Cluster of Mycobacterium Chelonae Keratitis Cases Following Laser

Cluster of Mycobacterium Chelonae Keratitis
Cases Following Laser In-situ Keratomileusis
NAVEEN S. CHANDRA, MD, MARK F. TORRES, MD, KEVIN L. WINTHROP, MD,
DAVID A. BRUCKNER, SCD, DAVID G. HEIDEMANN, MD, HELENE M. CALVET, MD,
MITCHELL YAKRUS, MS, MPH, BARTLY J. MONDINO, MD,
AND GARY N. HOLLAND, MD
● PURPOSE:
To describe a cluster of Mycobacterium
chelonae keratitis cases involving patients who underwent laser in-situ keratomileusis (LASIK) at a single
refractive surgery center.
● DESIGN: Descriptive case series of four patients and
cohort study to identify disease associations.
● METHODS: Examination schedules, diagnostic tests,
and therapy were based on best medical judgment. Isolates from three patients were compared by pulsed-field
gel electrophoresis. Epidemiologic studies were performed to identify the source of infection.
● RESULTS: Seven of eight eyes developed M. chelonae
keratitis following bilateral simultaneous LASIK. Each
patient was thought to have diffuse lamellar keratitis
initially, but all seven eyes were noted to have opacities
suggestive of infectious keratitis by 13 to 21 days after
surgery. All eyes had undergone hyperopic LASIK over
four days in April 2001 by one surgeon in a communitybased refractive surgery center. A cohort study of all
patients undergoing LASIK at the same center in April
2001 revealed that M. chelonae keratitis occurred only
in persons undergoing correction of hyperopia (seven of
Accepted for publication Sep 5, 2001.
From the Ocular Inflammatory Disease Center, Jules Stein Eye Institute, and Department of Ophthalmology, UCLA School of Medicine, Los
Angeles, California (Drs Chandra, Torres, Mondino, and Holland); The
Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia (Dr Winthrop), National Center for Infectious
Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
(Mr Yakrus); The California Department of Health Services, Berkeley,
California (Dr Winthrop); The Division of Laboratory Medicine, Department of Pathology and Laboratory Medicine, UCLA School of Medicine,
Los Angeles, California (Dr Bruckner); Michigan Cornea Consultants,
Southfield, Michigan (Dr Heidemann); The Department of Health and
Human Services, Long Beach, California (Dr Calvet).
Supported in part by Research to Prevent Blindness, Inc., New York,
New York (Drs. Mondino and Holland), The Skirball Foundation, Los
Angeles, CA (Dr. Holland), and The David May II Endowed Professorship (Dr. Holland). Dr. Holland is a recipient of a Research to Prevent
Blindness-Lew R. Wasserman Merit Award. Drs. Chandra and Torres are
David May II Fellows in Cornea-External Ocular Disease and Refractive
Surgery.
Reprint requests to Gary N. Holland, MD, Jules Stein Eye Institute,
100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003; fax: (310)
794-7906; e-mail: [email protected]
0002-9394/01/$20.00
PII S0002-9394(01)01267-3
©
2001 BY
14 eyes vs. none of 217 eyes undergoing myopic LASIK,
P < .001). The only difference identified between
procedures was use of masks created from a soft contact
lens in hyperopic LASIK. Three isolates (three patients)
were indistinguishable by pulsed-field gel electrophoresis.
Eyes were treated with a combination of antimicrobial
agents, including topical azithromycin in three patients,
with resolution of infection in all eyes over 6 to 14
weeks. The source of infection was not identified on
environmental cultures.
● CONCLUSION: Postoperative nontuberculous mycobacterial keratitis can occur in an epidemic fashion
following LASIK. Topical amikacin, azithromycin, clarithromycin, ciprofloxacin, or a combination of these
agents, appears to be effective treatment for these infections. (Am J Ophthalmol 2001;132:819 – 830.
© 2001 by Elsevier Science Inc. All rights reserved.)
I
NFECTIOUS KERATITIS AFTER REFRACTIVE SURGERY IS
uncommon. Nevertheless, there have been several reports of bacterial, fungal, and mycobacterial keratitis
after laser in-situ keratomileusis (LASIK).1–18 Rapidly
growing mycobacteria (one group of the nontuberculous or
“atypical” mycobacteria) account for a substantial proportion of these cases, with Mycobacterium chelonae being the
most frequently reported species.1,4,5,9,16 To date, all reports of nontuberculous mycobacterial keratitis after
LASIK in the medical literature have described single
isolated cases.1,4,5,9,16
In May 2001, on behalf of the Centers for Disease
Control and Prevention (CDC), the American Academy
of Ophthalmology issued an alert to its members regarding
nontuberculous mycobacterial infections after LASIK, in
response to a reported cluster of cases from a single
community-based refractive surgery center in Southern
California (published in the American Academy of Ophthalmology’s EyeNet magazine, July 2001, pages 60 to 61).
The cluster involved four patients (seven eyes) who
developed M. chelonae keratitis after undergoing bilateral,
ELSEVIER SCIENCE INC. ALL
RIGHTS RESERVED.
819
FIGURE 1. (Left) The right eye of case 1, 26 days after LASIK, showing focal and diffuse infiltrates at the interface below the
lamellar keratectomy flap. (Right) The same eye, 1 month later. There is complete necrosis and nonadherence of the lamellar
keratectomy flap, which was subsequently excised. A portion of the central white material is precipitated clarithromycin that is
adherent to necrotic tissue.
FIGURE 2. (Left) The left eye of case 2, 23 days after LASIK, showing diffuse infiltrates at the interface below the lamellar
keratectomy flap. (Right) The same eye, 2 months later, after resolution of infection. There is a central, nonvascularized scar at the
level of the interface that also involves the lamellar keratectomy flap. The surrounding cornea is clear.
simultaneous hyperopic LASIK by one surgeon during a
four-day period.
