Keywords

Early antibiotic administration and ability to penetrate the infected site can be critical in preserving vision when treating various types of ocular infections [1]. An understanding of the pharmacokinetics and pharmacodynamics of antibiotics while acknowledging the bactericidal or bacteriostatic properties of these agents aids in prescribing appropriate therapy. A variety of antibiotic agents are currently available to treat ocular infections. Topical antibiotic agents are most commonly used to treat superficial or external ocular infections, whereas infections that are located farther away from the cornea or within the eye require additional methods of administration (i.e., intravitreal injection or parenteral therapy) to achieve therapeutic concentration at the site of infection [2]. Therefore, early identification of the depth of eye involvement and potential causative microorganisms is essential in choosing the most appropriate mode of medication administration and therapeutic option. This chapter provides the enumeration of relevant antibiotics by class, antimicrobial activity, antibiotic mechanism of action, mode of application, and antibiotic toxicity.

Overview of Antibiotics: Mechanisms of Action, Spectrum of Activity

Topical Antibiotics

Topical antibiotic agents can provide direct delivery of antibiotic in high concentration at the site of infection when treating bacterial conjunctivitis, keratitis, or uncomplicated blepharitis [1, 3]. Ophthalmic antibiotic solutions are preferred in adults as they do not interfere with vision, although more frequent administration is required due to short contact time with the eye. Antibiotic ointments have prolonged contact time and will be more resistant to medication loss through dilution by tears [4]. Often, ointments are recommended in children or adults who do not have concerns for visual interference.

The most extensively developed topical antibiotic class with a broad spectrum of activity is the fluoroquinolones (Table 9.1) [5–12]. Fluoroquinolones (besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, and ofloxacin) cause rapid bacterial cell death due to inhibition of bacterial DNA synthesis. These agents limit the activity of two key topoisomerase classes of enzymes that play an important role in bacterial DNA replication. DNA gyrase introduces negative supercoils into DNA within the bacterial cell, and topoisomerase IV divides the chromosomal DNA during bacterial cell division [13]. Antibacterial activities of fluoroquinolones vary between the generations. Although the initial generations such as ofloxacin and ciprofloxacin have limited gram-positive activity, especially against streptococci, ciprofloxacin still shows the best activity against Pseudomonas aeruginosa [13]. New generations such as levofloxacin, gatifloxacin, moxifloxacin, and besifloxacin have a broader spectrum of activity including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and Streptococcus species [13]. In a recent surveillance study that reviewed ocular microorganisms and antibiotic activity, ciprofloxacin was the least potent agent against staphylococcal isolates with 80 % resistance to MRSA, whereas besifloxacin was the most potent agent in the class followed by moxifloxacin [14]. All fluoroquinolones have great atypical coverage such as Chlamydia trachomatis; however moxifloxacin is the only fluoroquinolone that has additional anaerobic coverage [13].

Table 9.1 Topical antibiotic agents of ocular infections
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Macrolides (azithromycin, erythromycin) are generally thought to inhibit RNA-dependent protein synthesis at the chain elongation step; however the ability to bind to the 50S ribosomal subunit differs between azithromycin and erythromycin which results in varying antibacterial activities [15–17]. When compared to erythromycin, azithromycin may have better penetrating ability to the outer envelope of gram-negative organisms such as Moraxella catarrhalis and Haemophilus influenzae. Also, C. trachomatis coverage is much better with azithromycin compared to erythromycin [18]. With regard to gram-negative and atypical coverage, macrolides have great activity against Neisseria gonorrhoeae and M. catarrhalis. Macrolides also have activity against actinomycetes and mycobacteria which have been identified as causative pathogens in canaliculitis and keratitis [3].

Macrolides have been highly potent against S. pneumoniae and group A streptococcus isolates; however, the prevalence of erythromycin resistance to S. pneumoniae is continuously increasing in the United States and worldwide [19–21]. Although group A streptococcus resistance to erythromycin has been reported, the prevalence of resistance is not as high as is seen with S. pneumoniae [22, 23]. Erythromycin has activity against viridans group streptococcus; however, Europe and Asia have higher resistance rates than those that occurred in North America [24]. MRSA is generally resistant to erythromycin; therefore, the use of erythromycin should be based on the local antibiogram or culture result [15].

