Coryneform Endophthalmitis Two Case James W.
clinical studies have emphasized the importance of diphtheroids, previously regarded as nonpathogenic bacteria or contaminants, as causes of ocular disease. We encountered two patients with endophthalmitis following cataract extraction and anterior chamber intraocular lens implantation. Both patients had previously been treated with subconjunctival and/or oral corticosteroids for presumed sterile endophthalmitis. Vitreous cultures in each case yielded pure growth of a diphtheroid that was subsequently identified as coryneform group A-4. The clinical response to standard intraocular therapy with gentamicin and cefazolin was delayed, although both patients eventually had restoration of functional vision. A comparison of the antibiotic minimum inhibitory and minimum bactericidal concentrations of the isolates may help to explain the delayed response to therapy seen in these two patients.
(Arch Ophthalmol. 1990;108:942-944)
T^he family of coryneform bacteria
organisms from the gen¬ Corynebacterium, Brevibacterium, Arthrobacter, Cellulomonas, Curtobacterium, Microbacterium, Caseobacter, Rhodococcus, and Oerskovia; includes
era
many authorities also include Pro-
Corynebacterium pionibacterium. ' diphtheriae2 and Propionibacterium well-documented ocular
pathogens. Microbiologists define diphtheroids as a group of gram-posi¬ tive pleomorphic rods in the coryne¬ form family that stain irregularly; they may be confused with C diph¬ theriae.1 Diphtheroids are ubiquitous in the environment and can be readily isolated from soil, water, and air. They commonly colonize both plants and animals' and are part of the normal skin and mucous membrane flora.10
Previously regarded as nonpathogenic organisms or as contaminants, diph¬ theroids are increasingly recognized as
100 with the anterior chamber reaction
McManaway III, MD; Robert S. Weinberg, MD; Philip
are
Three days after initiation of antibiotic therapy, the patient's visual acuity was 20/
Reports
\s=b\ Recent
acnesiSS
500 mg of cefazolin sodium every 6 hours.
the cause of serious systemic912 and
Accepted for publication March 28, 1990. From the Department of Ophthalmology (Drs McManaway and Weinberg) and the Clinical Microbiology Laboratory (Dr Coudron), Medical College of Virginia, Richmond. Dr McManaway is now with the Department of Ophthalmology at the Milton S. Hershey Medical Center, Hershey, Pa.
Reprint requests to Department of Ophthalmology, Hershey Medical Center, PO Box 850, Hershey, PA 17033 (Dr McManaway).
E.
Coudron, PhD
ocular13 diseases. This article presents the clinical his¬ tory and response to therapy of two patients with coryneform group A-4 endophthalmitis, allowing further def¬ inition of the spectrum of diphtheroidinduced disease. Endophthalmitis caused by diphtheroids is exceedingly rare,14 although a report of one patient with coryneform group A-4 endoph¬ thalmitis exists,15 and a recent article"' describes a patient who developed coryneform endophthalmitis follow¬ ing penetrating keratoplasty with con¬ taminated donor material. REPORT OF CASES
Two patients were found to have coryne¬ form group A-4 endophthalmitis after intracapsular cataract extraction with im¬ plantation of Surgidev Leiske-style ante¬ rior chamber lenses. Case 1.—A 66-year-old white woman who had had bilateral intracapsular cata¬ ract extractions underwent an uncompli¬ cated secondary intraocular lens implanta¬ tion in one eye 7 years later. On the fourth postoperative day, her visual acuity was 20/60 with 1+ anterior chamber cells and flare. On postoperative day 10, she devel¬ oped pain and redness in the eye that had been operated on. Her visual acuity was hand motions only, and the vitreous humor was cloudy. The patient was treated with 500 mg of oral penicillin V potassium four times daily. Topical prednisolone acetate therapy, started on postoperative day 1, was increased to every 2 hours. The exam¬ ination findings were unchanged on day 16; penicillin therapy was stopped, and 3 mg of subconjunctival betamethasone sodium phosphate was given. The examination findings were unchanged 2 weeks later; treatment with 100 mg of oral prednisone every other day was started, and an addi¬ tional injection of betamethasone was given. Over the next 10 days, a hypopyon developed with loss of the red reflex, and the patient was referred to one of us (R.S.W.) for treatment. Examination on postoperative day 40 showed hand motions visual acuity, con¬ junctival injection hyperemia (3+), multi¬ ple keratic precipitates, and anterior cham¬ ber cells and flare (4+). The vitreous humor showed stringy white debris with a white fundus reflex. The patient underwent a pars plana vitrectomy, and material was ob¬ tained for bacterial, fungal, and mycobacterial cultures. Two hundred micrograms of gentamicin sulfate and 2.25 mg of cefazolin sodium were injected into the vitreous cav¬ ity and 20 mg of gentamicin sulfate was given subconjunctivally. The patient was also started on intravenous therapy with 80 mg of gentamicin sulfate every 8 hours and
un¬
changed; the vitreous humor was still hazy. The microbiology laboratory reported heavy growth of diphtheroidlike organisms in pure culture, but final identification and
antibiotic sensitivities were not available. Visual acuity on the sixth day of treatment was 20/200 with cells and flare (3+) in the anterior chamber and vitreous cells (3+). Antibiotic sensitivities, delayed because of slow growth of the organism on secondary cultures, became available on the ninth day. The disk-diffusion method demonstrated sensitivity to all antibiotics tested, includ¬ ing penicillin, gentamicin, and cefazolin. On day 10, the examination results were unchanged; the administration of intrave¬ nous gentamicin and cefazolin was discon¬ tinued and treatment with 250 mg of oral penicillin V potassium every 8 hours was started. Topical prednisolone acetate solu¬ tion was also restarted. At discharge on day 13, the patient's visual acuity was 20/70 with anterior chamber cells and flare (3+) and vitreous cells (3+). Oral penicillin treatment was continued for 2 weeks. There was gradual clearing of the ante¬ rior chamber and vitreous inflammation. The patient's visual acuity was 20/30 sev¬ eral months later. The organism was iden¬ tified by the microbiology laboratory and confirmed by the Centers for Disease Con¬
trol, Atlanta, Ga,
as
coryneform
group
A-4. Case 2.—An 83-year-old white woman underwent uncomplicated intracapsular cataract extraction and anterior chamber intraocular lens implantation in the left eye. Twelve weeks after surgery, her visual acuity was 20/30 with a clear anterior chamber and vitreous cavity. Two exposed sutures were noted. During the 16th post¬ operative week, the patient developed in¬ termittent pain and gradual visual loss in the eye that had been operated on. Her vi¬ sual acuity was hand motions, with cells and flare (3+) in the anterior chamber and a hazy vitreous humor. She was treated with subconjunctival dexamethasone so¬ dium phosphate for presumed sterile en¬ dophthalmitis, and an exposed limbal su¬ ture was removed. Her visual acuity im¬ proved to 20/300 but subsequently fell to light perception with a hypopyon by post¬ operative week 17. She was treated with daily subconjunctival dexamethasone for 7 days. The hypopyon cleared, but because of persistent vitreous clouding, she was re¬ ferred to one of us (R.S.W.) for treat¬ ment.
Examination during postoperative week 18 revealed 20/300 visual acuity, diffuse corneal endothelial dusting, anterior cham¬ ber cells and flare (3+), a 1-mm hypopyon, vitreous cells (3+), dense white vitreous opacifications, and a pale red reflex (Fig¬ ure). The patient underwent a pars plana vitreous aspiration; material was taken from the area of the vitreous densities for bacterial and fungal cultures. Intravitreal injections of 400 ßg of gentamicin sulfate and 2.25 mg of cefazolin sodium, as well as subconjunctival injections of 20 mg of gen-
Downloaded From: http://archopht.jamanetwork.com/ by a Georgetown University Medical Center User on 05/25/2015
Antibiotic Sensitivities of Coryneform
Group
A-4
Organisms Isolated From Human
Vitreous* Minimum Inhibitory Concentration, mg/L Penicillin
Patient
G Sodium 0.0975 0.0975
Minimum Bactericidal
Concentration, mg/L
Cefazolin Sodium
Gentamicin Sulfate
0.195
1.56 1.56
0.195
Penicillin
Cefazolin
Gentamicin
0.78
25.0 25.0
25.0
1.56
50.0
From Coudron et al.!
Anterior segment demonstrating small hy¬ popyon (arrow) in patient with coryneform group A-4 endophthalmitis.
tamicin sulfate and 100 mg of cefazolin
so¬
dium, were given. Intravenous therapy with 80 mg of gentamicin sulfate every 8 hours
and 500 mg of cefazolin sodium every 8 hours was started. Gram's stain of the vit¬ reous specimen showed rare gram-variable rods. The patient showed little improvement over the next several days with a visual acuity of counting fingers at 30 cm and a 1-mm hypopyon. The microbiology labora¬ tory reported moderate growth of a grampositive pleomorphic rod 48 hours after re¬ ceiving the vitreous specimen. Cefazolin dosage was increased to 1 g intravenously every 6 hours on day 4. On day 7, antibiotic sensitivity studies by the disk-diffusion method showed the organism to be sensi¬ tive to all antibiotics tested, including pen¬ icillin, cefazolin, and gentamicin. The or¬ ganism from the vitreous specimen was also identified as coryneform group A-4. On day 8, intravenous antibiotic therapy was stopped. Treatment with 500 mg of oral penicillin V potassium four times daily and topical prednisolone acetate was started and continued for 2 weeks. Over the next several days, the patient showed gradual improvement with increasing visual acuity and decreasing vitreous haze. Visual acuity on day 12 was 20/400 with anterior chamber cells and flare (2+), no hypopyon, and min¬ imal vitreous haze. Three months after vit¬ reous aspiration, the visual acuity was 20/ 50 with a clear anterior chamber and vitre¬ ous cells (1+). COMMENT
Diphtheroids
are
ubiquitous in the
environment and are part of the nor¬ mal flora of skin, mucous membranes,10 and conjunctivae.17 Therefore, they may contaminate clinical specimens sent to the microbiology laboratory.10 When isolated, diphtheroids are usu¬ ally dismissed by microbiologists as contaminants. In addition, some spe¬ cies of Corynebacterium grow more slowly than routine clinical isolates.11 Consequently, the culture media may be discarded prematurely unless spe¬ cial instructions accompany the speci¬ men. In both of our patients, however, coryneform group A-4 bacteria were isolated in large numbers on the pri-
mary agar media and in the broth me¬ dia in pure culture. These findings
strongly suggest that our isolates were true pathogens and not contaminants. A recent report13 decribes diphthe¬ roids as the causative agent in eight patients with bacterial keratitis. Since diphtheroids are part of the normal conjunctival flora in 7% of individ¬ uals,17 factors that compromised the corneal surface may have predisposed these patients to develop bacterial keratitis. Diphtheroids have similarly been reported as the causative agent in endocarditis, meningitis, pneumonia, and cutaneous infections,'12 generally in immunocompromised patients. The two cases reported herein ex¬ pand the spectrum of diphtheroid-in-