To provide the ophthalmic community with additional
information about these cases, we present a description of
their clinical findings, course of disease, and response to
treatment (Figures 1–3), as well as information regarding
attempts to identify the source of infection. We also
describe the use of topical azithromycin as a possibly
effective agent for treatment of nontuberculous mycobacterial keratitis.
Initial specimens for culture were obtained by scraping
the surface of the cornea with a Kimura spatula in areas of
epithelial defects. Subsequent specimens for culture were
obtained by scraping the corneal stroma with a Kimura
spatula after elevation of the lamellar keratectomy flap.
Specimens were placed directly on the following culture
media: blood agar, chocolate agar, thioglycolate broth,
Sabouraud agar, and Middlebrook 7H11 agar. Specimens
were also placed on glass slides for microscopic examination using the following stains: Gram, Giemsa, Zeihl–
Nielson, and fluorochrome.
Susceptibility testing was performed in the UCLA
Clinical Laboratories according to National Committee for
Clinical Laboratory Standards guidelines.19 Isolates were
susceptible to amikacin (mean inhibitory concentration
[MIC]: 8 ␮g/ml) and clarithromycin (MIC: ⱕ 0.5 ␮g/ml)
in vitro. There are no standards for susceptibility testing to
azithromycin in vitro. Clarithromycin is used as the class
agent for the newer macrolides when performing suscepti-
● SUBJECTS AND METHODS: Disease assessment was
based on slit-lamp biomicroscopic examination at frequencies dictated by best medical judgment. Medical and
surgical treatments, including changes in therapy, were
based on best medical judgment. Indications for surgical
excision of lamellar keratectomy flaps were nonadherence
of the flap or lack of clinical improvement, as judged by the
treating ophthalmologist.
820
AMERICAN JOURNAL
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OPHTHALMOLOGY
DECEMBER 2001
FIGURE 3. The right eye (top left) and left eye (top right) of case 4, shown 20 days after bilateral, simultaneous LASIK. The right
eye shows focal round corneal opacities at the interface below the lamellar keratectomy flap. The left eye shows a similar focal
infiltrate in front of the inferior pupillary margin, as well as early diffuse cellularity at the interface. The right eye (bottom left) and
left eye (bottom right) of case 4, 1 month after photographs shown in top left and top right. A hypopyon has developed in the right
eye, and there is substantial irritation (corneal epitheliopathy, conjunctival redness and chemosis, eyelid swelling and redness)
attributed to topical clarithromycin. Increased diffuse opacity at the level of the interface can be seen in the left eye. Precipitated
clarithromycin that is adherent to mucus strands can be seen in both eyes.
bility testing; organisms susceptible to clarithromycin are
considered to be susceptible to azithromycin.20
All positive culture isolates from patients were sent to
the CDC for molecular analysis. Isolates were compared
using pulse-field gel electrophoresis.
Topical fortified amikacin (50 mg/ml) was prepared by
local pharmacies from drug for intravenous injection,
according to routine procedures. A commercially available
preparation was used for topical ciprofloxacin (Ciloxan,
Alcon Laboratories, Inc., Fort Worth, TX). Topical clarithromycin (10 mg/ml) was prepared as a suspension from
clarithromycin granules for oral suspension (Abbott Laboratories, Inc., North Chicago, IL), as described by Ford
and associates.21 Topical azithromycin was prepared from
lyophilized drug for intravenous injection (Pfizer Inc., New
York, NY) according to the following procedures. One vial
of drug was reconstituted with 4.8 ml of sterile water per
the manufacturer’s instructions. The resulting solution was
diluted further with normal saline to achieve a concentration of 2 mg/ml. This solution was then filtered through a
VOL. 132, NO. 6
CLUSTER
OF
0.22 ␮m filter into a sterile ophthalmic dropper vial.
Patients were instructed to refrigerate the solution between
applications. According to the manufacturer’s package
insert, azithromycin solution containing 2 mg/ml of drug
will be stable for 7 days when refrigerated.
When initial culture results from the patients suggested
a common source of infection related to surgery, the local
health department (the Department of Health and Human
Services, Long Beach, CA) was notified. That agency then
contacted the California Department of Health Services in
Berkeley, CA and the Epidemic Intelligence Service,
Centers for Disease Control and Prevention (CDC) for
assistance in epidemiologic studies to identify the source of
infection.
A case was defined as any patient who developed
keratitis after LASIK by the identified surgeon. The
surgeon agreed to alert the CDC regarding any new cases
of M. chelonae keratitis that were discovered during postoperative care of all surgical patients. To help identify
other possible cases, an e-mail alert was sent to all
MYCOBACTERIUM CHELONAE KERATITIS CASES
821
members of the American Academy of Ophthalmology,
asking for information about any recent cases of nontuberculous mycobacterial corneal infection throughout the
country. Similar alerts were posted on the CDC e-mail
list-server “Epi-X” and on a national e-mail list-server for
clinical microbiology laboratories, “ClinMicroNet.”
On May 8, 2001 (24 days after the last procedure
associated with a known M. chelonae infection), physicians
from the CDC, as well as from state and local health
agencies, visited the surgical practice in question. The
surgeon and refractive surgery center staff were interviewed
regarding the reported cases and the details of the LASIK
procedures performed. Included were questions about the
handling of surgical instruments during and between surgical procedures. Information was requested from the
surgeon about all surgical procedures performed 2 weeks
before and 2 weeks after the week during which case
patients had undergone LASIK. For each procedure, the
following information was obtained: patient demographic
data, type of procedure (hyperopic LASIK, myopic
LASIK), date of procedure, postsurgical examination findings, and staff present during procedures.
