writer attributed identical cases to McNabt and Angus

42 Pages·2005·5.61 MB·English

456 Joy: Experimental Bacillus Pyocyaneus Ulcer
Thomas, J. W. T.: Brit. M. J. 1:114, 1937.
Thomas, J. W. T.: Brit. M. J. 2:740, 1938.
Verhoeff, F. H.: Tr. Am. Ophth. Soc. 37: 125, 1939.
Wiener, M.: J.A.M.A. 53:762, 1909.
Wiener, M.: In: Contributions to Ophthalmic Science, Menasha, Wis., 1926,
p. 193.
Zentmayer, W.: J.A.M.A. 53:764, 1909.
THE TREATMENT OF EXPERIMENTAL BACILLUS
PYOCYANEUS ULCER OF THE CORNEA WITH
SULFAPYRIDINE*t
HAROLD H. JOY, M.D.
Syracuse, NewYork
Infection ofthe corneabyBacilluspyocyaneusisrelatively
rare, only 64 cases being reported in the literature. Case re-
ports have been collected by several authors, but those of
Mauersberg,l Jacobi,2 and Morelli3 have been the most thor-
ough. In 1910 Mauersberg collected 24 cases, to which he
added one case of his own. Two years later Jacobi again
reviewed the literature and added four cases that had oc-
curred during the intervening period. In 1922 Morelli, after
describing three cases, tabulated 38 found in the literature.
There apparently was a duplication in this report, for this
writer attributed identical cases to McNabt and Angus,
whereas Angus is the given name of McNab. Of the cases
recorded, nine had occurred since J-acobi's paper was pub-
lished, but Axenfeld's4 case, described in 1917, was omitted.
As no complete report has been published since Morelli's
article appeared, the 23 cases that have been described in the
literature since 1922 are presented in Table 1.§
*From the DepartmentofOphthalmology, Syracuse University College of
Medicine. This investigation was aided by a grant from the Hendricks Re-
search Fund. The sulfapyridine sodium was donated by Merck and Co.,
Rahway, NewJersey.
tCandidate'sthesisformembershipacceptedbytheCommitteeonTheses.
tThisnameoccurs intheliterature bothas McNab andas MacNab.
§One case6 is included in which the infecting organism was identified as
Pseudomonas chlororaphis, which differs from Pseudomonas aeruginosa (Ba-
cillus pyocyaneus) in certain cultural characteristics.6
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457
458 Joy: Experimental Bacillus Pyocyaneus Ulcer
In spite of its infrequent occurrence, B. pyocyaneus ulcer
of the cornea is an important diesase, because it usually runs
a severe and rapid course and has an unfavorable termina-
tion. B. pyocyaneus is perhaps the most virulent organism
that attacks the cornea.7 8 Although most strains are highly
pathogenic, they may vary in virulence, and the severity of
the infection will vary accordingly.,9'"0 Occasionally mild
cases occur, but, as a rule, B. pyocyaneus produces a rapidly
destructive lesion of the cornea, involving the lids and the
anterior segment of the globe. According to Salani," four
characteristics of B. pyocyaneus keratitis are: (1) The rapid
course; (2) the extent of corneal infiltration, which often in-
cludes the whole cornea; (3) the amount of hypopyon, which
islikelytobemostmarked; (4) themucous consistence ofthe
pus covering theulcer, and the color, which is often greenish.
Theinfectionmayappearintheformofaprogressiveulcer,
or, less frequently, of a ring abscess. Of the reported cases
collected by Morelli, a ring abscess occurred in 17 per cent.
Whether or not it will develop is probably dependent upon
the virulence of the organism and the resistance of the
tissues.91"0 2 Its occurrence is dependent upon the toxic re-
actionoftheinvadingbacteriaanddoesnotdenoteadifferent
form of infection.9
Even in the less severe cases, vision is usually greatly
reduced by the formation of leukomas. More frequently,
however, there is complete corneal destruction, resulting in
anterior staphylomas or panophthalmitis. Of his cases,
Morelli reported loss of the eye in 23, leukoma in 14, and
nebulainone; inthreethe outcomewasnotstated. Analysis
of the cases that have been reported since 1922 shows that in
15 there was complete loss of vision; in 12 of these the globe
was enucleated or eviscerated, generally because of impend-
ing or actual panophthalmitis. In five eyes vision was re-
duced to an extremely low degree, whereas in two there was
little or no loss of vision; in one the final vision was not
stated. In Garretson's and Cosgrove's'3 cases, the favorable
Joy: Experimental Bacillus Pyocyaneus Ulcer 459
results reported were probably due to the fact that the or-
ganism was not exceedingly virulent. Using the same strain,
Jackson and Hartman'4 were unable to produce infection in
therabbit's corneaexceptby making intracorneal injections.