duced ocular disease and demonstrate important points regarding the diag¬ nosis and treatment of patients pre¬ senting with unexpected postoperative intraocular inflammation. First, both patients presented with delayed en¬ dophthalmitis following surgery. Pa¬ tient 1, presumably infected from her conjunctival flora at the time of or shortly after surgery, developed pain on postoperative day 10 and a hy¬ popyon on postoperative day 40. Pa¬ tient 2, possibly infected by an exposed
suture, developed pain during postop¬
erative week 16 and a hypopyon during postoperative week 17. This indolent presentation contrasts distinctly with the abrupt onset and progressive course of typical bacterial endoph¬ thalmitis.18 It is certainly comparable with the course of patients infected with other slow-growing organisms or patients having "sterile" endoph¬ thalmitis." The prevalence of diphthe¬ roids in the conjunctiva, and the dem¬ onstration that these bacteria can cause an
atypical endophthalmitis, un¬
derscores the importance of diagnostic intraocular cultures in eyes with a re¬ cent history of an intraocular proce¬ dure that have persistent severe in¬ flammation. Second, many systemic and ocular diphtheroid infections are associated with locally13 or systemically912 immu¬ nocompromised and/or elderly pa¬ tients; both of our patients were el-
derly. Patient 1 had no identifiable factors predisposing to infection; pa¬ tient 2 had an exposed suture as well as non-insulin-dependent diabetes mellitus. It is important to note that both patients received subconjunctival and/or oral steroid therapy prior to adequate antibiotic therapy shortly after becoming symptomatic. The use of corticosteroids in this setting for a presumptive, rather than proved, di¬ agnosis of "sterile" endophthalmitis may have contributed to the worsening clinical status of both patients. Third, both patients had a delayed response following standard therapy for endophthalmitis with intravitreal/
subconjunctival/intravenous
genta¬
micin and cefazolin. Neither patient showed clinical improvement until 10 days after the initiation of antibiotic therapy. This may be explained by ex¬ amining the minimal inhibitory anti¬ biotic concentration and minimal bac¬ tericidal antibiotic concentration (MBC) data obtained by Coudron et al20 (Table) for these two isolates. The minimum inhibitory concentration is the lowest antibiotic concentration re¬ quired to prevent visible turbidity in inoculated broth after overnight incu¬ bation. The MBC is the antibiotic con¬ centration needed to effect a 99.9% re¬ duction in the initial inoculum in 24 hours as measured by colony counts. Antibiotic concentrations greater than the MBC are required to kill, rather than just inhibit, the patho¬
genic organism. Comparison of the MBC of
our iso¬ lates with attainable serum antibiotic concentrations from intravenous dos¬ ing and with attainable intravitreous antibiotic concentrations from intra¬ vitreal injection yields the following: 1. A typical intravenous dose of 1 mg/kg of gentamicin sulfate in a pa¬ tient with normal renal function will give a serum peak level of 4 to 9 mg/L, which will result in a peak concentra¬ tion of less than 0.8 mg/L in the aque¬ ous fluid and even less in the vitreous gel.21 The gentamicin concentration in the vitreous gel attained by intrave¬ nous administration is well below the 25- to 50-mg/L MBC of our isolates.
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2. An injection of 200 to 400 ßg of gentamicin into a 4-mL vitreous vol¬ ume will provide a peak level of 50 to 100 mg/L, which is marginally above the MBC of 25 to 50 mg/L. The dura¬ tion of gentamicin concentration greater than 50 mg/L is unknown but could conceivably be as short as 10 hours if the half-life reported by Kane
et al22 in inflamed rabbit eyes can be extrapolated to inflamed human eyes. 3. A typical intravenous dose of 500 to 1000 mg of cefazolin sodium will give a serum peak level of 30 to 110 mg/L, which will result in a peak concentra¬ tion of less than 0.6 mg/L in the aque¬ ous
fluid and
even
less in the vitreous
gel.21 The cefazolin concentration in the vitreous gel attained by intrave¬ nous
administration is well below the
25-mg/L MBC of our isolates. 4. An injection of 2.25 mg of cefazo¬
lin sodium into a 4-mL vitreous volume will provide a peak level of 562 mg/L, which is well above the MBC of 25 mg/ L. This antibiotic concentration may be above the MBC of our isolates for a duration as short as 24 hours if the pharmacokinetics of cefazolin in in¬ flamed human eyes parallels that in inflamed rabbit eyes as reported by Fisher et al.23 5. Five hundred milligrams of oral penicillin V potassium will give a se¬ rum peak level of 3.0 mg/L,21 but the peak level in the vitreous gel is much less24 and below the 0.78- to 1.56-mg/L MBC of our isolates. The above vitreous antibiotic con¬ centrations obtained from intravenous antibiotic administration assume sin¬ gle doses. As Martin et al25 recently
pointed out, intravenous antibiotics are administered in multiple doses to patients with inflamed eyes. The in¬
travitreal antibiotic concentration achieved may be higher than that in¬ dicated by the single-dose figures but is probably still below the MBC of our isolates. A large, clinically significant dis¬ crepancy exists between the minimum inhibitory concentration and MBC for all three antibiotics: by a factor of 8 to 16 for penicillin, 16 to 32 for gentami¬ cin, and 128 for cefazolin (Table). The disk-diffusion method provides antibi¬ otic sensitivities that correlate with the minimum inhibitory concentration and contrast sharply with the MBC data. Because all choices of antibiotic
