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Endogenous Proteus Panophthalmitis*
ENDOGENOUS Z.
LAFFERS,
PROTEUS M.D.,
A N D S.
Budapest, CASE
PANOPHTHALMITIS* BOZSOKY,
M.D.
Hungary w a s diagnosed a s metastatic panophthalmitis o r i g i nating f r o m sepsis. I n order t o identify the pathogenic agent, t o find the origin o f the sepsis and t o determine the therapeutic methods to be employed the f o l l o w i n g e x aminations w e r e m a d e : A b o u t 0.3 ml. o f yellow-tinted, fibrinous aqueous humor w a s obtained b y puncturing the c h a m ber w i t h a n A m s l e r needle and w a s replaced b y 20,000 u. o f penicillin. A subsequent uveal puncture with an A m s l e r needle yielded a minimum amount of semisolid pus. T h e bulging f o r n i x o f the conjunctiva w a s incised and p u s similar to that found in the uvea w a s obtained. A f t e r the sample w a s taken and m o s t o f the pus drained off, the probe entered a cavity which pointed in the direction o f the internal rectus muscle. A strip o f g a u z e soaked in penicillin and streptomycin w a s inserted and 100,000 u. o f penicillin and 0.25 g m . o f streptomycin w e r e injected s u b conjunctivally. Conjunctival, aqueous and uveal specimens w e r e taken f o r bactériologie study. Blood w a s obtained f o r hémoculture. Treatment consisted o f 1,000,000 u. o f penicillin, 1.0 g m . streptomycin, strophoside and Germicid suppository, the latter t o combat fever. A f t e r h a v i n g instituted this therapy, clinical and laboratory study w a s continued. T h e diagnostic opinion w a s sepsis and jaundice. T h e sepsis presumably originated f r o m the bile ducts. U r i n a l y s i s : specific gravity 1,024, albumin + , U B G slightly i n creased, sugar 1.9-percent, acetone negative, sediment 4 0 t o 60 leukocytes. L i v e r function t e s t s : thymol 13 u., U c k o + - ( - + > serum bilirubin 12.7 m g . percent. Internal medical examination. T h e heart w a s normal i n size and sound. P u l m o n a r y emphysema w a s present. T h e liver w a s palpable s i x cm. below the right costal m a r g i n ; i t s m a r g i n w a s acute, not tender. T h e r e w a s sacral edema and marked jaundice. Opinion. T h e sepsis orginates presumably from the bile ducts but t h e results o f urinalysis suggest that t h e urogenital tract should a l s o be suspected as a potential source o f infection. U r o l o g i e study s h o w e d the kidney areas free, t h e prostate moderately enlarged and glandular. N o tumor w a s palpable. T h e residue w a s 2 0 0 ml. T w o days after admission the results f o r the bactériologie and serologic examination o f the aqueous, vitreous and conjunctiva w e r e a s f o l l o w s : T h e aqueous w a s sterile. F r o m the vitreous and conjunctiva a g r a m - n e g a t i v e bacterium, s h o w i n g the same morphology, had been g r o w n , which w a s being identified. T h e strain w a s susceptible to streptom y c i n and tetran, moderately sensitive t o chlorocid, resistant to aureomycin, penicillin and ultraseptyl ( s u l f a t h i a z o l e ) . S e r o l o g i c findings:
REPORT
S z . J., a man, aged 72 years, w a s brought t o the Department o f Ophthalmology o f the Institute o f Rheumatology and Medical H y d r o l o g y b y ambulance o n D e c e m b e r 2 9 , 1959, w i t h the diagnosis o f retrobulbar inflammation, O . S . T h e patient w a s in poor condition and g a v e vague, uncertain answers to our questions. H e told u s h e had had frequent episodes o f chills and high fever during the past t w o weeks. T w o days before admission h e developed pain and blindness i n the left e y e though the vision o f that e y e had been g o o d before. H i s doctor g a v e h i m a penicillin injection. T h e n e x t d a y an ophthalmologist w a s consulted and the patient w a s immediately hospitalized. A relative told u s that the patient had recently been o n a diabetic diet. O n examination, the patient w a s found t o be in a very poor condition and had obviously lost much weight. T h e tongue w a s dry and coated. T h e skin and sclera s h o w e d an intense y e l l o w color. T h e left l e g w a s thicker than the right. T h e right ankle w a s e x t r e m e l y tender. T h e r e w a s an enormous scrotal hernia. T h e sensorium w a s normal. P u l s e rate 96 in o n e minute, blood pressure 150 m m . H g , systolic, 90 mm. H g , diastolic. Ocular findings. V i s i o n w a s : R e a d s fingers at four meters, photosensitivity w a s lost. N o correction w a s attempted because of h i s poor condition. T h e right e y e w a s normal. Sclerotic blood v e s sels were found in the eyegrounds and fine degeneration in the macula. T h e left e y e s h o w e d edema, s w e l l i n g and redness of both eyelids, more marked in the upper. A s a result o f exophthalmos, there w a s a constant three to four-mm. space between the palpebral m a r g i n s and the left e y e could not be closed. T h e conjunctiva showed strong injection, Chemosis and circular overlapping o f the cornea. I n the upper conjunctival fold the conjunctival sac s h o w e d a y e l l o w translucence, corresponding t o an accumulation o f pus. Ciliary injection, corneal opacity, a v e r y deep c h a m ber, fibrinous aqueous w i t h a three-mm. hypopyon in the inner lower area and a dirty green iris w e r e found. T h e pupil w a s moderately dilated, round, c e n tral and did not respond t o light. I n the area o f t h e pupil the iris circularly adhered t o the anterior surface o f the lens. T h e r e w a s a thick membrane of exudate in the area o f the pupil. N o pink g l o w could be obtained. T h e deeper structures o f the eye could not be visualized. T h e eyeball w a s s o f t to palpation, protruded and w a s looking downward. T h e ocular m o v e m e n t s w e r e greatly restricted. O n the basis o f the examinations the condition * F r o m the State Institute o f R h e u m a t o l o g y and Balneology. 83
84
Ζ. L A F F E R S A N D S. B O Z S Ô K Y TOTAL PROTEIN
Serum Aqueous
(mg.%) A S O 6400 60 3100 120
Staph. 1.0/ml. 0.5/ml.
Brucella 4 2
MlDDLEBROOKDUBOS
4 2
CRP
1024 512
Cytologic study o f a smear made of the aqueous (fig. 1) showed many leukocytes, lymphocytoid and monocytoid cells, at sites iris pigment, as well as microphages, macrophages and phagocytosing bacteria. T h e cellular morphology w a s extremely variable. T o locate the primary focus, a throat swab, duodenal juice and urine w e r e sent for bactériologie study. Other laboratory findings. Blood count: erythrocytes, four million ; leukocytes 24,000 ; hemoglobin, 12-percent. Differential count: juveniles, one-perc e n t ; stabs, eight-percent; polymorphonuclears, 87percent, lymphocytes, four-percent. T h e r e w a s toxic granulation. Blood sugar, 338 m g . percent. A n E C G and chest X - r a y films showed no substantial alterations. T h e n e x t day the patient felt better. T h e swelling of the eyelid and conjunctiva, as well as t h e protrusion, w a s diminished. H e could close his eyes. P u l s e rates w a s 100/min., body temperature 37.7°C. Antibiotics (penicillin, s t r e p t o m y c i n ) , insulin, vitamins, infusion and cardiaca were given. H e continued t o make good progress on the third and four days, too. T h e jaundice diminished but the temperature remained around 3 8 ° C . and the blood pressure dropped from 150 mm. H g , systolic, and 100 mm. H g , diastolic, t o 100/65 mm. H g , in spite of the administration o f analeptics. T h e pulse
Fig.
1
(Laffers and B o z s o k y ) . A q u e o u s s h o w i n g phagocytes.
smear,
rate w a s 120/min. I n the morning o f the fifth d a y chills developed, the limbs w e r e cold and moist and cyanosed. T h e pulse rate w a s 120/min., the pulse w a s weak, blood pressure 60 m m . H g , and the fever 38.1°C. T h e chills ceased within a f e w minutes in response to t w o ampules of steralgin. T o combat the severe collapse an intravenous noradrenaline drip infusion w a s started, combined w i t h H o s t a c y c l i n (aureomycin, 2 5 0 m g . in four h o u r s ) , vitamins and cardiaca. S o m e laboratory tests w e r e done or repeated in the meantime. T h e r e w a s n o sugar o r acetone in the urine, the blood sugar w a s 144 m g . percent. N P N : 108 m g . percent. U r e a N : 52 m g . percent. Liver function tests: U c k o + + + + , total bilirubin 8.8 m g . percent, direct 6.9 m g . percent, indirect 1.9 m g . percent. T h e leukocyte count w a s 10,000/cu. mm. A W a s s e r m a n n test w a s negative. O n the second d a y of incubation a g r a m - n e g a t i v e bacterium, s h o w i n g propertie- identical to that g r o w n from the eye, g r e w from the hémoculture taken on December 30th. T h e same bacterium strain could be g r o w n from the urine, duodenal juice and throat swab. T h e strain proved to be B . proteus mirabilis, with an antigenic structure of 0 : 2 8 , H : l . ( W e express our thanks to D r . B. Lânyi for identifying the strain and for determining its antigenic structure.) S e r u m from the patient showed an Ο agglutination of 1:128, and a Η agglutination of 1:512 with the proteus strain isolated. O n the basis o f the laboratory findings and the results of physical examinations ( t h e size o f the liver had decreased considerably), it w a s suggested that renal failure had been joined by an imminent hepatargic coma, and therefore the patient w a s transferred to the Department o f Medicine N o . 2. T h e r e treatment w a s continued as before and w a s supplemented with sodium thiosulfate, adrenal cortical hormone and A C T H . O n the seventh d a y o f admission the patient developed a severe collapse, with cardiovascular failure due to arteriosclerosis, and died. T h e jaundice, the enlarged and tender liver s u g gested a sepsis due to cholangiohepatitis, originating f r o m cholelithiasis. I n support o f this v i e w w e r e t h e increase o f the mostly direct serum bilirubin, the positivity o f the tests f o r liver function and the fact that m o r e than 50 percent o f N P N w a s urea. U r i n a r y retention and the urinary sediment indicated renal involvement. T h e diabetes w a s mild throughout and caused n o trouble. S e v e n days after admission the pathogen could be identified ( B . proteus) and on the basis o f sensitivity tests adequate therapy could be instituted. H o w e v e r , the primary focus, the original site o f the sepsis, could be detected only post mortem. Postmortem findings. A stone, about the size o f a pigeon's e g g , w a s found in the gall bladder, w h o s e wall w a s thickened and w h i c h contained w h i t e mucous bile. T h e left kidney w a s enlarged, several abscesses of pea and bean size w e r e visible on and in it. T h e renal pelvis w a s filled w i t h viscous pus. M o s t of the renal pyramids showed necrosis. T h e r e w a s a
ENDOGENOUS PROTEUS large, bean-sized stone in the ureter, about five cm. from the pelvis, causing dilatation of the ureter, with several decubital ulcers in the mucosa o f the d i s tended area. T h e left eyeball w a s soft and flaccid. In place of vitreous, dense y e l l o w i s h - g r a y pus w a s found. A pinhead-sized perforation w a s detected near the insertion of the internal rectus muscle and around it a small bean-sized preformed cavity with very viscous pus on its wall. T h e postmortem analysis indicated pyonephrosis of the left side as a complication of nephrolithiasis, leading to sepsis, with the metastatic inflammation of the left eye as an uncommon complication ( D r . Fodor). A t autopsy specimens were taken from the gall bladder, spleen and renal abscess under sterile c o n ditions for culture study. B. proteus of the antigenic structure already mentioned g r e w f r o m all three specimens. H i s t o l o g i c changes in the eye are shown in F i g u r e 2 . In the H u n g a r i a n literature P r i k k e l and F o d o r have described a lethal sepsis caused by P r o t e u s mirabilis. T h e strain w a s isolated f r o m three different sites—wound serum, cerebrospinal fluid and cerebral abscess. DISCUSSION
The pathogenic significance of B. proteus has been increasing since the advent of antibiotics, especially in the urologie practice (Hanson, et al.). However, proteus sepsis is still uncommon. In his survey published in 1948 Abrams mentions 52 cases in the world literature. In 1951, Norgaard, et al., reported one more case. In 1954, seven cases were described by Spittel, et al., and, in 1957, Dobrzynski described one case. Under the age of 40 years, proteus sepsis is usually otogenic, over this age it tends to be of urogenital origin. It is not always possible to locate the source of the sepsis in vivo. For example, in Dobrzyski's case, it was only during postmortem study that the primary focus (a lung abscess) could be identified. The prognosis is most unfavorable, the proteus strains usually being resistant to antibiotics. According to Abrams, 64.6 percent of the published cases were fatal. On the basis of animal experiments and in vitro studies, Armstrong and Lamer have recommended the use of combinations of antibiotics in the treatment of proteus sepsis.
PANOPHTHALMITIS
85
F i g . 2 (Laffers and Bozsoky). Site of scleral perforation, s h o w i n g numerous leukocytes.
In their seven cases, Spittel and his associates employed a combination of streptomycin and Oxytetracycline and lost none of their patients. In this country, Lânyi has studied in detail the pathogenicity of proteus strains, having analyzed about 1,600 proteus strains from various sources biochemically and for antigenic structure. H e has found that most of the proteus strains isolated from pathologic processes (enteritis, urogenital infections, and so forth) belonged to the antigen groups 0 : 3 , 6, 10, 13, 26 and 28. As is known, Perch makes distinction between 49 O-groups and 110 types. In our case the pathogen showed the 0 : 2 8 , H : l antigenic pattern. Its pathogenicity is indicated by the fact that the patient's serum showed an Ο titer of 1:128 and a Η agglutination titer of 1:512 against it. A detailed evaluation of the serologic evidence for blood and aqueous will be discussed elsewhere. Many pathogens (bacteria, viruses, protozoa) may cause endophthalmitis or panophthalmitis. They may invade the eye through wounds caused by injury or at ocular operation (for example, after cataract
86
Ζ. L A F F E R S A N D S. B O Z S Ô K Y
extraction), or eventually by endogenous metastasis. In the monograph by Verrey the pathogens producing endophthalmitis are grouped as follows : 1. Pathogens that may equally cause exogenous and endogenous endophthalmitis. To this group belong the pneumococci, staphylococci, gonococci, the influenza bacillus of Pfeiffer, the coli-type bacilli and the blastomycetae. The latter three play no important role. 2. Exclusively metastatic endophthalmitis is produced among others by Mycobacterium tuberculosis, Treponema pallidum, meningococcus, Bacillus leprae, pestis, leptospira, and so forth. 3. Some bacteria produce or are involved in exogenous endophthalmitis only. In this group belong Proteus vulgaris and B. pyocyaneus. In the ophthalmologic literature of the past few years the number of reports on gram-negative bacteria causing exogenous panophthalmitis (mainly following cataract extraction) has been increasing. A s early as 1939, Popova described the case of a man, aged 65 years, in whom B. proteus vulgaris had caused postoperative panophthalmitis after cataract extraction. In 1945, Leopold reported on a case of panophthalmitis caused by Pseudomonas aeruginosa, a gram-negative bacterium. B. coli has often been reported as the cause of panophthalmitis (Glover, