Fig. 17.1
(Left) Patient with postoperative endophthalmitis on day 1 after cataract surgery. Managed with pars plana vitrectomy and intravitreal antibiotics. (Right) Quiet eye showing resolved infection at 6-month follow-up. Vitreous grew Serratia marcescens and was sensitive to aminoglycosides and cephalosporins
Prevalence and Classification
The clinical settings in which endophthalmitis caused by gram-negative bacteria can occur include postoperative, post open-globe injury, and endogenous. Postoperative endophthalmitis is more common. The rate of endophthalmitis caused by gram-negative bacteria is reported to be 26–42% in developing countries and 5.9–12% in developed countries [1–4] (Table 17.1). It is important to note that gram-negative bacteria constitute <5% of the conjunctival and lid flora in adults [5]. Hence, in most cases, the organism is introduced from an exogenous source.
Gram-negative bacteria could be classified into cocci and bacilli. On the basis of biochemical profile and antibiotic resistance, gram-negative bacteria could also be classified in two groups—enterics (Enterobacteriaceae) and non-enterics (non-Enterobacteriaceae) (Table 17.2, [1]).
Common gram-negative bacteria causing endophthalmitis | |
|---|---|
Enterobacteriaceae group | Non-Enterobacteriaceae group |
Proteus species | Pseudomonas species |
Serratia species | Haemophilus species |
Achromobacter species | Burkholderia species |
Bacteroides species | |
Neisseria species | |
Enterobacteriaceae group have pathogens that are increasingly becoming multidrug resistant particularly to third-generation cephalosporins due to the overproduction of beta-lactamases. The non-Enterobacteriaceae group are known to be inherently resistant to many third-generation cephalosporins and fluoroquinolones.
Virulence Factors and Pathogenesis
Gram-negative bacteria have various virulence factors, which act like enzymes that dissolve tissues or toxins that kill the cells. Virulence factors include endotoxin/lipopolysaccharide (LPS), exotoxins, and enterotoxins [6]. Some virulence factors are organism specific and will be discussed along with organisms subsequently.
Endotoxin/LPS—This virulence factor is present in the outer membrane of the gram-negative bacteria. These are the glycopeptides, which make up about 75% of outer membrane of gram-negative organisms that are capable of causing lethal shock. Lipopolysaccharide consists of a lipid-A domain, an oligosaccharide core, and the outermost O-antigen polysaccharide. Lipid-A domain is the region identified by innate immune system, and even small concentration of it is sufficient to trigger immune response that manifests in release of cytokines (interleukin-1β, tumor necrosis factor-α) from macrophages. Lipid-A component of LPS can also cause endothelial cell injury by promoting the expression of tissue factor and pro-inflammatory cytokines, leading to apoptosis of these cells. Presence of lipid-A in bloodstream can lead to endotoxin shock. LPS binds to the toll-like receptors (TLR-4) and activate it resulting in further release of inflammatory cytokines.
Exotoxin/Protein A—Exotoxin A is part of an enzyme family called mono-ADP-ribosyltransferase [6]. The toxin catalyzes the ADP ribosylation of eukaryotic elongation factor 2 and affects the protein synthesis in host cells by a mechanism similar to diphtheria toxin. This secreted exotoxin is a potent virulence factor specifically for Pseudomonas species.
Specific Gram-Negative Endophthalmitis
Endophthalmitis caused by the common gram-negative bacteria is discussed in this section. These bacteria have some specific toxins and virulence factors that may be associated with severe inflammation and tissue damage.
Endophthalmitis Caused by Proteus Species
Proteus species is a part of normal colonic flora and is often associated with urinary tract infections, pneumonia, otitis media, and wound infections. Endophthalmitis by Proteus species results from inoculation of normal flora into the eye. It could occur in the following settings: postcataract surgery, retained lens fragment during cataract surgery, penetrating keratoplasty, scleral buckle procedure, trauma, and ocular prosthesis. Proteus species are the most frequent gram-negative bacteria causing postoperative endophthalmitis after cataract surgery [7, 8]. In the Endophthalmitis Vitrectomy Study (EVS), Proteus species accounted for 6/19 (32%) cases of gram-negative bacteria among 291 cases (323 isolates) studied (Table 17.3) [1].
Gram-negative organisms reported in the EVS (19/323 isolates from 291 patients) | |
|---|---|
Gram-negative organisms | n/N (%) |
Proteus mirabilis | 6/19 (1.9) |
Pseudomonas aeruginosa | 3/19 (0.9) |
Pseudomonas vesicularis | 1/19 (0.3) |
Pseudomonas fluorescens | 1/19 (0.3) |
Morganella morganii | 2/19 (0.6) |
Citrobacter diversus | 2/19 (0.6) |
Serratia marcescens | 1/19 (0.3) |
Enterobacter agglomerans | 1/19 (0.3) |
Enterobacter aerogenes | 1/19 (0.3) |
Flavobacterium species | 1/19 (0.3) |
Infection with Proteus species progresses rapidly and causes extensive tissue destruction. Virulence factors such as endotoxin, hemolysin (aids in spread of infection), urease (increases tissue pH), and presence of fimbriae on surface (aid in adherence and colonization of tissues) in Proteus species help bacteria in tissue damage [9]. Visual prognosis is poor in most of the studies. Aminoglycosides and beta-lactam antibiotics (ceftazidime) are active against most of the Proteus species. The reported resistance to aminoglycosides and beta-lactam drugs is an important concern as these are the first-line intravitreal drugs used in the empiric management of endophthalmitis against gram-negative bacteria.
Leng et al. reported a retrospective consecutive case series of all culture-positive endophthalmitis cases over a period of 24 years, 1983–2007 [9]. In this series, 1751 organisms were isolated from intraocular culture, and 244 were gram-negative organisms. Proteus species was identified in 13 cases (5%; 13/244). All the isolates in this study were susceptible to aminoglycoside antibiotics. Visual outcomes in this study were poor despite treatment with sensitive antibiotics. Visual acuity of 20/200 or worse was reported in 12 patients including 8 patients with light perception or worse. The patients who underwent early vitrectomy did better than those who were managed with initial tap and injection of antibiotics; however, due to small number of cases, no statistical conclusion could be made.
Endophthalmitis Caused by Klebsiella Species
Klebsiella is part of the normal flora of nasopharynx and gastrointestinal tract. Klebsiella species have emerged as a leading cause of pyogenic liver abscess in Asia. Patients with liver abscess, diabetes mellitus, immunocompromised status, delayed treatment of systemic Klebsiella infection, and poor glycemic control are at high risk of developing endogenous endophthalmitis. Klebsiella liver abscesses are associated with 3–11% incidence of endogenous endophthalmitis [10, 11]. Polysaccharide capsule (specific capsular serotypes conferring resistance to phagocytosis) and genetic susceptibility to K1 and K2 serotypes of Klebsiella pneumoniae act as virulence factors and help the organism evade immune response of the host with resultant infection [12]. Patients with endogenous endophthalmitis caused by Klebsiella species have higher rate of mortality.
Klebsiella species infection was not reported in the EVS [1]. Endophthalmitis caused by Klebsiella species, though hitherto less common, is increasingly reported worldwide and in the USA [13–18]. It is generally associated with poor visual outcomes despite adequate treatment. Endogenous endophthalmitis cases have higher rates of enucleation or evisceration. Some advocate early surgical intervention such as pars plana vitrectomy, in view of poor visual and anatomical outcomes.
Sridhar et al. compiled a non-comparative consecutive case series of seven patients with Klebsiella endophthalmitis during a period of 22 years, 1990–2012, from a large university referral center [19]. They reported that endogenous cases in this series were associated with poorest outcomes and that all cases underwent evisceration or enucleation. In another case series, three patients of multidrug-resistant Klebsiella species endophthalmitis ran a rapid and fulminant course with severe intraocular inflammation [20]. The organisms in this small series of three cases were susceptible only to imipenem, and despite treatment the outcome was poor.
Endophthalmitis Caused by Achromobacter Species
Achromobacter xylosoxidans is an aerobic, motile, gram-negative bacillus common in humid environment and is an important nosocomial pathogen. Achromobacter is the part of normal flora of ear and gastrointestinal tract. Although it is an uncommon pathogen, it could cause both acute-onset and delayed-onset postoperative endophthalmitis. Achromobacter xylosoxidans infection is more commonly seen in immunocompromised hosts, renal insufficiency, diabetes mellitus, carcinoma, alcoholism, tuberculosis, or endogenous immunosuppressed individuals [21, 22]. It may infect immunocompetent individuals as well. This organism has been shown to produce biofilm to survive in toxic environment [23]. It is important to differentiate between Pseudomonas species and Achromobacter xylosoxidans as both organisms are gram-negative, non-fermentative bacilli growing in humid environment and opportunistic pathogens with very similar antibiotic resistance pattern. Pseudomonas species are invariably associated with a fulminant and a severe disease course as compared to indolent course for Achromobacter xylosoxidans. A retrospective study suggested that ceftazidime and amikacin are the antibiotics of choice for ocular infections by Achromobacter xylosoxidans [24].
In 2014, Villegas et al. reported non-comparative consecutive case series of culture-proven Achromobacter xylosoxidans endophthalmitis between 1970 and 2012 at a university referral center in the USA [25]. All four patients in this series with endophthalmitis caused by Achromobacter xylosoxidans underwent capsulectomy, intraocular lens removal, and intravitreal injection of antibiotics at the time of pars plana vitrectomy. Two of four patients recovered to 20/40 or better, and the vision in other two patients was 20/200 or worse.
Endophthalmitis Caused by Serratia Species
Serratia marcescens is a gram-negative bacillus most often implicated as a cause of nosocomial infections such as hospital-acquired pneumonia, urinary tract infection, and wound infection [26]. In the EVS, Serratia marcescens was not identified in any of the culture-positive isolates [1]. The visual and anatomic outcomes are usually poor [26].