therapy ultimately depend on appro¬ priate determination of the sensitivity of the organism and the ability to de¬
liver effective antibiotic concentra¬ tions to the site of infection, the anti¬ biotic sensitivity data available to us
while
our
patients
were
hospitalized
somewhat misleading and inade¬ quate. Thus, we recommend obtaining and using MBC data to select antibiot¬ ics for patients with clinically unre¬ sponsive infections. Additionally, if the organism has a high MBC, we rec¬ ommend considering additional intra¬ vitreal antibiotic injections in patients with unresponsive infections because the half-life of the injected antibiotics in inflamed eyes may be such that a therapeutic antibiotic concentration may be present for an unexpectedly short duration. The two cases of delayed endoph¬ thalmitis presented in this article have important similarities to and differ¬ ences from recent reports of delayed endophthalmitis caused by acnes.3> The similarities include delayed onset of endophthalmitis after intraocular lens implantation and the presence of the infecting organism as part of the normal lid or conjunctival bacterial flora.17 Additionally, morphologic con¬ fusion between propionibacteria and corynebacteria exists because both were
pleomorphic, gram-positive, nonspore-forming bacilli.26 Differences in clinical presentation include the asso¬ ciation of extracapsular cataract ex¬ are
traction and retained lens cortex with
Propionibacterium infections, while both of our patients with coryneform group A-4 infections had undergone intracapsular cataract extraction. The only previous report of coryneform group A-4
endophthalmitis
was
in
a
patient with metallic intraocular for¬ eign body.15 Propionibacterium acnes and coryneform group A-4 are differ¬ entiated by their oxygen tolerance; propionibacteria are anaerobes and corynebacteria are aerobes.26 Defini¬ tive identification requires analysis of cell-wall components by a reference laboratory, as was done in our investi¬ gation. The authors have no commercial or proprietary interest in Surgidev Leiske-style intraocular lenses.
References 1. Coyle MB, Hollis DG, Groman NB. Corynebacterium spp and other coryneform organisms. In: Lennette EH, Balows A, Hausler WJ Jr, Shadomy HJ, eds. Manual of Clinical Microbiology. 4th ed. Washington, DC: American Society for Microbiology; 1985:193-204. 2. Chandler JW, Milam DF. Diphtheria corneal ulcers. Arch Ophthalmol. 1978;96:53-56. 3. Friedman E, Peyman GA, May DR. Endophthalmitis caused by Propionibacterium acnes. Can J Ophthalmol. 1978;13:50-52. 4. Beatty RF, Robin JB, Trousdale MD, Smith RE. Anaerobic endophthalmitis caused by Propionibacterium acnes. Am J Ophthalmol. 1986; 101:114-116. 5. Jaffe GJ, Whitcher JP, Biswell R, Irvine AR.
Propionibacterium acnes endophthalmitis seven months after extracapsular cataract extraction and intraocular lens implantation. Ophthalmic Surg. 1986;17:791-793. 6. Meisler DM, Palestine AG, Vastine DW, et al. Chronic Propionibacterium acnes endophthalmitis after extracapsular cataract extraction and intraocular lens implantation. Am J Ophthal-
mol. 1986;102:733-739. 7. Roussel TJ, Culbertson WW, Jaffe NS. Chronic postoperative endophthalmitis associated with Propionibacterium acnes. Arch Ophthalmol. 1987;105:1199-1201. 8. Meisler DM, Zakov ZN, Bruner WE, Plorde JJ. Endophthalmitis associated with sequestered intraocular Propionibacterium acnes. Am J Ophthalmol. 1987;104:428-429.
9. Lipsky BA, Goldberger AC, Tompkins LS, et al. Infections caused by nondiphtheria corynebacteria. Rev Infect Dis. 1982;4:1220-1235. 10. Kaplan K, Weinstein L. Diphtheroid infections of man. Ann Intern Med. 1969;70:919-929. 11. Locksley RM. The lowly diphtheroid: nondiphtheria corynebacterial infections in humans. West J Med. 1982;137:45-52. 12. Riley PS, Hollis GB, Utter DG, Weaver RE, Baker CN. Characterization and identification of 95 diphtheroid (group JK) cultures isolated from clinical specimens. J Clin Microbiol. 1979;9:418\x=req-\ 424. 13. Rubinfeld RS, Cohen EJ, Arentsen JJ, Laibson PR. Diphtheroids as ocular pathogens. Am J
Ophthalmol. 1989;108:251-254. 14. Brinser JH. Ocular bacteriology. In: Tabbara KF, Hyndiuk RA, eds. Infections of the Eye. Boston, Mass: Little Brown & Co Inc; 1986:129\x=req-\ 130. 15. Hanscom
T, Maxwell WA. Corynebacterium endophthalmitis: laboratory studies and report of a case treated by vitrectomy. Arch Ophthalmol. 1979;97:500-502. 16. Margo CE, Pavan PR, Groden LR. Chronic vitritis with macrophagic inclusions: a sequela of treated endophthalmitis due to a coryneform bacterium. Ophthalmology. 1988;95:156-161. 17. Perkins RE, Kundsin RB, Pratt MV, Abrahamsen I, Leibowitz HM. Bacteriology of normal and infected conjunctiva. J Clin Microbiol. 1975; 1:147-149. 18. Forster RK. Etiology and diagnosis of bacterial postoperative endophthalmitis. Ophthal-
mology. 1978;85:320-326. 19. Forster RK. Endophthalmitis. In: Duane TD, ed. Clinical Ophthalmology. New York, NY: Harper & Row Publishers Inc; 1986;4:1-20. 20. Coudron PE, Harris RC, Vaughan MG, Dalton HP. Two similar but atypical strains of coryneform group A-4 isolated from patients with endophthalmitis. J Clin Microbiol. 1985;22:475\x=req-\
477. 21. Sanford JP. Guide to Antimicrobial Therapy 1989. West Bethesda, Md: Antimicrobial Therapy Inc; 1989:100. 22. Kane A, Barza M, Baum J. Intravitreal injection of gentamicin in rabbits: effect of inflammation and pigmentation on half-life and ocular
distribution. Invest
Ophthalmol Vis Sci. 1981;
20:593-597. 23. Fisher JP, Civiletto SE, Forster RK. Toxicity, efficacy, and clearance of intravitreally in-
jected cefazolin. Arch Ophthalmol. 1982;100:650\x=req-\ 652. 24.