Aminoglycosides such as gentamicin and tobramycin have limited activity against gram-positive organisms and anaerobic bacteria [25–27]. These agents work by binding to the 30S ribosomal subunit to inhibit protein synthesis and require aerobic metabolism to cause antibacterial effect [28]. In general, aminoglycosides have great activity against gram-negative bacilli such as Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp.; however, no activity has been shown for Stenotrophomonas maltophilia or Burkholderia cepacia.

Combination topical antibiotics are typically paired with narrow spectrum antibiotics to expand the overall spectrum of activity. Polymyxin B is a polypeptide with high molecular weight and works by penetrating the cell membrane of bacteria and interacting with phospholipids [29, 30]. The main antibacterial activity of polymyxin B is P. aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae (CRE). Most gram-positive organisms are resistant to polymyxin B; thus it is commonly paired with another antibiotic with good gram-positive coverage such as bacitracin or trimethoprim. Bacitracin inhibits cell wall synthesis by preventing transfer of mucopeptides into the growing cell wall [31]. As a combination agent, bacitracin zinc/polymyxin B sulfate has activity against S. aureus, S. pneumoniae, Escherichia coli, H. influenzae, Klebsiella/Enterobacter species, Neisseria species, and P. aeruginosa [32]. Trimethoprim is a synthetic antibacterial agent that blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the enzyme dihydrofolate reductase. It has good activity against gram-positive and gram-negative organisms such as S. aureus, S. epidermidis, S. pyogenes, S. pneumoniae, H. influenzae, E. coli, Proteus vulgaris, E. aerogenes, and Serratia marcescens [33, 34].

Sulfonamides have bacteriostatic properties and inhibit bacterial growth by interfering with folic acid synthesis [35]. The sulfonamides show antibacterial activity against S. aureus, S. pneumoniae, viridans group streptococcus, E. coli, H. influenzae, Klebsiella species, and Enterobacter species. These agents should not be used empirically for Neisseria species, S. marcescens, P. aeruginosa, or resistant Staphylococcus species [36].

Topical Antifungal/Antiviral

Natamycin eyedrops (5 % suspension) is the only antifungal agent that is commercially available. Natamycin is a tetraene polyene agent that works by binding to the sterol of the fungal cell membrane, which causes membrane permeability changes [37]. It is used for the treatment of fungal keratitis caused by Candida species, Aspergillus, Cephalosporium, Fusarium, and Penicillium; however, poor corneal tissue penetration limits its use in intraocular infections [3, 37]. Amphotericin B, nystatin, fluconazole, miconazole, and flucytosine eyedrops have been compounded for use [3, 38], but extemporaneous preparations of these products are not widely used. Furthermore, topical amphotericin B made with a deoxycholate formulation is known to be toxic to the cornea [39].

Commercially available topical antiviral agents are more common than antifungal agents. Trifluridine ophthalmic suspension is used for the treatment of herpes simplex keratitis and keratoconjunctivitis [3]. It inhibits viral DNA synthesis and has activity against herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), and adenoviruses [40]. Vidarabine ointment is also available for the treatment of HSV keratitis. It has activity against idoxuridine-resistant and acyclovir-resistant HSV; however, it is more toxic and less effective compared to trifluridine for the treatment of HSV keratoconjunctivitis [3, 40]. Idoxuridine is approved for the treatment of HSV keratitis. Its mechanism of action is not completely understood, and it is also inferior to trifluridine and acyclovir for the treatment of HSV epithelial keratitis [40]. Topical 0.15 % ganciclovir ophthalmic gel is indicated for the treatment of acute herpetic keratitis [41]. Finally, topical acyclovir is not available in the United States [3].

Intravitreal/Subconjunctival Injection

Table 9.2 shows a list of commonly used antibiotic agents for intravitreal/subconjunctival injection. These agents are used since topical antibiotics are ineffective in treating endophthalmitis due to their inability to penetrate the intraocular site [42]. Antifungal agents such as voriconazole and conventional amphotericin B are often used for intravitreal infection, which result in rapid achievement of high concentration in the posterior chamber [43, 44].

