More Antisepsis, Less Antibiotics Whenever Possible

Abstract

Increasing bacterial resistance to antibiotics has recently become an important medical challenge. In ophthalmology antibiotics are widely used for treatment and prophylaxis of ocular infections. In many cases antiseptics may be a valuable adjunct and sometimes even an alternative to antibiotics for the prevention and treatment of infections, reducing the overuse of antibiotics. This review aims to highlight the available literature on the subject of antibiotic resistance in ophthalmology. Full understanding of this growing problem is necessary for tailoring effective pre-, intra-, and postoperative management to improve antibiotic stewardship programs.

The discovery of penicillin in 1928 was one of the most significant medical achievements of the 20^th century. It has changed the course of therapeutic medicine. Antibiotics drastically reduced mortality from bacterial diseases and their prevalence. For many years they were thought to be exclusively advantageous. Ophthalmology has also benefited from the use of antibiotics, both in the treatment and prophylaxis of ocular infections. However, recent research demonstrates the negative effects of the misuse and overuse of antibiotics. The World Economic Forum report on global risks recently concluded that the greatest risk to human health is antibiotic-resistant bacteria.¹ Increasing antibiotic bacterial resistance may result from exposing the environment to massive quantities of antibiotics. Huge amounts of antibiotics are administered to animals every year to promote the growth of livestock. The widespread use of antibiotics empirically in general medicine also has a significant influence in the emergence of resistant bacterial strains in patients. In ophthalmology this problem seems not to be dominant; however, antibiotic use involves caution and awareness of threats. Ongoing surveillance programs in the United States amalgamate data from the country and worldwide: Ocular Tracking Resistance in the U.S. Today (TRUST)² and Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR)³ provide reports showing high levels of resistance, including multidrug resistance in ophthalmology.⁴ Bacterial resistance may be promoted with using incorrect, too low doses, and too short duration of antimicrobial treatment. Antibiotics should never be used without explicit indications. For this reason, it is necessary to revise a number of procedures (both in prophylaxis and in treatment) in which antibiotics have been routinely used.

CATARACT SURGERY

For many years antibiotics have been commonly used in ocular surgery both pre- and postoperatively. Recently they are also increasingly used intraoperatively (intracameral administration). Results of the European Society of Cataract and Refractive Surgeons (ESCRS) study published in 2007 demonstrated several-fold reduction in postoperative endophthalmitis (POE) rates in patients who received intracameral injection of cefuroxime at the close of cataract surgery.⁵ Recent research by Haripriya et al⁶ has shown the effectiveness of intracameral moxifloxacin in endophthalmitis rate reduction in India (3-fold for manual small incision cataract surgery and nearly 6-fold for phacoemulsification). It should be emphasized that drug concentration after intracameral administration is much higher than after topical administration. It is also much higher than the minimal inhibitory concentration and probably does not promote drug resistance. Although there are a good number of retrospective studies showing that intracameral antibiotics are effective in POE prophylaxis, the ideal antibiotic for intracameral use has not been determined yet.^7-9 Moreover, several large retrospective studies have shown no additional benefit of using topical antibiotics pre- and/or postoperatively over antiseptics preoperatively and with intracameral antibiotics.^5,10,11 Thus, although preoperative antiseptic solutions are important in the prophylaxis of postoperative endophthalmitis, the role of antibiotics is still unclear. Several studies evaluated the role of conjunctival sac irrigation using antiseptics alone or in conjunction with antibiotics, and their results are contradictory. In some studies, when used in conjunction with povidone iodine (PVI) solutions, antibiotics have been reported to increase the efficacy of bacteria eradication, whereas the findings of other studies showed no additional effect of antibiotics preoperatively.¹¹ In eyes using intracameral cefuroxime intraoperatively, the additional protective effect of topical or systemic preoperative antibiotics along with postoperative subconjunctival antibiotics have not been demonstrated, and in several studies no effect was reported.^10-14 Therefore, additional use of topical antibiotics in these cases is not justified and should not be indicated. In Denmark and in Sweden, where endophthalmitis rates are monitored and annually reported in the National Cataract Register,¹² the incidence of endophthalmitis after cataract surgery is very low, although topical antibiotics are not routinely used perioperatively. This suggests that routine use of topical antibiotics in uncomplicated cataract surgery is not necessary. Subconjunctival antibiotic injections, systemic antibiotics, and antibiotics in irrigation solutions have been also used in several countries; however, in many retrospective studies their efficacy in POE prophylaxis has not been proven, and ESCRS guidelines do not recommend these means of prophylaxis.^14-17 Ophthalmologists should strive to reduce topical antibiotic use and when it is necessary use them at maximum doses at high frequency to prevent the development of drug resistance.

INTRAVITREAL INJECTIONS

The most common intraocular procedures worldwide have recently become intravitreal injections (IVI). Due to contamination of the ocular surface, the injection site has to be properly prepared. The incidence of endophthalmitis after IVI is generally low. Many studies showed no difference in the effectiveness of antisepsis alone and together with prophylactic antibiotherapy.¹⁸ Some retrospective studies comparing the incidence of endophthalmitis after intravitreal injection with and without topical postinjection antibiotic prophylaxis have shown that the use of topical antibiotics after injections is associated with a trend toward higher incidence of endophthalmitis.^19,20 Results of a recent meta-analysis show that antibiotic prophylaxis is not required in IVI, as it does not reduce the incidence of endophthalmitis and it can even contribute to drug resistance.²¹ Paradoxically, repeated exposure to topical antibiotics may increase the endophthalmitis rate by selecting resistant and often more virulent bacteria.^22,23 Thus, in recently published guidelines an expert panel of ophthalmologists advocates topical antisepsis with 5% PVI over 30 seconds as a safe and effective procedure preceding IVI.²⁴

THE ROLE OF ANTISEPTICS

In many situations antiseptics can be an alternative to antibiotics. Antiseptics have a nonselective mechanism of action that often prevents the development of resistance. Morover, antiseptics are inexpensive and available worldwide. The antiseptics most commonly used in ophthalmology are PVI and chlorhexidine (CHX).² Povidone iodine is the gold standard antiseptic in ophthalmology. It has the broadest spectrum of antimicrobial activity of the available antiseptics, which includes Gram-positive and Gram-negative bacteria, bacterial spores, fungi, protozoa, and viruses.²⁵ Moreover, it does not induce resistance or cross-resistance to antibiotics.²⁶ The effect of PVI is based on free iodine released from the solution and penetrating into microbial membrane causing cell death. Depending on the concentration it requires 15-120 seconds to kill bacteria. Safe and effective concentrations of PVI range from 0.005% to 10%. In a recent study, Shimada et al²⁷ showed that washing the ocular surface with 0.25% PVI solution exhibited a bactericidal effect even if the solution was diluted 25- to 50-fold in the operative field. Moreover, the time required to kill bacteria was shorter for diluted solutions (15 seconds for 0.1% to 1% solutions and 30-120 seconds for 2.5% to 10% solutions), as diluting the solution facilitates release of free iodine. In another study Shimada et al²⁸ have shown that irrigating the operative field every 20 seconds during cataract surgery with diluted iodine solutions (0.025% PVI or 0.0025% polyvinyl alcohol iodine) results in a very low bacterial contamination rate in the anterior chamber. These results indicate that iodine solutions can be useful and become an alternative to preoperative antibiotics for POE prophylaxis in cataract surgery. In 2013 Shimada et al²⁹ showed that repeated operative field irrigation with 0.25% PVI during 25-gauge vitrectomy reduced the contamination of the vitreous with no apparent ocular toxicity. This suggests that in future PVI can become a safe and effective method not only for prophylaxis but also treatment of POE; however, more studies on this topic are needed.

Compared with PVI, CHX is a much larger molecule that cannot penetrate the cell wall and cannot adsorb to some Gram-negative bacterial cell membranes. It is inactive against various Enterobacteriaceae, Pseudomonas aeruginosa, all Actinobacteria spp., and all spores. In contrast to PVI, there has been documented bacterial resistance to CHX, particularly among methicillin-resistant Staphylococcus aureus and other staphylococci.⁴ Povidone iodine is considered to be less irritating than CHX, which in high concentrations can be toxic to the corneal epithelium. There are also several reports of ocular toxicity and irreversible corneal injury with permanent stromal scarring or bullous keratopathy in the most severe cases after inadvertent exposure of the ocular surface to CHX applied to the skin before nonocular procedures.³⁰ However, it has been shown that aqueous chlorhexidine gluconate that does not contain alcohol or detergents may be safe and efficacious in preventing post-IVI endophthalmitis.³¹ Anaphylaxis after topical PVI in ophthalmic use has never been reported, and adverse skin reactions to topical PVI are very rare, which makes this solution safe and well tolerated by patients.³²

ANTERIOR SEGMENT INFECTIONS

Antibiotics are also often misused in ocular surface infections. It has been shown that although commonly used, antibiotics are not necessary in typical, uncomplicated cases of conjunctivitis, as up to 80% of all cases of acute conjunctivitis are caused by viruses.³³ Although topical antibiotics are effective in reducing the duration of bacterial conjunctivitis and transmissibility, most cases of suspected or confirmed bacterial conjunctivitis are self-limiting within 1 to 2 weeks; thus, it is more reasonable to observe a patient with mild symptoms than treat them with antibiotics.³³ In 2002, results of a prospective trial published by Isenberg³⁴ demonstrated that both antibiotics and PVI were equally effective in treatment for bacterial conjunctivitis; however, the number of studies on this topic is insufficient to make clear conclusions and recommend PVI as a treatment for these cases. The use of antibiotics has also some inconveniences. The dosage and duration of the therapy should be strictly followed. Patient compliance is crucial for the success of therapy, and that is often hard to achieve, especially in children. Moreover, many antibiotics are not approved for use in children. Antibiotics do not protect against secondary infections, and they can cause allergy or toxicity leading to delay in proper diagnosis of other possible conditions; consequently, they should be critically analyzed and reserved only for those patients with no improvement, when bacterial culture results are positive, contact lens wearers, in case of preexisting ocular surface disease, severely purulent conjunctivitis, or suspected chlamydial and gonococcal conjunctivitis.³³ The recent study by Shekhawat et al³⁵ (2017) showed that nearly 60% of patients with newly diagnosed acute conjunctivitis fill prescriptions for topical antibiotics, of which 20% filled prescriptions for antibiotic-corticosteroids that are contraindicated for acute conjunctivitis. These results are alarming.

Antibiotics are also routinely used in treatment of keratitis. However, recently published results of a large randomized controlled clinical trial carried out in the Philippines and India by Isenberg et al³⁶ compared 1.25% PVI solution with topical antibiotics for treatment of bacterial keratitis caused by a broad range of bacteria, showing no significant difference between these 2 therapies. Considering these results, the range of indications for PVI use might increase in the future. Neverthless, further research is needed.

CONCLUSIONS

In conclusion, the use of antibiotics should always be verified and based on clinical indication. Antibiotics should be prescribed only if necessary, proven to provide benefit, and ideally after identifying the pathogen along with resistance testing. The therapeutic role of povidone iodine may be underestimated, as in many cases it has similar effectiveness as antibiotics, but unlike them it does not increase bacterial resistance.