Investigators returned to the refractive surgery center on
May 19, 2001 (the date of the next scheduled hyperopic
LASIK) to observe in detail all presurgical, surgical, and
postsurgical practices at the center. As part of this investigation, the sterilizer at the refractive surgery center was
evaluated. Routine procedures employed by the staff in
using the sterilizer were reviewed and compared with the
manufacturer’s instructions. The sterilizer was tested three
times with Bacillus subtilis spore strips (SGM Biotech,
Bozeman, MT) to assess efficacy. The first test involved
one instrument and three spore strips; the second test
involved a full load of instruments and four spore strips,
and the third test included trephines as well as instruments
and five spore strips. Two spore strips, left unopened and
not placed in the sterilizer, were used as controls. All spore
strips were incubated and cultured according to manufacturer’s instructions.
Environmental cultures from potential contaminants in
the surgical center were performed at the time of the initial
visit on May 8, 2001. Because the case patients had been
diagnosed with diffuse lamellar keratitis, the surgeon had
replaced some materials related to the surgeries, including
distilled water, dish soap used for cleaning surgical instruments before sterilization, and balanced salt solution used
intraoperatively, before resuming LASIK procedures on
April 18, 2001. The stocks of distilled water and dish soap
used during the outbreak time-period were still stored at
the surgeon’s office, however, and samples from these
stocks were obtained for culture. One bottle of balanced
salt solution used during the outbreak time period was also
available and was obtained for culture. Four packages of
gentian violet corneal ink used during the outbreak timeperiod were also obtained for culture. Because tap water is
a common habitat for nontuberculous mycobacteria, tap
822
AMERICAN JOURNAL
water samples from the sink outside the operating room
were obtained for culture on May 21, 2001. The sink drain
was also swabbed for culture at that time.
The contact lens fragments used as masks in each
hyperopic LASIK case (see description in Results section
below) had been discarded at the end of each procedure,
and therefore could not be cultured. A copy of the
surgeon’s lens ordering and shipment information was
obtained, and the State of California Food and Drug
Branch obtained 25 soft contact lenses of the same lot
number as those used during the outbreak time period from
the lens manufacturer.
Water and sink drain cultures were performed at the
Long Beach (CA) Department of Health and Human
Services Laboratory. All other environmental cultures
were performed at the California Department of Health
Sciences Microbial Diseases Laboratory (Berkeley, CA).
Tap and distilled water samples were filtered through 45
␮m filters. Filters were placed into Bactec media and on
Lowenstein–Jenson slants. Sink drain swabs were inoculated directly into the same media. Samples of gentian
violet corneal ink, dish soap, and balanced salt solution
were inoculated directly into Bactec, Lowenstein–Jensen,
and Middlebrook 7H10 media. Lens packaging fluid from
the 25 contact lens containers and five ground contact
lenses were plated onto Middlebrook 7H10 media and
inoculated into MGIT broth media. All cultures were
incubated at 35°C and held for 6 weeks.
Ground contact lenses and packaging fluid were also
sent to CDC for polymerase chain reaction (PCR) analysis, using mycobacteria-specific PCR probes.
We performed a MEDLINE literature search to identify
previously published cases of infectious keratitis following
refractive surgery. A separate MEDLINE literature search
revealed no previous publications describing the use of
topical azithromycin for the treatment of nontuberculous
mycobacterial keratitis in any setting.
● STATISTICAL ANALYSIS:
Relative risk (RR), 95% confidence intervals, and P values (Fisher exact test) were
calculated using Epi Info 2000 software version 1.1 (CDC,
Atlanta, GA). A per eye analysis was performed because
one patient had a unilateral infection; such an analysis
might allow identification of factors related to infection
between first and second procedures on an individual
patient.
● REPRESENTATIVE
CASE REPORT: A 57-year-old
woman (case 4) with no history of ocular problems
underwent bilateral, simultaneous hyperopic LASIK. She
was in good general health. On the second postoperative
day, diffuse lamellar keratitis was diagnosed in both eyes,
and therapy with prednisolone acetate 1% hourly while
awake was initiated. Oral prednisone (60 mg/d) was added
to her treatment regimen on the third postoperative day.
On examination 2 weeks after surgery, the diffuse lamellar
OF
OPHTHALMOLOGY
DECEMBER 2001
keratitis had resolved in both eyes, and the topical corticosteroid therapy was tapered but not stopped. Examination during the third postoperative week revealed multiple
white anterior stromal granular opacities (each less than
0.5 mm diameter) in the central cornea at the level of the
interface below the lamellar keratectomy flap in the right
eye (Figure 3 [top left]), and a single similar lesion in the
left eye (Figure 3 [top right]). She had no ocular or visual
symptoms. She was referred to the Jules Stein Eye Institute
for evaluation and management. Visual acuity without
correction was 20/20 in both eyes. The lamellar keratectomy flap was lifted in the right eye to obtain specimens by
scraping for culture and microscopic examination. Acidfast bacteria were seen on smears, and cultures on Middlebrook 7H11 agar grew M. chelonae 1 week later. Based on
the presence of acid-fast bacteria on smears, corticosteroid therapy was stopped and topical therapy using
amikacin (50 mg/ml), ciprofloxacin (0.3%), and clarithromycin (10 mg/ml) hourly around the clock was
initiated. She was also given oral doxycycline (100 mg
twice daily). Despite treatment, there was enlargement
of the focal infiltrates and increased diffuse infiltration
and haze at the interface in both eyes. There was also
necrosis and thinning of the inferotemporal portion of
the flap, although it remained adherent to the underlying stroma. After 2 weeks of therapy, there was some
evidence of decreased inflammatory signs and the frequency of topical medications was reduced to one drop
every 2 hours while awake. There was a subsequent
increase in inflammatory signs in both eyes over the
next week, with development of a hypopyon in the right
eye (Figure 3 [bottom left]). At the same time, the
patient began to report intolerance to instillation of
topical clarithromycin in both eyes and developed
diffuse, coarse epitheliopathy; diffuse, increased conjunctival redness and swelling; and eyelid margin redness in both eyes. Topical instillation of clarithromycin
was discontinued, with immediate improvement in comfort, as well as improvement in corneal epithelial,
conjunctival, and eyelid margin signs. Topical azithromycin (2 mg/ml; hourly while awake), and oral clarithromycin (500 mg twice daily) were added to her
treatment regimen. Focal corneal infiltrates resolved in
the right eye over the next week, and diffuse inflammation and haze at the interface decreased in both eyes
over the next 4 weeks. There was progressive ingrowth
of superficial corneal vessels in both eyes during this
interval. At 5 weeks after the change in therapy, there
were no signs of active inflammation in either cornea,
and all medications were discontinued 1 week later.