Leopold IH. Intravitreal penetration of penicillin and penicillin therapy of infections of the vitreous. Arch Ophthalmol. 1945;33:211-216. 25. Martin DF, Ficker LA, Aguilar HA, Gardner SK, Wilson LA, Meredith TA. Vitreous cefazolin levels after intravenous injection: effects of inflammation, repeated antibiotic doses, and surgery. Arch Ophthalmol. 1990;108:411-414. 26. Cummins CS, Johnson JL. Genus Propionibacterium. In: Sneath PH, Mair NS, Sharpe ME, Holt JG, eds. Bergey's Manual ofSystematic Bacteriology. Baltimore, Md: Williams & Wilkins; 1986:1346-1353.
Downloaded From: http://archopht.jamanetwork.com/ by a Georgetown University Medical Center User on 05/25/2015
clinical studies have emphasized the importance of diphtheroids, previously regarded as nonpathogenic bacteria or contaminants, as causes of ocular disease. We encountered two patients with endophthalmitis following cataract extraction and anterior chamber intraocular lens implantation. Both patients had previously been treated with subconjunctival and/or oral corticosteroids for presumed sterile endophthalmitis. Vitreous cultures in each case yielded pure growth of a diphtheroid that was subsequently identified as coryneform group A-4. The clinical response to standard intraocular therapy with gentamicin and cefazolin was delayed, although both patients eventually had restoration of functional vision. A comparison of the antibiotic minimum inhibitory and minimum bactericidal concentrations of the isolates may help to explain the delayed response to therapy seen in these two patients.
(Arch Ophthalmol. 1990;108:942-944)
T^he family of coryneform bacteria
organisms from the gen¬ Corynebacterium, Brevibacterium, Arthrobacter, Cellulomonas, Curtobacterium, Microbacterium, Caseobacter, Rhodococcus, and Oerskovia; includes
era
many authorities also include Pro-
Corynebacterium pionibacterium. ' diphtheriae2 and Propionibacterium well-documented ocular
pathogens. Microbiologists define diphtheroids as a group of gram-posi¬ tive pleomorphic rods in the coryne¬ form family that stain irregularly; they may be confused with C diph¬ theriae.1 Diphtheroids are ubiquitous in the environment and can be readily isolated from soil, water, and air. They commonly colonize both plants and animals' and are part of the normal skin and mucous membrane flora.10
Previously regarded as nonpathogenic organisms or as contaminants, diph¬ theroids are increasingly recognized as
100 with the anterior chamber reaction
McManaway III, MD; Robert S. Weinberg, MD; Philip
are
Three days after initiation of antibiotic therapy, the patient's visual acuity was 20/
Reports
\s=b\ Recent
acnesiSS
500 mg of cefazolin sodium every 6 hours.
the cause of serious systemic912 and
Accepted for publication March 28, 1990. From the Department of Ophthalmology (Drs McManaway and Weinberg) and the Clinical Microbiology Laboratory (Dr Coudron), Medical College of Virginia, Richmond. Dr McManaway is now with the Department of Ophthalmology at the Milton S. Hershey Medical Center, Hershey, Pa.
Reprint requests to Department of Ophthalmology, Hershey Medical Center, PO Box 850, Hershey, PA 17033 (Dr McManaway).
E.