Table 9.2 Commonly used anti-infective agents for intravitreal injection
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Systemic Therapy

The data for intraocular penetration of antibiotic therapy delivered via parenteral routes is limited. There are a few antibiotic classes that are used as adjunctive therapy when treating endophthalmitis or when the use of systemic antibiotics is the best treatment option (i.e., orbital cellulitis, preseptal cellulitis) [42, 45]. All B-lactams inhibit bacterial cell wall synthesis by inhibiting high-molecular-weight penicillin-binding proteins (PBPs) [46]. Vancomycin is a tricyclic glycopeptide that works by binding to the D-alanyl-D-alanine part of a cell wall precursor and thus inhibiting the late stages of bacterial cell wall synthesis [47]. Linezolid is one of the oxazolidinones that works by inhibiting protein synthesis. It binds to the 50S ribosome within the 30S unit to prevent 70S complex formation [48]. B-lactam antibiotics (penicillins, cephalosporins, and carbapenems), vancomycin, and linezolid may be added to cover gram-positive and gram-negative organisms depending on the culture result (Table 9.3).

Table 9.3 Pathogens and systemic treatment for ocular infections
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Invasive ocular infections caused by fungi are rare but associated with poor response rate; thus the treatment consists of systemic antifungal agents in combination with surgery, intravitreal injections, or both. Amphotericin B has been most studied and experienced in treating intraocular fungal infection to date [43]. It is a fungicidal agent that works by binding to ergosterol in the cell membrane of susceptible fungi and changes membrane permeability, which results in the leakage of intracellular potassium and other molecules and cell death [49]. Currently there are four different amphotericin B formulations: amphotericin B deoxycholate, amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B. It is a broad-spectrum antifungal agent that has activity against most Candida species except for C. lusitaniae; dimorphic fungi such as Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and filamentous fungi such as Aspergillus spp. and the Mucorales group [50]. Spectrum of activity is not influenced by different amphotericin B products.

Flucytosine is often used with amphotericin B as it is synergistic against Candida spp. and Cryptococcus neoformans. It is a fluorinated pyrimidine that works by disrupting RNA and DNA synthesis [43]. Flucytosine lacks activity against the dimorphic fungi and filamentous fungi, and it should not be used as monotherapy due to rapid development of resistance for the treatment of candidiasis [49].

Azoles are ergosterol synthesis inhibitors, and each azole has slight variation in its spectrum of activities. Fluconazole is mainly active against Candida species, C. neoformans, and dimorphic fungi such as C. immitis, H. capsulatum, and B. dermatitidis. Although most Candida albicans are susceptible to fluconazole, fluconazole-resistant C. albicans has been reported. Resistance in other Candida species such as Candida glabrata has been noted [43]. Fluconazole is not active against Candida krusei, Aspergillus spp., Fusarium spp., Scedosporium spp., and Mucorales [50]. Itraconazole is active against some Candida species, dimorphic fungi, and Aspergillus species; however, it does not penetrate the ocular structure well [49]. Similarly, posaconazole has poor ocular penetration. It has a broad-spectrum coverage including Candida species, C. neoformans, Aspergillus species, Fusarium species, and Zygomycetes [49, 51]. Voriconazole is a broad-spectrum azole that is the drug of choice for treatment of invasive aspergillosis. It also has activity against Candida species, C. neoformans, Scedosporium species, and Curvularia species [49, 51]. Unlike posaconazole and itraconazole, voriconazole penetrates the eye and can adjust the dose based on the trough goal level of 2–5 mg/L [52, 53]. The newest addition to the class of azole is isavuconazonium sulfate. It is a prodrug of isavuconazole with broad spectrum of activity including most Candida species, dimorphic fungi, C. neoformans, Aspergillus species, and Mucorales [54]. To date, no data are available regarding ocular penetration of this new agent.

Echinocandins work by inhibiting the synthesis of 1, 3-β-D-glucan, which is the predominant component of the fungal cell wall. Currently there are three echinocandins on the market: caspofungin, micafungin, and anidulafungin. In general, echinocandins are active against Candida species and Aspergillus species, but lack activity for Fusarium, Scedosporium, and Zygomycetes [49, 51]. Furthermore, echinocandins do not penetrate the ocular structure; therefore, it is not widely used to treat invasive ocular infections.

Viral conjunctivitis can be caused by HSV and adenovirus [55]. Although no effective treatment is available for viral conjunctivitis caused by adenovirus, oral antivirals are used to shorten the course of HSV conjunctivitis [55]. Acyclovir and valacyclovir work by blocking viral DNA synthesis and are much more potent against HSV type 1 and 2 compared to cytomegalovirus [40]. Ganciclovir and valganciclovir are potent against CMV and have better activity against herpes B virus compared to acyclovir [40].

Mode of Administration and Pharmacokinetics

Delivering a therapeutic concentration of antibiotic at the site of infection is a challenge. Important factors that could influence the intraocular penetration of antibiotics are the charge of the drug, corneal epithelium status, drug formulation, drug concentration, and the dosage regimen [1]. Natural barriers such as eyelids, iris, tears, and cornea prevent diffusion of antibiotics into intraocular tissue. In order to promote corneal absorption, certain formulation factors should be considered (Table 9.4) [2]. Furthermore, the corneal area can only contain about 30 μl; therefore, topical solutions are given more frequently to ensure adequate absorption of medication [2]. Ophthalmic medications that have both lipid- and water-soluble properties will help enhance overall drug absorption [4]. Due to these challenges of the topical application method, infections involving vitreous humor, sclera, or cornea may require additional strategies to administer drug therapy.

Table 9.4 Factors to improve corneal absorption
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Unlike topical antibiotic application, subconjunctival injection can reach high antibiotic concentration in sclera and cornea. This mode of administration is used to treat intraocular infection as it gains access to the episcleral and conjunctival vessels [4]. However, subconjunctival injection does not provide adequate antibiotic penetration into the vitreous humor [42].

Intravitreal injection of air has been practiced by ophthalmologists to repair retinal detachments since 1911 [56]. Intravitreal injection is used to treat endophthalmitis, cytomegalovirus (CMV) retinitis, and more. This method provides direct exposure of antibiotic to the infected site for a prolonged period with minimal systemic absorption [57]. Thus, bypassing the blood-retinal barrier ensures immediate high concentration of antibiotic in the vitreous cavity [42].

Systemic antibiotic therapy is used as an adjunctive strategy to intravitreal injection, subconjunctival injection, and/or topical administration. This mode of administration is added when treating ocular infections that involve the posterior segment of the eye or the orbit (i.e., endophthalmitis, orbital cellulitis, or chorioretinitis), where topical antibiotics will provide negligible drug penetration [4]. Limited data concerning systemic antibiotics and ocular penetration are available; however, linezolid and fluoroquinolones such as levofloxacin and moxifloxacin have been shown to achieve good ocular penetration [42].

Antibiotic Toxicity

Antibiotics can cause serious side effects if not used appropriately. Topical antibiotics are concentrated locally; therefore, systemic side effects should not occur. However, topical antibiotic formulations can cause some serious tissue side effects. Tissue side effects could be due to the antibiotic or the preservatives and vehicles used in the formulation [1]. Topical chloramphenicol is no longer used, but this drug had been known to cause idiosyncratic bone marrow suppression, aplastic anemia, and death [1, 4]. Topical neomycin is in multiple combination products such as Polytrim® and Neosporin®. Neomycin has been associated with punctate staining of the cornea [1]; therefore, patients should be informed about this undesirable side effect. Fluoroquinolones are one of the commonly used topical antibiotics, yet these agents also have side effects. One study found that moxifloxacin had the least cytotoxic effects against corneal and/or conjunctival epithelial cells compared to other fluoroquinolones, while all caused thinning of the corneal epithelial layer after 7 days of treatment [58]; however, other studies have not shown the same effects [59, 60]. The conflicting data on moxifloxacin was explained by the absence of preservatives such as 0.005 % or 0.006 % benzalkonium chloride, whereas other fluoroquinolones have preservatives which have been associated with tissue toxicity [61].