Although many methods have been utilized in combating
theinfection, as arule all have provedineffective.'12"15"6 Itis
probable that the degree of virulence of the organism is more
responsible for the outcome than is any particular form of
therapy.1"'0"17 The two local measures considered most effi-
cacious appear to be cauterization and the Saemisch sec-
tion, 2,3,13,18,19but these,as well as the use of local antiseptics,
have generally proved unsatisfactory.10" 2
The ineffectiveness of local therapy is demonstrated by
Safar's'0 experiments on rabbits, in which all measures failed
to check the progress of the infection after the first clinical
appearance of the corneal infiltration. These measures in-
cluded irrigation with a 25 per cent. solution of argyrol or a
2 per cent. solution of tripoflavin, the application of boric
acid powder, the subconjunctival injection of septoiodine
solution, and trepanation of the infiltration. Furthermore,
infection was not prevented nor was its course altered if, im-
mediately after inoculation, the eye was irrigated for from
ten to fifteen minutes with a 25 per cent. solution of argyrol,
or if it was exposed for five minutes to the rays of short-wave
light. On the other hand, an ulcer did not develop if boric
acidpowderwas immediatelydusted on the abrasion. Voss20
andPassow,21 amongothers, hadpreviouslycommentedupon
the action of boric acid on B. pyocyaneus, whereas Bolesch,22
in experiments on rabbits, found that the drug caused a
diminution of the conjunctival discharge but did not curb
the corneal destruction.
On the basis of clinical and experimental evidence, Safar'0
affirmed that local therapy, begun after the appearance of
corneal infiltration, is not generally successful. Acceptance
of his concept of pathogenesis would explain the inefficacy
of local treatment. In a rabbit's eye, enucleated thirty-two
460 Joy: Experimental Bacillus Pyocyaneus Ulcer
hours after inoculation, this observer demonstrated the pres-
ence ofbacilliinnormalcornealtissue oftenfarremoved from
the site of inoculation.'5 Safar was not the first to call atten-
tion to this migration of the B. pyocyaneus, for both De Ber-
ardinis2" and Ldhlein24 hadpreviously demonstrated this fact.
Safar's"interpretationisthattheorganismsprogress actively
in the lymphatic spaces of normal corneal tissue. He con-
tends that they multiply rapidly at the point ofentry, propa-
gate vigorously in the normal parenchyma, and produce
destruction principally by the formation of endotoxins and
exotoxins. If this concept is true, it explains the rapid and
malignant course of B. pyocyaneus infection of the cornea
and the unsatisfactory results that attend local therapy. By
the time treatment is instituted, the organisms, having al-
ready invaded the normal cornea, are inaccessible to what-
ever measures are applied.
From what has been said, it would seem that to be effec-
tive, measures thatwillactwithpotencyandrapidityagainst
theorganismswithinthecorneal stromamustbeused. These
measures include immunization, stimulation of the defense
mechanismbyforeign protein therapy, anddirect destruction
of the organisms by chemotherapy. Both active and passive
immunologic-treatment is impractical because of the relative
infrequency of B. pyocyaneus infection, and, in the case of
the former, because of the time element. Giannini'2 cites
some evidence of the effectiveness of foreign protein therapy,
and it is surprising that this form of treatment has not been
used more widely.
THE SULFONAMIDE DERIVATIVES
There appears to be an ever-widening applicability of the
sulfonamide derivatives as their efficacy against more types
of organisms is demonstrated. Although recent literature
gives them increasing attention, the reports contain little ex-
perimental or clinical evidence regarding their use against
B. pyocyaneus.
Joy: Experimental Bacillus Pyocyaneus Ulcer 461
Priority in this respect belongs to Helmholz,25 who in 1937
reported that the urine of patients receiving sulfanilamide
possessed bacteriostatic properties against B. pyocyaneus.
Shortly after this he and Osterberg26 27 concluded that a
greater degree of bacteriostasis was obtained when the urine
was alkaline than when it was acid. Using urine cultures,
Long and Bliss28 confirmed the bacteriostatic power of sulf-
anilamide against B. pyocyaneus in in vitro experiments.