Coudron, PhD
ocular13 diseases. This article presents the clinical his¬ tory and response to therapy of two patients with coryneform group A-4 endophthalmitis, allowing further def¬ inition of the spectrum of diphtheroidinduced disease. Endophthalmitis caused by diphtheroids is exceedingly rare,14 although a report of one patient with coryneform group A-4 endoph¬ thalmitis exists,15 and a recent article"' describes a patient who developed coryneform endophthalmitis follow¬ ing penetrating keratoplasty with con¬ taminated donor material. REPORT OF CASES
Two patients were found to have coryne¬ form group A-4 endophthalmitis after intracapsular cataract extraction with im¬ plantation of Surgidev Leiske-style ante¬ rior chamber lenses. Case 1.—A 66-year-old white woman who had had bilateral intracapsular cata¬ ract extractions underwent an uncompli¬ cated secondary intraocular lens implanta¬ tion in one eye 7 years later. On the fourth postoperative day, her visual acuity was 20/60 with 1+ anterior chamber cells and flare. On postoperative day 10, she devel¬ oped pain and redness in the eye that had been operated on. Her visual acuity was hand motions only, and the vitreous humor was cloudy. The patient was treated with 500 mg of oral penicillin V potassium four times daily. Topical prednisolone acetate therapy, started on postoperative day 1, was increased to every 2 hours. The exam¬ ination findings were unchanged on day 16; penicillin therapy was stopped, and 3 mg of subconjunctival betamethasone sodium phosphate was given. The examination findings were unchanged 2 weeks later; treatment with 100 mg of oral prednisone every other day was started, and an addi¬ tional injection of betamethasone was given. Over the next 10 days, a hypopyon developed with loss of the red reflex, and the patient was referred to one of us (R.S.W.) for treatment. Examination on postoperative day 40 showed hand motions visual acuity, con¬ junctival injection hyperemia (3+), multi¬ ple keratic precipitates, and anterior cham¬ ber cells and flare (4+). The vitreous humor showed stringy white debris with a white fundus reflex. The patient underwent a pars plana vitrectomy, and material was ob¬ tained for bacterial, fungal, and mycobacterial cultures. Two hundred micrograms of gentamicin sulfate and 2.25 mg of cefazolin sodium were injected into the vitreous cav¬ ity and 20 mg of gentamicin sulfate was given subconjunctivally. The patient was also started on intravenous therapy with 80 mg of gentamicin sulfate every 8 hours and
un¬
changed; the vitreous humor was still hazy. The microbiology laboratory reported heavy growth of diphtheroidlike organisms in pure culture, but final identification and
antibiotic sensitivities were not available. Visual acuity on the sixth day of treatment was 20/200 with cells and flare (3+) in the anterior chamber and vitreous cells (3+). Antibiotic sensitivities, delayed because of slow growth of the organism on secondary cultures, became available on the ninth day. The disk-diffusion method demonstrated sensitivity to all antibiotics tested, includ¬ ing penicillin, gentamicin, and cefazolin. On day 10, the examination results were unchanged; the administration of intrave¬ nous gentamicin and cefazolin was discon¬ tinued and treatment with 250 mg of oral penicillin V potassium every 8 hours was started. Topical prednisolone acetate solu¬ tion was also restarted. At discharge on day 13, the patient's visual acuity was 20/70 with anterior chamber cells and flare (3+) and vitreous cells (3+). Oral penicillin treatment was continued for 2 weeks. There was gradual clearing of the ante¬ rior chamber and vitreous inflammation. The patient's visual acuity was 20/30 sev¬ eral months later. The organism was iden¬ tified by the microbiology laboratory and confirmed by the Centers for Disease Con¬
trol, Atlanta, Ga,
as
coryneform
group
A-4. Case 2.—An 83-year-old white woman underwent uncomplicated intracapsular cataract extraction and anterior chamber intraocular lens implantation in the left eye. Twelve weeks after surgery, her visual acuity was 20/30 with a clear anterior chamber and vitreous cavity. Two exposed sutures were noted. During the 16th post¬ operative week, the patient developed in¬ termittent pain and gradual visual loss in the eye that had been operated on. Her vi¬ sual acuity was hand motions, with cells and flare (3+) in the anterior chamber and a hazy vitreous humor. She was treated with subconjunctival dexamethasone so¬ dium phosphate for presumed sterile en¬ dophthalmitis, and an exposed limbal su¬ ture was removed. Her visual acuity im¬ proved to 20/300 but subsequently fell to light perception with a hypopyon by post¬ operative week 17. She was treated with daily subconjunctival dexamethasone for 7 days. The hypopyon cleared, but because of persistent vitreous clouding, she was re¬ ferred to one of us (R.S.W.) for treat¬ ment.
Examination during postoperative week 18 revealed 20/300 visual acuity, diffuse corneal endothelial dusting, anterior cham¬ ber cells and flare (3+), a 1-mm hypopyon, vitreous cells (3+), dense white vitreous opacifications, and a pale red reflex (Fig¬ ure). The patient underwent a pars plana vitreous aspiration; material was taken from the area of the vitreous densities for bacterial and fungal cultures. Intravitreal injections of 400 ßg of gentamicin sulfate and 2.25 mg of cefazolin sodium, as well as subconjunctival injections of 20 mg of gen-
Downloaded From: http://archopht.jamanetwork.com/ by a Georgetown University Medical Center User on 05/25/2015
Antibiotic Sensitivities of Coryneform
Group
A-4
Organisms Isolated From Human
Vitreous* Minimum Inhibitory Concentration, mg/L Penicillin
Patient
G Sodium 0.0975 0.0975
Minimum Bactericidal
Concentration, mg/L
Cefazolin Sodium
Gentamicin Sulfate
0.195
1.56 1.56
0.195
Penicillin
Cefazolin
Gentamicin
0.78
25.0 25.0
25.0
1.56
50.0
From Coudron et al.!
Anterior segment demonstrating small hy¬ popyon (arrow) in patient with coryneform group A-4 endophthalmitis.