Sridhar et al. reported ten cases over 20-year period, 1993–2012, of Serratia marcescens endophthalmitis at a large university referral center. All isolates were sensitive to gentamicin, ceftazidime, imipenem, and levofloxacin and further reported that MIC90s of isolates for antibiotics tested remained unchanged from 1980 onward. All isolates were resistant to vancomycin. In this series, outcomes were generally poor with a high rate of complete visual loss in the affected eye. Final visual acuity was no light perception in six of ten patients.
Endophthalmitis Caused by Pseudomonas Species
In the EVS, Pseudomonas aeruginosa accounted for approximately 1% of culture-positive endophthalmitis cases (Table 17.3) [1]. Few other large series have reported incidence of Pseudomonas aeruginosa acute postoperative endophthalmitis from 8% to 34% [3, 27, 28]. Pseudomonas aeruginosa produces elastases and exotoxins that may cause permanent damage to the intraocular contents and cause severe globe disorganization. This bacteria can survive well in aqueous environment for long periods as multiple outbreaks of Pseudomonas aeruginosa endophthalmitis have been reported secondary to contaminated ophthalmic solutions, phacoemulsifier internal fluid, intraocular lens solution, and contaminated phacoprobes [29–32]. There are reports of increasing drug resistance among Pseudomonas aeruginosa to fluoroquinolones, aminoglycosides, piperacillin-tazobactam, and ceftazidime [4, 33]. In one case of endophthalmitis due to gram-negative bacteria resistant to aminoglycoside and cephalosporin, intravitreal imipenem helped resolution of infection [20]. Efflux pumps and inhibition of drug intake are common components of multidrug-resistant Pseudomonas isolates that prevent accumulation of antibacterial drugs within the bacterium [34].
Sridhar et al. reported 12 consecutive cases of Pseudomonas aeruginosa endophthalmitis over a 10-year period. The primary surgeries were cataract surgery, penetrating keratoplasty, pars plana vitrectomy, glaucoma filtration surgery, and endogenous infection [35]. In this series, all patients presented with hypopyon and poor visual acuity (hand motions or worse). All isolates were susceptible to ceftazidime and levofloxacin and the MIC90 remained stable as compared to isolates from 1987 to 2001. Visual and anatomical outcomes were poor in this series despite early and appropriate treatment. Visual acuity at final follow-up was 20/400 or worse in 11 of 12 patients, light perception in 8 of 12 patients, and enucleation was required in five patients.
Endophthalmitis Caused by Haemophilus Species
Haemophilus influenzae is a fastidious, aerobic, gram-negative coccobacillus, which is an uncommon cause of endophthalmitis. Endophthalmitis caused by Haemophilus influenzae could occur in following clinical settings: filtering surgery, cataract surgery, strabismus surgery, vitrectomy, intraocular lens (IOL) implantation, IOL extrusion, and corneal ulceration [36–38]. Delayed onset endophthalmitis more often occurs in bleb-associated endophthalmitis caused by Haemophilus influenzae [39]. In the EVS, none of the cases were reported with Haemophilus species infection [1].
Yoder et al. reported a retrospective, non-comparative, 16 consecutive cases of Haemophilus influenzae endophthalmitis during 22 years at a university teaching center [39]. In this cohort, vitreous tap and intravitreal antibiotic injection was given initially in nine eyes, and a vitrectomy was performed initially in the remaining seven eyes. In addition to all eyes receiving intravitreal antibiotics at initial treatment presentation, 11 eyes also received intravitreal dexamethasone. The organisms were sensitive to at least one of the initial intravitreal antibiotics administered in all cases. The visual outcome was poor despite prompt treatment with sensitive intravitreal antibiotics. Final visual acuity was 5/200 or better in six eyes, and in six eyes, the final visual acuity was no light perception.
Antimicrobial Susceptibilities
Intravitreal ceftazidime or amikacin are commonly used drugs for the empiric treatment of gram-negative endophthalmitis. In the EVS, 89.5% of gram-negative bacteria were sensitive to both amikacin and ceftazidime. However, Kunimoto et al. reported gram-negative isolates susceptibility to ciprofloxacin (87.5%), amikacin (82.1%), and ceftazidime (60.9%) [40]. In a recent publication by the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study in 2015, there was no increase in overall ocular resistance during the 5-year study period (January 2009–December 2013) [41]. A recent report on antimicrobial susceptibilities (measured by disk diffusion, Vitek 2, and E-test) evaluated the records from culture-positive vitreous isolates (endophthalmitis cases with gram-negative bacteria) during a 24-year period (December 1990–December 2014), at the Microbiology Department of Bascom Palmer Eye Institute, Miami, Florida, USA, for four antibiotic groups: aminoglycosides, cephalosporins, carbapenems, and fluoroquinolones (Wilson et al. submitted to JAMA Ophthalmology 2016). This report showed no increase in drug resistance. A prior 9-year (January 1982–December 1990) study from the same center also showed no increase in the drug resistance among gram-negative bacteria [36]. The collective experience from these studies shows that antibiotic susceptibility pattern of gram-negative bacteria from vitreous isolates has not changed.
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