There was no evidence of recurrent infection in either
eye during 3 weeks of additional observation. There was
stable anterior scarring and superficial vascularization,
which was worse in the right eye. Visual acuity with
spectacle correction at 19 weeks after LASIK was RE:
20/80 and LE: 20/25.
VOL. 132, NO. 6
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RESULTS
AS OF AUGUST 22, 2001, FOUR INDIVIDUALS MEETING THE
case definition had been identified. All were female, with
a mean age of 58 years (range 56 to 64 years). All had
undergone bilateral, simultaneous hyperopic LASIK during the period April 11–14, 2001. Three patients developed bilateral M. chelonae keratitis and one patient (case
1) developed unilateral infection, involving the first eye
that underwent LASIK. Two patients had surgery consecutively on April 11, 2001 (case 1, followed by case 2); one
patient had surgery on April 12, 2001 (case 3); and one
patient had surgery on April 14, 2001 (case 4). The
surgeon performed LASIK on 54 eyes during this 4-day
period; no additional hyperopic LASIK was performed
during this period.
During the period April 4 –28, 2001, the same surgeon
performed LASIK on 231 eyes (120 patients) in the same
refractive surgery center. The majority of patients (113
patients, 217 eyes) underwent myopic LASIK. Seven
(50%) of 14 eyes undergoing hyperopic LASIK during this
period developed M. chelonae keratitis, in contrast to none
of 217 eyes undergoing myopic LASIK (P ⬍ .001; RR is
undefined statistically because no myopic LASIK cases
were associated with infection). All hyperopes underwent
bilateral simultaneous LASIK (seven patients), while 104
myopes underwent bilateral simultaneous LASIK and nine
myopes underwent unilateral LASIK. A per patient analysis also revealed a significant association between hyperopic procedures and infection (P ⬍ .001).
With the exception of one case patient (case 3), who
relocated to Michigan during the first week after surgery,
all patients who underwent LASIK during the period April
4 –28, 2001 were examined for at least 3 weeks postoperatively by the surgeon. Because of the infections that had
occurred in the four case patients, particular attention was
paid to the other three patients who underwent hyperopic
LASIK; each was followed for at least 14 weeks with no
signs of infection.
A representative case history is presented above, and
specific details for each case patient are listed in Table 1.
Initial clinical characteristics were similar in all four case
patients. By the second postoperative day, each exhibited
cellularity at the interface below the lamellar keratectomy
flap, which was diagnosed as probable diffuse lamellar
keratitis. All patients were treated with prednisolone
acetate 1% (hourly while awake). Signs resolved in two
patients (cases 1 and 2), and their topical corticosteroid
treatments were stopped after 1 week. Oral prednisone (60
mg daily) was also prescribed for two patients (cases 3 and
4). The patient who relocated to Michigan (case 3)
stopped oral prednisone after 6 days, but was still using
topical prednisolone acetate 1% at the time a diagnosis of
presumed M. chelonae keratitis was made, as described
below. One patient (case 4) was still receiving both oral
prednisone and topical prednisolone acetate 1% when
MYCOBACTERIUM CHELONAE KERATITIS CASES
823
824
TABLE 1. Characteristics of Mycobacterium chelonae Keratitis in Patients Following Bilateral Laser In-situ Keratomileusis
Visual Acuity
Clniical Features at Diagnosis
Age
(years)/ Eye(s)
Case* Gender Involved
1
56/F
RE
Symptoms
Ache, irritation,
Final‡
Drug Treatment
Slit Lamp
Basis of
Biomicroscopic
M. chelonae
Findings
Keratitis Diagnosis
Multiple linear Positive culture
Drug
Combination†
Initial:
Interval From
Diagnosis to
Start of
Duration
Drugs
of Drugs
Immediate
6 weeks
At Diagnosis
Response
Persistent stromal
Excision of
Best
Flap (Interval
Through
Spectacle
After
Diagnosis) Uncorrected Pinholes Uncorrected Corrected
Yes
20/200
20/40
HM
20/100-
(4 weeks)
Final Corneal
Status‡
Diffuse anterior
stromal scars
AMERICAN JOURNAL
burning,
opacities at
from flap
Ciprofloxacin,
infiltration,
blurring
level of flap
interface; AFB in
amikacin,
hypopyon,
and superficial
interface
flap biopsy
clarithromycin,
epithelial toxicity
vessels
specimen
oral
doxycycline
Subsequent:
6 weeks
8 weeks
Resolution of
OF
Ciprofloxacin,
inflammatory
amikacin,
signs after 6
azithromycin,
weeks
oral
OPHTHALMOLOGY
clarithromycin
2
56/F
OU
OU:
64/F
OU
Ciprofloxacin,
Immediate
6 weeks
OU: Resolution of
photophobia,
opacities at
from flap
amikacin,
inflammatory
burning,
level of flap
interface (LE)
clarithromycin,
signs after 5
blurring
3§
Multiple round Positive culture
Mild irritation
interface
Diffuse
oral doxcycline
Clinical
Initial OU:
6 weeks
OU: Persistent
stromal infiltration,
level of flap
amikacin,
hypopyon,
interface
clarithromycin
epithelial toxicity
characteristics
Subsequent OU:
RE: 20/70
20/20
20/50
20/25
LE: 20/50
20/25
20/50
20/25
Focal anterior
stromal scars
RE:¶ NA
NA
NA
20/200
RE: stromal scars
LE:¶ NA
NA
NA
20/80
weeks
Immediate
ciprofloxacin,
keratitis at
No
6 weeks
9 weeks
OU: Resolution of
RE: Yes
(4 weeks)
LE: Yes
(7 weeks)
and superficial
vessels; focal
stromal
thinning
ciprofloxacin,
inflammatory
LE: anterior
azithromycin,
signs after 6
stromal
oral
weeks
scarring and
clarithromycin
superficial
vessels; focal
stromal
DECEMBER 2001
thinning
VOL. 132, NO. 6
TABLE 1. Continued
Visual Acuity
Clniical Features at Diagnosis
CLUSTER
Age
(years)/ Eye(s)
Case* Gender Involved
OF
4§
57/F
OU
Symptoms
Asymptomatic
Drug Treatment
Slit Lamp
Basis of
Biomicroscopic
M. chelonae
Findings
Keratitis Diagnosis
Multiple round Positive culture
Drug
Combination†
Initial OU:
Interval From
Diagnosis to
Start of
Duration
Drugs
of Drugs
Immediate
6 weeks
Response
OU: Persistent
Final‡
At Diagnosis
Excision of
Best
Flap (Interval
Through
Spectacle
After
Diagnosis) Uncorrected Pinholes Uncorrected Corrected
No
MYCOBACTERIUM CHELONAE KERATITIS CASES
RE: 20/20
NA
20/200
20/80-
LE: 20/20
NA
20/30
20/25-
Final Corneal
Status‡
RE: Diffuse
anterior
opacities at
from flap
Ciprofloxacin,
stromal infiltration,
level of flap
interace (RE);
amikacin,
hypopyon,
stromal scars
interface
AFB on smear
clarithromycin,
epithelial toxicity
and superficial
from flap
oral
interface (RE)
doxycycline
Subsequent OU:
vessels
LE: Inferior
6 weeks
8 weeks
OU: Resolution of
anterior
Ciprofloxacin,
inflammatory
stromal scars
amikacin,
signs after 5
and superficial
azithromycin,
weeks
vessels
oral
clarithromycin
AFB ⫽ acid fast bacteria; F ⫽ female; HM ⫽ hand motion; NA ⫽ not available.
*Cases are presented in the order of surgery: cases 1 and 2 underwent LASIK on April 11, 2001; case 3 underwent surgery on April 12, 2001; case 4 underwent surgery on April 14, 2001.
†
All drugs listed were administered topically unless otherwise specified.
‡
Article prepared at 19 weeks after LASIK procedures were performed.
§
Cases 3 and 4 were being treated with topical prednisolone acetate 1% at diagnosis of M. chelonae keratitis; case 4 was being treated with oral prednisone at diagnosis. Corticosteroids had
been prescribed for presumed diffuse lamellar keratitis.
¶
Best corrected visual acuity with spectacles at onset of antimycobacterial drug treatment was RE: 20/40; LE: 20/40.
825
patient (case 1), biopsy of necrotic flap tissue from the
same eye was performed after the flap was raised initially,
but before results of the initial cultures were obtained; this
specimen also contained acid-fast bacteria, and repeat culture
of the interface taken at the same time grew M. chelonae.
Because of the experience with these three patients, the
surgeon contacted the fourth patient (case 3) in Michigan.
She was being followed by a local optometrist, still with a
diagnosis of presumed diffuse lamellar keratitis. Her findings, as described by the optometrist, were similar to those
in the three patients in California, and a presumptive
diagnosis of M. chelonae keratitis was made. The same
antimycobacterial treatment being used for the other three
patients was initiated empirically, and the patient was
eventually referred to Michigan Cornea Consultants for
additional evaluation and management.
Initial antibiotic therapy for all four patients consisted of
topical ciprofloxacin 0.3%, fortified amikacin (50 mg/ml),
and clarithromycin (10 mg/ml), as well as oral doxycycline
(100 mg, twice daily). One patient (case 2) responded well
to this treatment regimen, and no further modifications in
medical therapy were made. The other patients had persistence of active infection on this treatment regimen and
developed irritation and signs of ocular surface toxicity
caused by topical clarithromycin (corneal epitheliopathy,
increased conjunctival redness, chemosis, eyelid margin
redness, and pain with instillation) (Figure 3 [bottom left
and bottom right]). Oral clarithromycin was substituted for
oral doxycycline, and topical azithromycin (2 mg/ml) was
substituted for topical clarithromycin after 6 weeks of
treatment for each patient. All three patients tolerated this
revised treatment regimen well, with eventual resolution
of inflammatory signs over the next 5 to 6 weeks. All
medications were stopped for three patients (cases 1, 2, and
4) and there were no clinical signs of recurrent infection
during 3 to 6 weeks of additional follow-up. One patient
(case 3) had no sign of active disease, but was still being
treated with topical azithromycin and ciprofloxacin at a
reduced frequency at the time of this writing.
In one patient (case 1), the lamellar keratectomy flap
was removed from the right cornea at week 4, when it
became diffusely necrotic and nonadherent (Figure 1
[right]). In the other two patients being managed at the
Jules Stein Eye Institute (cases 2 and 4), all four flaps
remained adherent, although there were focal areas of
necrosis and thinning. The flap was excised from the worse
(left) cornea of the patient being managed at Michigan
Cornea Consultants (case 3), because of dense flap infiltrates, lack of appreciable response to medical therapy, and
published experience suggesting a therapeutic benefit of
flap removal.1 Improvement was noted in the left cornea
after flap removal; therefore, excision of the flap from the
right cornea was recommended as well, as inflammatory
signs had become more severe in that eye. On the same
day, topical azithromycin was added to the patient’s
FIGURE 4. Pulsed-field gel electrophoresis results showing
identical M. chelonae isolates from cases 1, 2, and 4 (lanes 5 to
7). Other numbered lanes show results for the following
organisms or references: 1, M. fortuitum (American Type
Culture Collection [ATCC], Rockville, MD); 2, M. mucogenicum (ATCC); 3, M. abscessus (ATCC); 4, M. chelonae
(ATCC); 8, 48.5 kb DNA ladder.
signs of infectious keratitis developed. Signs of infectious
keratitis (focal corneal stromal opacities at the level of the
interface) were first noted 13 to 21 days after surgery
(mean, 17 days) (Figure 3 [top left and top right]). The
three patients still in California were referred to the Jules
Stein Eye Institute for additional evaluation and management when evidence of infectious keratitis developed.
Diagnosis of M. chelonae keratitis for the three patients
in California (cases 1, 2, and 4) was based on culture
results. Initial cultures of specimens obtained from the
corneal surface in areas of epithelial defects overlying
deeper infiltrates were negative in all three cases. Additional specimens were then obtained from all three patients by lifting the lamellar keratectomy flap of the worse
eye and scraping the interface with a Kimura spatula.
Acid-fast bacteria were identified on slides prepared with
the same material in case 4 only. Growth was first detected
on Middlebrook 7H11 agar between 3 and 7 days in all
cases. All three M. chelonae isolates were indistinguishable
by pulsed-field gel electrophoresis (Figure 4). In one
826
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OPHTHALMOLOGY
DECEMBER 2001
treatment regimen. There was subsequent improvement in
the status of both eyes.
Following resolution of infection, findings were remarkably similar in all seven involved corneas. All had anterior
stromal scarring and superficial vascularization to varying
degrees. In addition, there were variable amounts of
necrosis and tissue loss from the lamellar keratectomy flap
in all eyes. It is our clinical impression that among those
patients whose flaps were not excised, stromal scarring and
superficial vascularization was most severe in areas where
the overlying flap was absent because of either necrosis or
biopsy. Areas of remaining flap that had been necrotic, but
healed, were diffusely opaque. Both corneas of one patient
(case 3) had focal deep stromal loss, with up to 90%
thinning (a 2 ⫻ 4 mm peripheral area in the right eye and
a 1 mm diameter central area in the left eye).
Epidemiologic studies identified one surgical factor that
was related to the cluster of infections, but failed to
identify the source of the infecting organisms. Evaluation
of the myopic and hyperopic LASIK procedures revealed
only one difference between procedures; during hyperopic
LASIK, the surgeon utilizes soft contact lens fragments to
mask a portion of the cornea during laser ablation. Three
masks of various sizes (3.5 mm, 4.5 mm, 5.5 mm) are
created from a single contact lens, using nondisposable
trephines that have been resterilized before each patient’s
procedure. During hyperopic LASIK, the three masks are
held with a pair of sterile jeweler’s forceps at approximately
1 cm above the cornea, for approximately 10 seconds each,
in succession from smallest to largest, as the laser is applied
to the cornea. All surgical equipment, with the exception
of the trephines used to create the masks, is the same for
both myopic and hyperopic LASIK.
The surgeon reported using a new contact lens for each
case patient, but the same masks were used for both eyes of
each patient. Masks were placed on a sterile tray between
procedures on the first and second eyes. Contact lenses
from two manufacturers were used during the month of
April 2001. All eyes undergoing hyperopic LASIK during
the period April 11–14, 2001 were masked with contact
lenses from a single manufacturer. The surgeon had received five contact lenses from that manufacturer at the
beginning of April 2001. The surgeon reported using four
of these five lenses to create masks for the four case
patients. The fifth lens was discarded by the surgeon before
use, and was not available for examination. All other
hyperopic LASIK procedures were performed using masks
created from contact lenses obtained from the other
manufacturer, but none of these cases were performed
during the period April 11–14, 2001.
The surgeon routinely wears sterile gloves while performing LASIK, but does not change instruments or gloves
between eyes of the same patient. Surgical staff was
constant throughout the month of April 2001, with the
same individuals being involved in all surgeries. They
reported that all surgical instruments, including trephines,
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had been sterilized between use on each patient. Other
products, including gentian violet corneal ink, sterile
gloves, and topical medications, were used in all procedures throughout the month. The brands of balanced salt
solution, distilled water, and dish soap were switched on
approximately April 18, 2001.
Tap water from the refractive surgery center sink grew
M. gordonae, a common contaminant. All other environmental cultures, as well as cultures of ground contact lenses
and lens package fluids, were negative. PCR tests of ground
contact lenses and lens package fluid were negative for
mycobacteria. In all tests, the office sterilizer worked
effectively, as all spore strips that underwent sterilization
failed to grow B. subtilis during culture, while both control
spore strips did grow B. subtilis during culture.