The preservatives or vehicles in the ophthalmic formulation can cause additive side effects such as hypersensitivity reaction or reduction in antimicrobial activity, which are mainly known from experience with thimerosal (a common preservative in contact lens solution) [1, 4]. As previously mentioned, benzalkonium chloride may inhibit epithelial adhesion, cause a loss of superficial epithelial cells, and delay healing of the epithelium [1].

Antibiotic toxicity could also occur due to the mode of administration. Retinal toxicity has been reported from intravitreal injection as well as subconjunctival injection of aminoglycosides. These modes of antibiotic administration will reach high concentration in the intraocular site; however, it increases the exposure of high drug concentration near the retina which could cause chemical damage. Multiple case series have shown that retinal toxicity and macular ischemia can occur with intravitreal injection of aminoglycosides such as amikacin or gentamicin [62, 63]. When using intravitreal injection, these medications should be administered close to the anterior part of the vitreous cavity to help avoid retinal side effects [42]. Another mode of administration is intracameral antibiotic injection which can be done after cataract surgery to prevent postoperative bacterial endophthalmitis [64]. This is often completed with cefuroxime, and multiple cases have been reported with retinal toxicity and hemorrhagic retinal infarction [65, 66].

Parenteral antibiotics are known to have numerous adverse side effects. Penicillin derivatives are most commonly associated with hypersensitivity reactions that range from minor drug rash to life-threatening reactions such as Stevens-Johnson syndrome or anaphylaxis [4, 46]. Patients may also develop serum sickness with fever, urticaria, joint pains, and angioneurotic edema; however, this syndrome is very rare. Penicillin and penicillin derivatives can also cause renal toxicity such as allergic angiitis or interstitial nephritis. Antistaphylococcal penicillins (i.e., methicillin or nafcillin) have been highly associated with interstitial nephritis which presents with fever, macular rash, eosinophilia, proteinuria, eosinophiluria, and hematuria [46]. Penicillin and penicillin derivatives can lower the seizure threshold; however, this effect is more common with large doses and in patient with renal dysfunction. When prescribing penicillin derivatives to treat ocular infections, it is important to obtain the patient’s allergy history to ensure that these antibiotics are appropriate for the specific patient.

Cephalosporins have adverse reactions that are similar to those encountered with penicillin and penicillin derivatives, but these medications are generally well tolerated. Hypersensitivity reactions can occur, although not as commonly as with the penicillins [67]. Adverse reactions between the different generations of cephalosporins include gastrointestinal, hematologic, and central nervous system effects that are mostly similar. However, the third-generation cephalosporin, ceftriaxone, has been specifically associated with obstructive biliary toxicity [68, 69]. This syndrome is reversible after antibiotic cessation [67], but the ophthalmologist should consider an alternative therapy in patients with known hepatic diseases and neonates younger than 28 days. Elevation of serum creatinine has been reported; however, renal toxicity is not as common as is seen with the penicillins [70]. Although cephalosporins may not play a significant role in renal toxicity, cefepime should be used with caution as encephalopathy and seizures have been reported in patients with renal insufficiency [71–73].

Carbapenems do not have major adverse effects and are generally well tolerated. The most serious side effect that requires monitoring is seizure activity, as all carbapenems possess a structural similarity to γ-aminobutyric acid (GABA) and can have an antagonistic effect on the action of this neurotransmitter [74]. Cross-reactivity with the penicillins has been documented as between 0 and 11 %; however, carbapenem use is considered safe if the penicillin skin test is negative [75].

Fluoroquinolones can cause severe adverse effects that need close monitoring. Although not generally severe or serious, gastrointestinal-related symptoms are the most common side effects. Similar to carbapenems, adverse events involving the central nervous system such as headache, dizziness, insomnia, and seizures can manifest with fluoroquinolone [13]. Cardiovascular effects, especially QT interval prolongation, are well known with the older quinolones; the newer generations also possess these side effects but with a lesser intensity [76–78]. Although tendinitis and joint toxicity have been reported with fluoroquinolones, these side effects are not as common. One adverse event of concern in ophthalmology patients is the potential for retinal detachment with fluoroquinolones. Due to their ability to achieve high concentration in the ocular tissue and cause collagen and connective tissue damage, the patients in one study who were prescribed fluoroquinolones carried a 4.5-fold increased risk for retinal detachment [79]. Another study has shown a similar result when fluoroquinolones were compared to amoxicillin [80]; however, a third study did not show the same effect [81]. Ophthalmologists should use caution when prescribing oral fluoroquinolones, especially in patients with high risk for retinal detachment.

As resistance has been increasing, more broad-spectrum antibiotics such as vancomycin and linezolid have been used to treat intraocular infection with methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin has been used for the past 50 years, and its adverse effects have been studied extensively. The most common side effect of vancomycin is related to medication infusion rate, also known as red man syndrome. This can be minimized with reduction of infusion rate or premedication with antihistamines. Numerous studies have been done to find the risk factors for vancomycin-associated nephrotoxicity. Such risk factors are large total daily dose (≥4 g/day), obesity (weight ≥ 101.4 kg) [82], higher vancomycin trough levels (≥15 μg/mL), concomitant use of nephrotoxic medications, and prolonged duration of therapy [83, 84]. Other adverse events such as drug rash, drug-related fever, thrombocytopenia, and neutropenia can occur, but these effects are not as common [47].

Thrombocytopenia with linezolid has been well documented in the literature. The decrease in platelet count occurs with longer duration of therapy, at least 2 weeks; however, it can occur earlier and thus requires close monitoring [85]. Another serious side effect associated with linezolid is a potential drug interaction with serotonergic agents and serotonin syndrome with fever, agitation, mental status changes, and tremor [85]. Therefore, caution should be practiced when prescribing linezolid to a patient who is already taking other serotonergic agents. Although not as common, peripheral neuropathy and optic neuropathy can occur when taking linezolid [86]. Optic neuropathy is another consequence of its enhanced ability to penetrate the eye which can cause vision loss [48]. Therefore, patients who are taking linezolid for a prolonged duration should follow up with an ophthalmologist for early detection of any vision changes to prevent visual loss.

One of the serious side effects associated with amphotericin B is nephrotoxicity. It damages renal tubular cells, which disrupts tubular basement membrane and causes functioning nephron loss [49]. It also leads to electrolyte wasting, especially of potassium, magnesium, and bicarbonate [49]. This is associated with all four formulations; however, amphotericin B deoxycholate is associated with acute infusion-related reactions such as chills, fever, and tachycardia. Nausea, vomiting, and liver enzyme elevations have been associated with amphotericin B. Similarly, flucytosine should be used with caution in patients with renal dysfunction. It can cause fatal bone marrow toxicity such as leukopenia and thrombocytopenia [49]. Therapeutic drug monitoring is recommended for flucytosine twice weekly. It is also teratogenic, therefore, contraindicated in pregnancy. Azoles are generally well tolerated with minimal side effects such as gastrointestinal and hepatic toxicity. Voriconazole has been known to cause visual disturbances, hallucination, and confusion [49]. For patients who are intolerant to voriconazole due to visual disturbances, the newest azole, isavuconazonium sulfate, could be an alternative option if broad-spectrum coverage is necessary. Echinocandins infrequently cause adverse reactions. Occasionally histamine-mediated symptoms such as rash, pruritus, dyspnea, and hypotension may occur, but echinocandins are not hepatotoxic or nephrotoxic [49].

Intravenous acyclovir can cause reversible renal dysfunction and neurotoxicity. Clinical manifestations such as lethargy, confusion, hallucinations, seizures, or coma could occur, and patients can experience neurotoxicity within 1–3 days of treatment [40]. This is more common with valacyclovir. Oral acyclovir is generally well tolerated but could cause diarrhea, rash, and headache. Ganciclovir and valganciclovir cause myelosuppression and CNS toxicity. The most common reasons for early discontinuation of these agents are severe neutropenia and thrombocytopenia [40].

Summary

Ocular infections can be treated with topical antibiotic agents, subconjunctival or intravitreal antibiotic injections, or systemic antibiotics depending on the type of infection and the depth of intraocular eye involvement. Each mode of administration has advantages and disadvantages with regard to delivery of an appropriate drug concentration at the site of infection and the potential for antibiotic toxicity. Choosing the right therapy with appropriate bacterial, fungal, and/or viral coverage, mode of administration, and pharmacologic activity is critical when treating ocular infections.