**7. Treatment of acute postoperative infectious endophthalmitis**

#### **7.1 Intravitreal antibiotics and other pharmacologic therapies**

Initial and one of the mainstays of treatment for APIE include intravitreal antibiotic therapy [3–5, 12]. Treatment with IAI should be started empirically before

having any culture results. For many years, the EVS conclusions and recommended IAI had been a paradigm in APIE patients' care [4, 12]. Nonetheless, it is currently critical in most cases that clinical judgment should be used to determine treatment on a case-by-case basis. Moreover, first-line IAI recommendations have changed after EVS was published and, some authors have proposed vitrectomy as a concomitant treatment of IAI, for the treatment of APIE [27–29].

The EVS was a prospective, multicenter, randomized clinical trial evaluating the efficacy of immediate PPV and intravenous antibiotics to treat APIE. The EVS included endophthalmitis cases after cataract surgery. Patients were randomized to either vitrectomy or vitreous needle biopsy and intravenous antibiotics or no intravenous antibiotics [4, 13, 30]. The study endpoints were media clarity and best-corrected visual acuity. Patients received vancomycin and amikacin IAI. Furthermore, subconjunctival ceftazidime, vancomycin, dexamethasone, topical vancomycin, amikacin, cycloplegic, 1% topical prednisolone acetate and 30 mg bid of oral prednisone, for 5–10 days were prescribed as well [13, 30].

The EVS conclusions included no difference in final vision or media clarity whether or not intravenous antibiotics were used. In addition, patients with light perception visual acuity who received PPV had a three-fold increment in the probability of achieving 20/40, and a 50% reduction in the probability of severe visual loss than patients receiving only vitreous needle biopsy [13].

Patients with hand-motions or better vision showed no significant difference in final best-corrected visual acuity or media clarity whether or not an early vitrectomy was performed.

IAI recommendations have changed over the years. Initial treatment includes mainly intravitreal, as well as oral and topical antibiotics. Currently, two antibiotics are recommended by most retina specialists as first-line IAI treatment for APIE:


Vancomycin and/or amikacin are considered as intravitreal antibiotics alternatives in cases of cephalosporin allergy and/or the presence of ceftazidime resistant Gram-negative strains. Vancomycin has an excellent Gram-positive coverage despite isolated reports of resistance (**Table 3**) [4].

For fungal APE cases, voriconazole, 50–100 μg/0.1 ml, and amphotericine B, 5–10 μg/0.1 ml are described as first-line treatments.

Ceftazidime has emerged as first-line treatment for Gram-negative organisms due to its safer profile than amikacin. Another advantage of ceftazidime is that it may show synergy with vancomycin against gram-positive organisms [4, 12]. Oral, subconjunctival, and systemic antibiotics are used as adjuvant therapy in some hospital settings, although there is little or no evidence of their clinical effectiveness [3, 12]. Among all systemic antibiotics, ciprofloxacin is a first-generation fluoroquinolone that has been routinely used in APIE due to adequate ocular penetration and low side effect profile [4].

Third- and fourth-generation fluoroquinolones have shown a better Grampositive coverage than ciprofloxacin while maintaining an adequate level of Gram-negative activity. Moxifloxacin has the most potent in vitro activity against Gram-negative and Gram-positive endophthalmitis pathogens [3–5]. It has been used as an intracameral antibiotic for cataract surgery prophylaxis, and there has been a three-fold decline in endophthalmitis rates with its use in phacoemulsification surgery. It is increasingly being used as an alternative intravitreal antibiotic for APIE cases [31]. Furthermore, moxifloxacin has also exhibited adequate ocular *Acute Postoperative Infectious Endophthalmitis: Advances in Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.97545*


#### **Table 3.**

*Intravitreal antibiotics used for the management of acute postoperative infectious endophthalmitis [5]. Intravitreal injections of vancomycin and ceftazidime are currently recommended as first-line treatment in acute postoperative endophthalmitis.*

penetration after systemic administration, with vitreous levels above minimum inhibitory concentration (MIC90) for most bacteria [32].

Vitreous moxifloxacin pharmacokinetics have shown in several studies comparable bioavailability characteristics to ciprofloxacin, with reasonable safety [4, 5, 32]. Moreover, cases of vancomycin-resistant bacteria have been reported to respond adequately to intravitreal injection of moxifloxacin [4, 5, 32].