tamicin sulfate and 100 mg of cefazolin
so¬
dium, were given. Intravenous therapy with 80 mg of gentamicin sulfate every 8 hours
and 500 mg of cefazolin sodium every 8 hours was started. Gram's stain of the vit¬ reous specimen showed rare gram-variable rods. The patient showed little improvement over the next several days with a visual acuity of counting fingers at 30 cm and a 1-mm hypopyon. The microbiology labora¬ tory reported moderate growth of a grampositive pleomorphic rod 48 hours after re¬ ceiving the vitreous specimen. Cefazolin dosage was increased to 1 g intravenously every 6 hours on day 4. On day 7, antibiotic sensitivity studies by the disk-diffusion method showed the organism to be sensi¬ tive to all antibiotics tested, including pen¬ icillin, cefazolin, and gentamicin. The or¬ ganism from the vitreous specimen was also identified as coryneform group A-4. On day 8, intravenous antibiotic therapy was stopped. Treatment with 500 mg of oral penicillin V potassium four times daily and topical prednisolone acetate was started and continued for 2 weeks. Over the next several days, the patient showed gradual improvement with increasing visual acuity and decreasing vitreous haze. Visual acuity on day 12 was 20/400 with anterior chamber cells and flare (2+), no hypopyon, and min¬ imal vitreous haze. Three months after vit¬ reous aspiration, the visual acuity was 20/ 50 with a clear anterior chamber and vitre¬ ous cells (1+). COMMENT
Diphtheroids
are
ubiquitous in the
environment and are part of the nor¬ mal flora of skin, mucous membranes,10 and conjunctivae.17 Therefore, they may contaminate clinical specimens sent to the microbiology laboratory.10 When isolated, diphtheroids are usu¬ ally dismissed by microbiologists as contaminants. In addition, some spe¬ cies of Corynebacterium grow more slowly than routine clinical isolates.11 Consequently, the culture media may be discarded prematurely unless spe¬ cial instructions accompany the speci¬ men. In both of our patients, however, coryneform group A-4 bacteria were isolated in large numbers on the pri-
mary agar media and in the broth me¬ dia in pure culture. These findings
strongly suggest that our isolates were true pathogens and not contaminants. A recent report13 decribes diphthe¬ roids as the causative agent in eight patients with bacterial keratitis. Since diphtheroids are part of the normal conjunctival flora in 7% of individ¬ uals,17 factors that compromised the corneal surface may have predisposed these patients to develop bacterial keratitis. Diphtheroids have similarly been reported as the causative agent in endocarditis, meningitis, pneumonia, and cutaneous infections,'12 generally in immunocompromised patients. The two cases reported herein ex¬ pand the spectrum of diphtheroid-in-
duced ocular disease and demonstrate important points regarding the diag¬ nosis and treatment of patients pre¬ senting with unexpected postoperative intraocular inflammation. First, both patients presented with delayed en¬ dophthalmitis following surgery. Pa¬ tient 1, presumably infected from her conjunctival flora at the time of or shortly after surgery, developed pain on postoperative day 10 and a hy¬ popyon on postoperative day 40. Pa¬ tient 2, possibly infected by an exposed
suture, developed pain during postop¬
erative week 16 and a hypopyon during postoperative week 17. This indolent presentation contrasts distinctly with the abrupt onset and progressive course of typical bacterial endoph¬ thalmitis.18 It is certainly comparable with the course of patients infected with other slow-growing organisms or patients having "sterile" endoph¬ thalmitis." The prevalence of diphthe¬ roids in the conjunctiva, and the dem¬ onstration that these bacteria can cause an
atypical endophthalmitis, un¬
derscores the importance of diagnostic intraocular cultures in eyes with a re¬ cent history of an intraocular proce¬ dure that have persistent severe in¬ flammation. Second, many systemic and ocular diphtheroid infections are associated with locally13 or systemically912 immu¬ nocompromised and/or elderly pa¬ tients; both of our patients were el-
derly. Patient 1 had no identifiable factors predisposing to infection; pa¬ tient 2 had an exposed suture as well as non-insulin-dependent diabetes mellitus. It is important to note that both patients received subconjunctival and/or oral steroid therapy prior to adequate antibiotic therapy shortly after becoming symptomatic. The use of corticosteroids in this setting for a presumptive, rather than proved, di¬ agnosis of "sterile" endophthalmitis may have contributed to the worsening clinical status of both patients. Third, both patients had a delayed response following standard therapy for endophthalmitis with intravitreal/
subconjunctival/intravenous
genta¬
micin and cefazolin. Neither patient showed clinical improvement until 10 days after the initiation of antibiotic therapy. This may be explained by ex¬ amining the minimal inhibitory anti¬ biotic concentration and minimal bac¬ tericidal antibiotic concentration (MBC) data obtained by Coudron et al20 (Table) for these two isolates. The minimum inhibitory concentration is the lowest antibiotic concentration re¬ quired to prevent visible turbidity in inoculated broth after overnight incu¬ bation. The MBC is the antibiotic con¬ centration needed to effect a 99.9% re¬ duction in the initial inoculum in 24 hours as measured by colony counts. Antibiotic concentrations greater than the MBC are required to kill, rather than just inhibit, the patho¬
genic organism. Comparison of the MBC of
our iso¬ lates with attainable serum antibiotic concentrations from intravenous dos¬ ing and with attainable intravitreous antibiotic concentrations from intra¬ vitreal injection yields the following: 1. A typical intravenous dose of 1 mg/kg of gentamicin sulfate in a pa¬ tient with normal renal function will give a serum peak level of 4 to 9 mg/L, which will result in a peak concentra¬ tion of less than 0.8 mg/L in the aque¬ ous fluid and even less in the vitreous gel.21 The gentamicin concentration in the vitreous gel attained by intrave¬ nous administration is well below the 25- to 50-mg/L MBC of our isolates.
