herein.

c. Contributions of Authors:

P.N. contributed to the study conception and design. Material preparation, data collection, and analysis were performed by A.L. The first draft of the manuscript was written by A.D., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

All authors attest that they meet the current ICMJE criteria for authorship

Author Contribution

P.N. conceived the projectA.L. wrote the main manuscript textI.S. provided for the statistical analysisF.R. contributed to the revision of the textF.P. supervised the implementation of the project and revised the text

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No competing interests reported.

The use of Aprokam® (cefuroxime sodium) in the management of post-operative infectious risk in pediatric cataract surgery

Status:

Version 1

Abstract

INTRODUCTION

METHODS

STATISTICS

RESULTS

DISCUSSION

Declarations

Author Contribution

References

Additional Declarations

Status:

Version 1