Linezolid is an oxazolidinone-class antibiotic that the FDA approved in 2000 [5, 33, 34]. It has excellent bioavailability when administered orally, and intraocular levels can reach therapeutic levels within one hour of being administered. Linezolid provides mainly gram-positive coverage [5, 33]. If Gram-positive organisms have shown resistance to vancomycin, it might be reasonable to supplement with oral linezolid, and likewise, oral ciprofloxacin or moxifloxacin may increase the antimicrobial properties of intravitreal ceftazidime [5, 33]. Other IAI used in animal models or humans for endophthalmitis include quinupristin-dalfopristin [5, 34–37], daptomycin [5, 38–40], tygecicline [5, 41], imipenem [5], among others [42, 43]. New antifungals for APIE, include miconazole, caspofungin, and micafungin [5]. In **Table 4**, some of the antibiotics that have been used in endophthalmitis are summarized.

Another debated topic in APIE treatment is the use of steroid therapy. Experimental endophthalmitis animal models have shown that the degree of retinal tissue damage is partly secondary to the elicited severe inflammatory response in the eye [4]. Hence, it is appropriate to address this issue besides the use of antimicrobial therapy, and aggressive steroid therapy should be prescribed in APIE patients, which include topical 1% prednisolone acetate as frequently as every hour as well as oral steroids [3, 4, 44]. Cycloplegic topical medication such as 1% atropine, BID should be prescribed as well, to help decrease pain.

Controversy, however, still prevails regarding the use of intravitreal steroids in APIE. Some authors reported an improvement in inflammation and final visual results with intravitreal injection of steroids and antibiotics, whereas other studies have described worse inflammation and worse visual outcomes [44]. Histopathology reports have also shown contradictory outcomes for intravitreal steroids. In addition, intravitreal triamcinolone has been shown a favorable effect for APIE when combined with IAI in some reports [44].

Dexamethasone implants have been approved for use in several forms of uveitis, which has led to evaluate their possible use in endophthalmitis patients. Moisseiev et al. [45] reported APIE patients treated with immediate intravitreal dexamethasone at the time of vitreous tap. Compared to a group without steroid use, a trend towards the reduced need for antibiotic re-injection was observed in the steroid group. Currently, intravitreal dexamethasone recommended dose is 400 μg in 0.1 ml.


*Moxifloxacin is increasingly being used as part of APIE prophylaxis and as alternative intravitreal antibiotic in acute postoperative endophthalmitis cases [5, 30].*

#### **Table 4.**

*Main alternative antibiotics for potential use in the management of endophthalmitis caused by resistant microorganisms to standard IAI. Evidence of their use comes from case reports and case series in humans and animal models.*

#### **7.2 Vitrectomy for postoperative endophthalmitis**

The EVS concluded that early vitrectomy in endophthalmitis was only beneficial in patients with visual acuity of light perception or worse [13]. Hence, delaying vitrectomy in APIE patients with a better presenting vision has been a common practice among retina specialists. Nonetheless, there is still debate on the adequate timing to perform vitrectomy in APIE patients.

The methods and results of EVS may not reflect modern surgery practice patterns. Furthermore, with the advent of more refined surgical techniques in recent years like minimally-invasive vitrectomy surgery (MIVS), which entail a lower complication rate compared to conventional vitrectomy, the EVS study's conclusions are possibly obsolete. Currently, performing both vitrectomy and IAI as first-line treatments might be more beneficial for many APIE cases [6, 7, 27–29, 46].

In many hospital settings, vitrectomy is usually performed in those APIE patients that do not respond to an initial dose of IAI. In these patients, repeating IAIs instead of performing PPV is likely to be of little benefit. Persisting levels of vitreous antibiotic above MIC90 for three days or more after IAI and repeating the same agents after 2–3 days may be deleterious to the eye due to an increased risk of retina toxicity. In addition, some authors [47] have hypothesized that bacterial sequestering or biofilm production might reduce the bacteria's sensitivity to IAI; furthermore, vitrectomy might help remove the bacterial load and increase antibiotic bioavailability in the vitreous cavity.

Peyman et al. were the first to report the use of early vitrectomy in endophthalmitis patients [48]. Cases underwent vitrectomy 24 hours after diagnosis, 65% achieving a final visual acuity of 20/400 or better.

The EVS evaluated the early vitrectomy role and contrasted immediate vitrectomy within six hours of diagnosis against inject-only as subgroups. Only core vitrectomy was performed on the included patients. While no advantage for

#### *Acute Postoperative Infectious Endophthalmitis: Advances in Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.97545*

performing PPV was found unless vision was light perception or worse, no disadvantage in the final visual outcome was found in performing vitrectomy [13].

Moreover, the induction of a posterior hyaloid separation and a complete vitrectomy were usually avoided in the EVS. Contrary to the EVS methods, some reports suggest that removing the posterior hyaloid and using silicone oil as a tamponade in APIE patients could improve anatomic and visual outcomes [13].

Kuhn et al. [46] described a series of patients who underwent early vitrectomy for endophthalmitis with a more thorough surgical vitrectomy and found no rhegmatogenous detachment cases. Ninety one percent of the cases had a final vision of 20/40 or better, contrary to 53% in the EVS study group. They postulated that removing the posterior vitreous cortex may remove the toxic load from proximity to the macula. Other case series have reached similar conclusions [6, 7, 27–29].

Current vitrectomy techniques include 23 Ga, 25 Ga, or 27 Ga MIVS rather than conventional 20 Ga techniques. In addition, some key points should be considered while performing vitrectomy in APIE patients:

First, because the media is frequently hazy for the surgeon to visualize a pars plana port, an infusion cannula sometimes cannot be used for the initial stages of the operation. It is advisable to place an inferotemporal port, reserving its use later in the procedure, once the tip's location in the vitreous cavity can be verified. Alternatively, an anterior chamber maintainer could be placed.

Second, opacities such as hypopyon and pupillary membranes should be aspirated from the anterior segment. Often, because of poor dilation of the pupil and visualization of the internal structures, the lens in phakic eyes must be removed. If the cornea remains too cloudy due to bacterial infiltration and inflammation, and it does not allow adequate visualization of the vitreous cavity, the use of keratoprosthesis should sometimes be considered.

Third, separation of the posterior hyaloid besides core vitrectomy should be attempted in some APIE cases. Some authors [46] have described performing complete vitrectomy to help decrease inflammatory cells and bacterial loads. It can be achieved with current vitrectomy systems, using high-cutting rates and low-flow to lessen the retina traction while removing vitreous strands, thus minimizing the risk of iatrogenic retinal breaks, as well. Nonetheless, caution should still prevail in performing peripheral vitrectomy, and posterior hyaloid separation in cases where the retina appears too necrotic since the risk of formation of retinal tears may increase in this scenario.

Video 1 (https://youtu.be/Q0lLB4Ozkoc) shows an APIE case where hypopyon aspiration, core and peripheral 23 Ga PPV, as well as posterior hyaloid separation were performed.

Fifth, the use of silicone oil as a tamponade has been shown to have a bactericidal effect in vitro and may be worth considering in the context of performing PPV in APIE patients, especially if retinal tamponade is also required in cases of retinal detachment. However, silicone oil's bactericidal effect has been challenging to prove in vivo [4, 6, 7, 27–29].

Another recently described surgical technique for endophthalmitis is endoscopic vitrectomy that uses an endoscopic probe inserted via pars plana to improve visualization in the vitreous cavity, identify intraocular structures, and avoid iatrogenic damage performing a PPV [49]. It has the advantage that it does not require clear anterior media, which is frequently compromised in endophthalmitis patients. It does not require waiting for media clearing, which carries an additional risk of tissue damage due to the infection and severe inflammation processes. Disadvantages of endoscopic vitrectomy include the steep curve for re-learning vitrectomy via an endoscope probe.

If an early vitrectomy is performed because of initial non-response to IAI or removing inflammatory debris, it is common to inject antibiotics concomitantly into the vitreous cavity. Antibiotics can be injected at the end of the vitrectomy or via the diluted solution infused into the vitreous cavity throughout the vitrectomy procedure.

The patient may be left with saline solution, air, gas, or silicone oil as tamponade. It is of the utmost relevance to consider that the volume of water-based fluid in the eye dictates the antibiotic's amount and concentration [4, 6, 7, 27–29, 46]. This is because high antibiotic levels present in the remaining meniscus of aqueous fluid may increase toxicity risk to the retinal tissue that may eventually induce further vision loss. Therefore, it is essential to consider injecting a third or fourth of the recommended intravitreal antibiotic dose in patients with gas or silicone oil-filled eyes to obtain an antibiotic's adequate concentration, as the concentration of the antibiotic changes in the small meniscus of aqueous fluid that will remain in the vitreous cavity.

Alternatively, antibiotic could be diluted at the proper concentration in the irrigation solution that enters the vitreous cavity, thus the remaining fluid will also have adequate antibiotic concentration. The antibiotic can be injected into the vitreous cavity before the tamponade [27–29, 46]. It may be necessary to position the patient face-down a few days after surgery to minimize macular exposure to antibiotics.

Some authors have described the successful use of infused vancomycin throughout vitrectomy at different concentrations. This approach might expose the retinal tissue to a more constant antibiotic level than an intravitreal injection. Nevertheless, it also may have the risk of using sub-therapeutic concentrations of the antibiotic [27].

#### **7.3 Endophthalmitis prophylaxis**

The single most effective prophylaxis of endophthalmitis includes preoperative application of 5% povidone-iodine (PI) conjunctival surface and cul-de-sac [50–53]. Bacteria have not developed resistance to PI, and PI is also effective against many microorganisms such as fungi and viruses. Several studies have proven the effectiveness of the aseptic technique and the use of PI in ophthalmological surgery. One report assessed the incidence of APIE over many years in the same hospital with the incorporation of PI, with no use of intraocular antibiotics. Over this time, the rate of APIE went from 0.38% to <0.03%. This rate is almost the same as the current studies looking into risk reduction using intracameral antibiotics [51].

Checking for lid infections like blepharitis, nasolacrimal duct obstruction, leaking wounds, and intracameral antibiotics like cefuroxime 1000 μg/0.1 ml or moxifloxacin at the end of the surgery, and the use topical postoperative antibiotics are some other measures that might decrease endophthalmitis incidence [3, 4].

A large study of eyes that underwent cataract surgery [54] showed that intracameral moxifloxacin declined postcataract surgery endophthalmitis incidence. Nonetheless, the routinary application of intracameral antibiotics has some risks, such as the development of resistant strains of pathogens, and retinal toxicity. For instance, hemorrhagic occlusive retinal vasculitis has been described after using intracameral vancomycin [53].

The most common causative bacteria in post intravitreal injections endophthalmitis are streptococci, common oral flora members. The use of masks and adhering to a strict no-talking policy has decreased post-injection endophthalmitis incidence.

Prompt surgical repair of open globe injuries and prophylactic IAI with or without systemic antibiotics have also been associated with reduced post-traumatic endophthalmitis incidence.

*Acute Postoperative Infectious Endophthalmitis: Advances in Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.97545*

#### **7.4 Other novel treatments and developments**

Nakashizuka et al. [52] reported the safety and efficacy of 1.25% povidoneiodine (PI) intravitreal injection followed by vitrectomy using 0.025% irrigation to treat endophthalmitis. Most of the cases included in the study resolved rapidly, and good visual results were observed. No adverse events were reported. Moreover, the electrorretinogram (ERG) results showed increases in the oscillatory potentials amplitudes, flicker ERG and the a-wave's implicit time, suggesting the functional improvement in the retinal inner and outer layers after surgery. They concluded that intravitreal injection of PI followed by PPV was thought to be an effective and safe therapy for APIE. Other authors have reported similar findings [52, 53].

Other novel therapies under investigation for APIE include the development of microdevices such as biomimetic nanosponge to treat endophthalmitis caused by virulent pathogens such as *Enterococcus faecalis* isolates. *Enterococcus faecalis* produces the pore-forming bicomponent cytolysin that adds to retinal tissue damage in endophthalmitis. LaGrow et al. [55] hypothesized that a biomimetic nanosponge, which imitates erythrocytes, could adsorb subunits of the cytolysin and decrease damage to the retina, preserving vision in endophthalmitis patients.

They reported that biomimetic nanosponges nullified cytolysin activity and protected the retinal tissue from damage. These outcomes indicate that this therapeutic option could guard eyes against the deleterious effects of pore-forming toxins of various aggressive ocular bacteria [55].