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2. An injection of 200 to 400 ßg of gentamicin into a 4-mL vitreous vol¬ ume will provide a peak level of 50 to 100 mg/L, which is marginally above the MBC of 25 to 50 mg/L. The dura¬ tion of gentamicin concentration greater than 50 mg/L is unknown but could conceivably be as short as 10 hours if the half-life reported by Kane
et al22 in inflamed rabbit eyes can be extrapolated to inflamed human eyes. 3. A typical intravenous dose of 500 to 1000 mg of cefazolin sodium will give a serum peak level of 30 to 110 mg/L, which will result in a peak concentra¬ tion of less than 0.6 mg/L in the aque¬ ous
fluid and
even
less in the vitreous
gel.21 The cefazolin concentration in the vitreous gel attained by intrave¬ nous
administration is well below the
25-mg/L MBC of our isolates. 4. An injection of 2.25 mg of cefazo¬
lin sodium into a 4-mL vitreous volume will provide a peak level of 562 mg/L, which is well above the MBC of 25 mg/ L. This antibiotic concentration may be above the MBC of our isolates for a duration as short as 24 hours if the pharmacokinetics of cefazolin in in¬ flamed human eyes parallels that in inflamed rabbit eyes as reported by Fisher et al.23 5. Five hundred milligrams of oral penicillin V potassium will give a se¬ rum peak level of 3.0 mg/L,21 but the peak level in the vitreous gel is much less24 and below the 0.78- to 1.56-mg/L MBC of our isolates. The above vitreous antibiotic con¬ centrations obtained from intravenous antibiotic administration assume sin¬ gle doses. As Martin et al25 recently
pointed out, intravenous antibiotics are administered in multiple doses to patients with inflamed eyes. The in¬
travitreal antibiotic concentration achieved may be higher than that in¬ dicated by the single-dose figures but is probably still below the MBC of our isolates. A large, clinically significant dis¬ crepancy exists between the minimum inhibitory concentration and MBC for all three antibiotics: by a factor of 8 to 16 for penicillin, 16 to 32 for gentami¬ cin, and 128 for cefazolin (Table). The disk-diffusion method provides antibi¬ otic sensitivities that correlate with the minimum inhibitory concentration and contrast sharply with the MBC data. Because all choices of antibiotic
therapy ultimately depend on appro¬ priate determination of the sensitivity of the organism and the ability to de¬
liver effective antibiotic concentra¬ tions to the site of infection, the anti¬ biotic sensitivity data available to us
while
our
patients
were
hospitalized
somewhat misleading and inade¬ quate. Thus, we recommend obtaining and using MBC data to select antibiot¬ ics for patients with clinically unre¬ sponsive infections. Additionally, if the organism has a high MBC, we rec¬ ommend considering additional intra¬ vitreal antibiotic injections in patients with unresponsive infections because the half-life of the injected antibiotics in inflamed eyes may be such that a therapeutic antibiotic concentration may be present for an unexpectedly short duration. The two cases of delayed endoph¬ thalmitis presented in this article have important similarities to and differ¬ ences from recent reports of delayed endophthalmitis caused by acnes.3> The similarities include delayed onset of endophthalmitis after intraocular lens implantation and the presence of the infecting organism as part of the normal lid or conjunctival bacterial flora.17 Additionally, morphologic con¬ fusion between propionibacteria and corynebacteria exists because both were
pleomorphic, gram-positive, nonspore-forming bacilli.26 Differences in clinical presentation include the asso¬ ciation of extracapsular cataract ex¬ are
traction and retained lens cortex with
Propionibacterium infections, while both of our patients with coryneform group A-4 infections had undergone intracapsular cataract extraction. The only previous report of coryneform group A-4
endophthalmitis
was
in
a
patient with metallic intraocular for¬ eign body.15 Propionibacterium acnes and coryneform group A-4 are differ¬ entiated by their oxygen tolerance; propionibacteria are anaerobes and corynebacteria are aerobes.26 Defini¬ tive identification requires analysis of cell-wall components by a reference laboratory, as was done in our investi¬ gation. The authors have no commercial or proprietary interest in Surgidev Leiske-style intraocular lenses.
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Ophthalmol. 1989;108:251-254. 14. Brinser JH. Ocular bacteriology. In: Tabbara KF, Hyndiuk RA, eds. Infections of the Eye. Boston, Mass: Little Brown & Co Inc; 1986:129\x=req-\ 130. 15. Hanscom
T, Maxwell WA. Corynebacterium endophthalmitis: laboratory studies and report of a case treated by vitrectomy. Arch Ophthalmol. 1979;97:500-502. 16. Margo CE, Pavan PR, Groden LR. Chronic vitritis with macrophagic inclusions: a sequela of treated endophthalmitis due to a coryneform bacterium. Ophthalmology. 1988;95:156-161. 17. Perkins RE, Kundsin RB, Pratt MV, Abrahamsen I, Leibowitz HM. Bacteriology of normal and infected conjunctiva. J Clin Microbiol. 1975; 1:147-149. 18. Forster RK. Etiology and diagnosis of bacterial postoperative endophthalmitis. Ophthal-
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distribution. Invest
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jected cefazolin. Arch Ophthalmol. 1982;100:650\x=req-\ 652. 24.
Leopold IH. Intravitreal penetration of penicillin and penicillin therapy of infections of the vitreous. Arch Ophthalmol. 1945;33:211-216. 25. Martin DF, Ficker LA, Aguilar HA, Gardner SK, Wilson LA, Meredith TA. Vitreous cefazolin levels after intravenous injection: effects of inflammation, repeated antibiotic doses, and surgery. Arch Ophthalmol. 1990;108:411-414. 26. Cummins CS, Johnson JL. Genus Propionibacterium. In: Sneath PH, Mair NS, Sharpe ME, Holt JG, eds. Bergey's Manual ofSystematic Bacteriology. Baltimore, Md: Williams & Wilkins; 1986:1346-1353.
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