# Severe Keratitis Caused byPseudomonas aeruginosa Successfully Treated with Ceftazidime Associated with Acetazolamide

Authors: Benoit Hue; Marc Doat; Gilles Renard; Marie-Laure Brandely; François Chast
Journal: Journal of Ophthalmology
 (2009)

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## Abstract

Purpose. To report a case of microbial keratitis caused by Pseudomonas aeruginosa treated with a combination of acetazolamide and ceftazidime. Methods. Case report. Results. We report the case of a 17-year-old contact lens-wearing female who developed severe keratitis due to Pseudomonas aeruginosa temporarily healed with topical fortified antibiotic eye drops. After few days, the patient relapsed, and topical and intravenous ceftazidime were added. Concomitantly, oral administration of acetazolamide was prescribed. This carbonic anhydrase inhibitor was added to the antibiotic regimen in order to decrease the anterior chamber pH, and then, the ceftazidime ionization. By lowering the state of ionization of the antibiotic in the aqueous humor, its concentration was increased. This was confirmed by an improvement of the patient within few days and a rapid eradication of the infection. Conclusion. This is the first reported case of keratitis caused by P. aeruginosa successfully treated using acetazolamide as an enhancer of ceftazidime effectiveness.


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## Body

## 1. Case Report

A 17-year-old woman was
referred with a 48-hour history of a painful left eye as a consequence of a
severe keratitis most likely of bacterial aetiology. Pain started after bathing
in a public swimming pool while continuing to wear her contact lenses on a
daily basis. On presentation, the left eye visual acuity was 2.3 LogMar (L). An
extensive necrotic stromal infiltrate was observed in the cornea with a dense
hypopyon. The corneal ulcer size was 7 mm× 7 mm. Cornea scrapings were performed for microbiological
staining and inoculated for culture. On admission, topical treatment included
vancomycin 5%, ticarcillin 0.66%, and amikacin 3% eye drops administered hourly in
the eye. On day 2, the bacterium was identified as Pseudomonas aeruginosa and antibiotic disc sensitivity testings revealed that the organism was
sensitive to most of antibiotics including ticarcillin, amikacin, ciprofloxacin,
and ceftazidime. Initial treatment was changed to ciprofloxacin 0.3% (Ciloxan, Alcon,
France),
ticarcillin 0.66%, and amikacin 3% (prepared by the hospital pharmacy). An amoebic
polymerase chain reaction (PCR) gave negative results. Six days after
admission, ulcer size and hypopyon were reduced, and the patient was discharged
from hospital but prescribed to continue the topical antibiotic treatment at
home, every 4 hours.The patient represented
to the emergency unit, on day 13. Ulcer size had increased and hypopyon was
observed again. It was decided to hospitalize the patient again. Initial
treatment with topical vancomycin, ticarcillin, and amikacin eye drops was
restarted. On day 16, due to the inefficacy of this treatment, corneal
scrapings were performed again for bacterial culture and amoebic PCR, results
of which were both negative. Three weeks after the start of the infection, the
clinical situation was still worsening and the integrity of the eye was
compromised (Figure1).Figure 1
Three weeks
after initial presentation, corneal ulcer associated with an intense
inflammation and a dense hypopyon were still observed.At this stage, a new therapeutic
strategy was prescribed; topical and intravenous ceftazidime were included in
the antimicrobial strategy. A fortified 5%-ceftazidime ophthalmic solution was
prepared by the hospital pharmacy. It was instilled hourly in the infected eye.
Additionally, a 1-g intravenous injection of ceftazidime (Fortum, GSK, Paris) was administered every
8 hours in association with 250-mg oral acetazolamide [1]
(Diamox, Sanofi-Aventis, France) every
24 hours. After 2 days (Day 23), clinical improvement was shown according to
corneal abscess regression and hypopyon disappearance.One week after the
initiation of this late treatment (Day 30), clinical improvement allowed a cessation
of the intravenous ceftazidime and a reduction in the frequency of instillation
of the topical fortified antibiotics. Ceftazidime was tapered gradually over
the next three weeks and eventually stopped. Abscess regression and hypopyon
disappearance are illustrated by Figure2.Figure 2
Four weeks after the start of ceftazidime treatment, we
noticed a central corneal scar, absence of hypopyon, and no evidence of active
keratitis.Four months after the
first hospitalization, the left eye visual acuity was 0.6 L. There was evidence of
central corneal scarring without inflammation or neo-vessels (Figure3).Figure 3
A slit lamp photograph of the left eye 4 months after initial
presentation illustrates a central corneal scar without inflammation or neovessels.


## 2. Discussion

P.
aeruginosa is the
predominant Gram-negative bacterium that infects the cornea. For many years, keratitis
caused by Pseudomonas has been commonly associated with the wearing of
soft contact lenses [2], and it
has recently been reported that the wearing of contact lenses was the most common
risk factor for keratitis and that the most commonly isolated organism was P.
aeruginosa [3, 4]. Even in compliant patients [5],
standard lens care hygiene precautions are probably not sufficient for preventing
the development of sporadic corneal infections.In this case, topical
broad-spectrum antibiotics were used initially in the empiric treatment [6, 7] and then switched, once the results
of cultures and antibiotic sensitivity patterns were recovered from the
laboratory. Two weeks after the start of treatment, scrapings were performed
again but, this time, without pathogen recovery.Three weeks after first
admission to hospital, the integrity of the eye was compromised. At this stage,
a topical and intravenous ceftazidime regimen was started [1, 8].
Ceftazidime is a third-generation cephalosporin antibiotic, with an extended
spectrum of activity against Gram-negative bacteria, especially Pseudomonas spp. It is one of the most effective antibiotics against P. aeruginosa, the organism
isolated after first corneal scrapings. Topical fortified 5%-ceftazidime
eye drops (50 mg/mL) were prepared (in an appropriate compounding aseptic
containment isolator maintaining an ISO 5 air quality environment) in saline, following
data showing a short-term stability (4 days at 4°C) [9]. Ceftazidime pharmacokinetic
properties in healthy volunteers give satisfactory penetration features of the
antibiotic into aqueous humor; a mean concentration of 11 ± 4 μg/mL (after a 2-g ceftazidime infusion),
corresponding to a penetration ratio of 19%, has been reported [8].This case report
illustrates the fact that concentrations obtained with topical antibiotic treatment
alone, even if delivered on an inflamed cornea may not be sufficient to
eradicate intermediate or poorly sensitivePseudomonas strains. In such cases, it is necessary to add systemic treatment to the
topical antibiotic regimen. We also decided to enhance the penetration of the antibiotic
in the anterior chamber by the means of an unusual but useful pharmacokinetic interaction
with acetazolamide. Concomitant administration of acetazolamide was decided
owing to a previous report demonstrating that it increases aqueous humor
concentration of intravenous ceftazidime. It has been established that 2, 4, and
6 hours after a 2-g ceftazidime infusion, antibiotic concentration in aqueous
humor was significantly increased after
acetazolamide (250 mg for every 6 hours) coadministration [1].Addition of acetazolamide,
a carbonic anhydrase inhibitor (CAI), in the therapeutic regimen, allows an
increase in the concentration of ceftazidime in the anterior chamber by a
factor 2 to 5. For instance, 2 hours after the end of the infusion,
concentrations of4.26±1.75 mg/L and 22.4±16.6 mg/L were measured,
respectively, in aqueous humor in patients without or with acetazolamide treatment [1].
For P. aeruginosa, ceftazidime
(Minimal Inhibitory Concentrations) MICs range from 2 to 6 mg/L [10].
These data suggest that the use of acetazolamide, by increasing the drug
concentration at its site of action 2-to 5-fold, is likely to allow exceeding
MICs for most P. aeruginosa strains.In the present case, the
length of the treatment was one week for intravenous ceftazidime associated with acetazolamide and one month for
topical ceftazidime. The choice of acetazolamide was based on its specific
pharmacological properties on the electrolytic balance in body fluids. Carbonic
anhydrase has the property to reversibly accelerate the reaction between
carbonic anhydride (CO2) and water (H2O). The presence of
this enzyme in ocular structures, including the ciliary body processes, and the
high concentration of bicarbonate in the aqueous humor allow an opportunity for
CAI to play an important role in ionic changes in both posterior and anterior
chambers. Within the anterior chamber, besides lowering intraocular pressure,
CAI will also lower the amount of bicarbonate (HCO3−)
production, [11]
thus decreasing the pH. As a
consequence of this phenomenon, the state of ionization of numerous
pharmacological agents is more or less modified. CAI will increase the
ionization of basic molecules and decrease the ionization of acidic drugs. It
is well known that nonionized molecules can easily diffuse across cell
membranes. In contrast, the ionized molecules are usually unable to penetrate
the lipid membrane because of their low lipid solubility. Ceftazidime, with two
carboxylic moieties, behaves as a weak acidic molecule in biological fluids. After
CAI intake, the amount of bicarbonate in aqueous humor is lowered and the fluid
is acidified as a result. In such conditions, ceftazidime ionization decreases,
and its intracellular penetration is then enhanced.Further investigations
and additional cases must be reviewed before definite conclusions can be made
as to the improvement in ceftazidime effectiveness when administered with
acetazolamide, to treat severe keratitis caused byP. aeruginosa.The anterior chamber is
a crucial target when considering that most ocular infections start with germ
penetration through the cornea, followed by colonization of the aqueous humor.
In various acute microbial keratitis, the use of acetazolamide could be
relevant when the antibiotic treatment is comprised of a weak acidic molecule
(carbenicillin, ticarcillin). In such cases, acetazolamide adjunction to
antibiotic treatment could be an easy and inexpensive way to obtain an increase
in antibiotic concentration within the anterior chamber, allowing the
antibiotic MIC to be reached more easily and facilitating improvement or
healing.



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*Source: 794935-2009-04-26.xml*