DISCUSSION
CORNEAL INFECTION IS AN UNCOMMON COMPLICATION OF
LASIK surgery, with reported rates of 1 to 2 cases per 1000
eyes.22,23 Isolated case reports have described corneal
infections with a variety of organisms, including Staphylococcus aureus, Aspergillus sp., Nocardia sp., and Mycobacteria
sp. Nontuberculous mycobacterial keratitis is one of the
most common infections to be reported. Among 22 culture-positive cases of post-LASIK infectious keratitis in 18
publications since 1995,1–18 Mycobacterium sp. were identified in six cases (five cases of M. chelonae keratitis1,4,5,9,16
and one case of M. fortuitum keratitis5). We were unable to
identify any previous reports describing a cluster of infections from a single refractive surgery center.
There are approximately 50 species within the genus
Mycobacterium, including M. tuberculosis, M. leprae, and
numerous nontuberculous mycobacterial species. The Runyon classification system categorizes nontuberculous mycobacteria into four categories, one of which (group IV)
contains the rapidly growing mycobacteria (so named
because these species usually grow in vitro within seven
days),24 including M. fortuitum, M. chelonae, and M.
abscessus. Nontuberculous mycobacteria are ubiquitous in
soil, animals, milk, foodstuffs, municipal tap water, and
laboratory water.25–28 Runyon group IV organisms multiply
readily in distilled water, and can remain viable for a year.
They are also resistant to chemical disinfectants, such as
chlorine.25 Nontuberculous mycobacterial infections are
not transmitted by human-to-human contact.25,29
M. chelonae and M. fortuitum are the most common
causes of nontuberculous mycobacterial ocular disease.
Other species reported to cause keratitis include M.
gordonae, M. marinum, M. avium-intracellulare, M. nonchromogenicum, and M. asiaticum.21,25,30 –32
The occurrence of multiple cases of M. chelonae keratitis
in a cluster provides an opportunity to understand clinical
features, disease course, and response to therapy. Clinical
features of these four cases were similar. All patients
MYCOBACTERIUM CHELONAE KERATITIS CASES
827
developed findings suggestive of diffuse lamellar keratitis in
the immediate postoperative period, but findings persisted
despite intense topical, and in some cases oral, corticosteroid therapy, and patients eventually developed focal,
dry-appearing opacities. Clinicians should be alert to the
possibility of nontuberculous mycobacterial keratitis in
patients with persistence of apparent diffuse lamellar keratitis, and in those who develop infiltrates at the level of
the interface.
With regard to diagnostic testing, elevation of the
lamellar keratectomy flap appears to be necessary for
obtaining culture material. Organisms will grow rapidly on
specific media, such as Middlebrook 7H11 media, but
rapidly growing mycobacteria will also grow on blood agar.
Acid-fast bacteria may not be seen in smears of material
obtained by scraping of the interface, however.
The course of infection, and late findings were also
similar between patients. Late changes in the corneas
include diffuse and focal anterior scarring, superficial vascularization, and variable amounts of tissue loss, especially
from the flap.
Whether the common characteristics in our patients are
unique to the specific isolate in this cluster or reflect the
nature of nontuberculous mycobacterial keratitis associated with LASIK (because of unique anatomic considerations) cannot be determined. The cases reported are
similar to other previously reported cases of nontuberculous mycobacterial keratitis after LASIK, however.1,4,5,9,16
In contrast, findings are different than those associated
with nontuberculous mycobacterial infections after penetrating injury, radial keratotomy, or penetrating keratoplasty; such cases are characterized by deep densely opaque
infiltrates, frequently with severe necrosis and tissue
loss.33–39 These differences probably reflect the different
types of incisions made. Following LASIK, infiltrates
develop at the level of the interface and inflammatory
material spreads along the plane of incision. Ford and
associates21 have speculated that organisms will remain
superficial unless introduced into deeper layers mechanically.
Amikacin has been the traditional drug of choice for
treatment of nontuberculous mycobacterial keratitis, and
topical ciprofloxacin has been shown to be an effective
treatment in animal studies.40 – 42 A recent clinical report
suggests that up to 60% of nontuberculous mycobacterial
keratitis cases are nonresponsive to amikacin, and an even
higher percentage are nonresponsive to ciprofloxacin.21
An animal model has also been used to show that
clarithromycin may be effective for treatment of nontuberculous mycobacterial keratitis.42,43 Based on limited experience, Ford and associates21 suggested that topical
clarithromycin should now be considered the drug of
choice for nontuberculous mycobacterial keratitis. Topical
clarithromycin has been used to treat several cases of M.
chelonae keratitis after LASIK.1,5,9 There is no commercially available intravenous formulation of clarithromycin
828
AMERICAN JOURNAL
from which fortified eye drops can be made; and dilution of
a commercially available suspension, marketed for oral use,
has been described for use as an eye drop.21 Our patients
found this topical preparation of clarithromycin to be
irritating, which prohibited its extended use. This irritation has also been reported previously.21
Azithromycin was chosen as an alternative macrolide for
continued treatment of our cases. Although clarithromycin appears to be more active in vitro than other macrolides, susceptibility testing may not reflect its relative
activity in vivo.20 In contrast, azithromycin is concentrated in tissues; thus, it has the potential for being more
effective than clarithromycin in vivo.20 Furthermore, the
fact that clarithromycin must be given as a suspension may
limit its efficacy as a topical preparation.
There are no standards for in vitro susceptibility testing
with azithromycin and we found no published reports
describing its use topically against M. chelonae keratitis.