However, these writers expressed the belief that the reaction
of the urine was unimportant. More recently Helmholz,29
in investigating the bactericidal effect of sulfathiazole and
sulfamethylthiazole in urinary infections, found that the
former drug was much more effective. In equal concentra-
tions (150 mg. per 100 c.c.) of the free drug, sulfathiazole
rapidlydestroyedtheorganisms, whereassulfamethylthiazole
allowedthemtoattainaluxuriantgrowth. Infurtherstudies
with sulfathiazole, Helmholz30 reported that B. pyocyaneus
was the most resistant of the bacteria usually found in
urinary infections.
The investigations of Helmholz and of Long and Bliss
would seem to substantiate the efficacy of sulfanilamide
against B. pyocyaneus in urine; however, urine attains an
unusually high concentration of the drug. Cooper, Gross,
and Lewis3' reported that both sulfanilamide and sulfapyri-
dine were ineffective in treating experimental peritonitis in
mice.
Soon after Helmholz described his first investigation,
Herrold32 reported the cure, with sulfanilamide, of two pa-
tients suffering from genito-urinary infection due to B.
pyocyaneus. SometimelaterBanerji33 reportedtherecovery
of a child with urinary infection treated with cystopurin and
prontosil. Three cases of septicemia have been published in
all of which the outcome was favorable. Soeters34 described
the case of an infant with septicemia complicating infection
of theperineum and vulva successfully treated with prontosil
and blood transfusions. Stewart and Bates35 reported the
462 Joy: Experimental Bacillus Pyocyaneus Ulcer
recovery of a patient in ten days with sulfanilamide, and
Kolmer36 cited a favorable outcome in a child who received
neoprontosil. In this last case the blood culture, which
showed 82 colonies per cubic centimeter, became sterile
within four days.37 Alport and Ghaliougui38 recorded a case
of pyelocystitis and one of liver abscess. In the former case
the patient was treated successfully with sulfanilamide after
all measures had failed. In the latter case a liver abscess
caused by the ameba had become secondarily infected with
B. pyocyaneus. This patient recovered with aspirations of
the abscess and the use of sulfanilamide after sulfapyridine
had proved unsuccessful. Schein39 reported the favorable
outcomewithsulfanilamide administrationinapatient suffer-
ing from osteomyelitis of the spine, and Wise and Musser40
recordedtherecoveryoffourpatientswithmeningitis treated
with sulfanilamide and repeated lumbar punctures. Guy-
ton4" 42 used sulfanilamide inapatient after almost the entire
corneawasinvolvedwitharapidlyprogressive B.pyocyaneus
ulcer. After instituting chemotherapy, the ulcer progressed
but little, but the drug had to be discontinued because of
acute hemolytic anemia. The local application of sulf-
anilamide had no appreciable effect upon the infection.
McKeown43 used sulfathiazole in treating a patient with
endophthalmitis following an intra-ocular operation. Al-
though the inflammation subsided rapidly, the globe atro-
phied and enucleation became necessary.
Kolmer36 concluded that sulfanilamide is "worthy of use"
in B. pyocyaneus infections. He based his conclusions
partly upon the results of Cooper and his associates. How-
ever, there seems to be a misinterpretation, for he classifies
their findings as demonstrating that the drugs proved effec-
tive when, as a matter of fact, they were not, except against
very small lethal doses.
The pharmacologic action of the sulfonamide derivatives
has not been determined definitely,44 nor is it known how
much of the action is quantitative and how much qualita-
Joy: Experimental Bacillus Pyocyaneus Ulcer 463
tive.45 However, there is apparently, at least, some speci-
ficity of action.45 One peculiarity is that some strains of the
same organism are usually more resistant than others.46 An
important action of the compounds is their rapid absorption
and penetration into the various tissues and body fluids, as
demonstrated by Marshall47 and his associates, and later by
Engelfried,48 Birkhaug,49 and others.
Penetrability of Ocular Tissues and Fluids.-Rambo50 was
the first to demonstrate the presence in the eye of any of the
sulfonamide derivatives. He detected the drugin the ocular
fluids and lens of a rabbit that had received sulfanilamide
orally. Some time later Guyton4' recovered the drug from
the aqueous humor, and Mengel5" found the drugin both the
aqueous humor and the vitreous humor of patients receiving
sulfanilarnide orally. At about the same time Scardaccione52
made quantitative studies regardingthe diffusion of the drug
into the aqueous humor, while Venco53 recovered it from the
ocular fluids of rabbits and from the lacrimal secretion of
human beings. Bellows and Chinn54 likewise found sulfanil-
amide in the tears of patients who received the drug orally.
Pinkhof55 was the first to report the permeation of sulfa-
pyridine into the ocular fluids. After oral administration
of the drug to rabbits, its concentration in the lacrimal fluid
closely approximated that in the blood, whereas the concen-
tration in the ocular fluids was about one-fourth as much.
That sulfanilamide and sulfapyridine penetrate into the
ocular tissues as well as into the fluids has been established.
Bellows and Chinn,5456 experimenting on dogs, found that
the permeation is rapid and widespread after a single large
dose (0.2 gm. per kg.). On the other hand, these observers
have recentlyreported that only traces of the drug appear in
the fluids and avascular tissues of the eye after the adminis-
tration of sulfathiazole under similar conditions.57
According to these investigators, after the administration
of sulfanilamide and sulfapyridine the concentration curve
oftheocularconstituentsfollowedthat oftheblood, although
464 Joy: Experimental Bacillus Pyocyaneus Ulcer
usually at alowerlevel. However, thevalues in the aqueous,
andparticularly inthe cornea, were relatively high. Meyer58
and his co-workers made similar observations. Moreover, the
latter reported that in rabbits receiving sulfapyridine orally
the drug concentration in the cornea equalled or exceeded
that attained by the blood after a period of seven hours. In
vitro experiments showed that the cornea attained a higher
concentration with sulfanilamide than with sulfapyridine.
Bellows andChinn5456 foundthatthemaximumconcentra-
tion ofthe druginthe ocular tissues andfluidswas reachedin
about four hours with sulfapyridine, and in about six hours
with sulfanilamide, and that both drugs were still present in
all components twenty-four hours afterreceivingmedication.
Therapeutic doses produced much lower levels, but the blood
concentrations, although considerably lower than those se-
cured in human beings receiving a proportional dose, re-
mainedfairlyconstant. Little difference couldbedetectedin
the drug concentrations of the ocular tissues and fluids
whether sulfanilamide was administered four times daily or
twice daily.
The local application of sulfanilamide and sulfapyridine
produces a lower concentration in the ocular tissues and
fluids than is obtained after oral administration. Bellows
and Chinn54 reported that the application of sulfanilamide
powdertothecorneaandconjunctivagaveapositivereaction
to the subconjunctival tissue and corneal stroma, but none
could be detected in the ocular fluids. These investigators
reported that the concentration of the drug in the aqueous
humor following subconjunctival injection of 1 c.c. of a satu-
ratedsolutionwasmuchlowerthanafteroral administration.
Likewise&Guyton4' and Mengel5" found, after instillation into
the conjunctival sac, a negligible amount in the aqueous
humor as compared to that following oral administration.
Pinkhof5s obtained similar results with sulfapyridine. None
ofthe drugwasrecoveredfromthe ocularfluids afterapplica-
tion of a paste of sulfapyridine to the conjunctiva, and only
Joy: Experimental Bacillus Pyocyaneus Ulcer 465
a small amount was found in the aqueous humor following
the subconjunctival injection of a 6 per cent. suspension of
the drug.
Variability in Permeation.-Both sulfanilamide and sulfa-
pyridine show considerable variability in their permeation,
one thatisnotnecessarily proportional to the dose.44 Notin-
frequently the concentration of the drug in the blood of
patients remains low in spite of large doses. Moreover, the
concentration in different patients may vary after identical
doses administered under similar conditions." This varia-
bility is even greater in animals, particularly in rabbits and
guinea-pigs." McMahon59 found wide variations in rabbits
receiving similar doses of sulfanilamide, and Lee60 and his
co-workers have shown that individual pregnant rabbits dis-
playedmarkedvariationsunderstandardconditions. Long,6'
Marshall,62 and their associates, and Chinn and Bellows56
have demonstratedthat sulfapyridine isirregularlyabsorbed,
and that its concentration is more variable than is that of
sulfanilamide. Long and Bliss" reported that frequently,
even after prolonged intensive therapy, only traces of free
sulfapyridine may be found in the blood. These workers
concluded that, in comparison with sulfanilamide, the ab-
sorption, distribution, conjugation, and excretion of sulfa-
pyridine are definitely more irregular and capricious, and
that one can not depend on this drug to reach the affected
tissues as one can depend on sulfanilamide to do. Although
sulfapyridine is less readily absorbed, its concentration in
the blood of animals is better maintained than is sulfanila-
mide. This is an important factor, and may account for the
better therapeutic results attained in certain experimental
infections."
Sulfapyridine Sodium.-In 1938 the mono-sodium salt of
sulfapyridine was introduced in the effort to overcome the
insolubilityanddifficult absorption ofsulfapyridine.62 Powell
and Chen3 have recently reviewed the literature on sulfa-
pyridine sodium, and have published the results of their
investigations.