The concentration of azithromycin was chosen in part for
its known stability, and in part on the basis of in vitro
susceptibility testing with clarithromycin, which is believed to reflect susceptibility to azithromycin. It is known
that dilutions of intravenous azithromycin to 2 mg/ml are
stable for 7 days with refrigeration (package insert; Pfizer
Inc., New York, NY); the stability of higher concentrations
has not been shown. Because it is concentrated in tissues,
we believed that a solution of 2 mg/ml would achieve
higher tissue concentration than the 10 mg/ml suspension
of clarithromycin and would be effective against an organism with an MIC ⱕ 0.5 ␮g/ml.
Disease was still active when topical azithromycin was
added to the treatment regimens for three patients, and
infection subsequently resolved in these cases. Azithromycin was not used as monotherapy, however, and thus its
efficacy cannot be established conclusively from this series.
It was better tolerated than topical clarithromycin.
Corticosteroid use has been implicated as a contributing
factor in the development of nontuberculous mycobacterial keratitis in both clinical33 and animal studies.44 The
role of corticosteroids in our cases is uncertain; all patients
had been treated with topical corticosteroids after surgery,
and two patients were receiving topical corticosteroids at
the time of diagnosis, including the patient who had areas
of 90% stromal thinning in both eyes (case 3). The patient
who developed infection in only 1 eye was treated with
topical corticosteroids for only one week (case 1), although
infection was severe in the involved eye. It is interesting to
note that the patient still receiving oral corticosteroids at
the time of diagnosis (case 4) was asymptomatic, while the
other three patients were symptomatic.
It has been suggested that removal of the lamellar
keratectomy flap may facilitate resolution of infection by
improving the penetration of topical medications1 and by
facilitating removal of loculated infiltrates at the level of
the interface.5 Although keratitis improved in case 3 after
flap removal, it cannot be determined whether improveOF
OPHTHALMOLOGY
DECEMBER 2001
ment was due to flap removal, additional medical therapy,
or both. Because the anterior stromal lamellae do not add
to the structural integrity of the cornea after separation
from the posterior stroma by the microkeratome, it is
probably acceptable to remove the flap, if necessary for
control of infection. In some cases, the flap becomes totally
necrotic and nonadherent, as occurred in our case 1. In our
patients with partial loss of flaps because of necrosis, there
was diffuse opacification of necrotic flap tissue that had
remained adherent and healed, while scarring and vascularization of the interface bed appeared to be worse where
overlying flap tissue had been lost.
Surgical extirpation by penetrating keratoplasty of infection has been advocated by several authors as treatment
for nontuberculous mycobacterial keratitis.4,9,16,21,32,33,38,39
This procedure may be more applicable for deep corneal
infections. Our series shows that resolution of infection,
with good visual outcome in some cases, can result from
medical therapy alone. Although recurrent infection after
medical therapy has been described in cases of deep
infection,39 we found no reports in the literature of
recurrent infection in cases of post-LASIK M. chelonae
keratitis that had apparently resolved with medical therapy
alone.1,4,5
Isolates were identical on pulsed-field gel electrophoresis
testing, indicating a common source. Investigation found
all infections to be associated with LASIK correction of
hyperopia. The contact lens fragments used as masks
during the procedures were implicated as the source of
infection, although the means by which they were contaminated, and the route by which organisms were transferred from the lens fragments to the corneas, could not be
determined. The association of infection with a specific
shipment of contact lenses suggested the possibility of
intrinsic contamination of the contact lenses, but mycobacteria could not be identified from five additional lenses
with the same lot number. Laboratory evaluation of the
contact lens lot was limited by the small sample size tested;
average lots contain thousands of lenses, but additional
lenses from the same lot were not available for testing at
the time of this writing. It is also possible that the lens
fragments were contaminated by the surgeon or surgical
assistant, although observation of the surgeon’s hyperopic
LASIK technique failed to identify a likely mechanism for
preoperative or intraoperative contact lens contamination.
Environmental cultures failed to reveal a source of the
organisms, but cultures were not performed until more
than 3 weeks after the case patients had surgery.
This cluster of nontuberculous mycobacterial keratitis
cases is not unique. The CDC has received reports of at
least three other recent, independent clusters of nontuberculous mycobacterial keratitis cases after LASIK; two
occurred in the United States and one occurred in a South
American country (CDC, unpublished data). Small clusters of M. chelonae keratitis have been associated with
other ophthalmic procedures. Robin and associates39 deVOL. 132, NO. 6
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scribed two cases following radial keratotomy performed by
the same surgeon in the same outpatient facility. Newman
and associates38 described three cases that occurred after a
variety of invasive procedures performed in the same office.
The source of infection was not determined for either
cluster.
In summary, nontuberculous mycobacterial keratitis can
occur in an epidemic manner after LASIK through contamination of surgical materials. Although the specific
source of infection was not identified in this cluster,
nontuberculous mycobacteria are ubiquitous in the environment, and surgeons must remain meticulous in maintaining sterile techniques during all aspects of LASIK and
associated procedures. In addition, surgeons must be aware
of the early signs of infection, which may be mistaken for
diffuse lamellar keratitis. Early diagnosis, with immediate
and aggressive antibiotic therapy, can lead to cure of
infection. Azithromycin is an additional drug that may be
useful for the treatment of nontuberculous mycobacterial
keratitis, and should be investigated further.
ACKNOWLEDGMENTS
The following individuals provided technical assistance in
the epidemiologic investigations described in this article:
Bruce K. Fujikawa, DrPH (Department of Health and
Human Services, Long Beach CA), Akiko Kimura, MD
(California Department of Health Services, Los Angeles
CA), Rachel Ramirez, MS (California Department of
Health Services, Berkeley CA), S. Benson Werner, MD,
M.P.H. (California Department of Health Services, Berkeley, CA), Andrea Winquist, MD (Centers for Disease
Control and Prevention, Atlanta, GA), and Duc J. Vugia,
MD, MPH (California Department of Health Services,
Berkeley, CA).
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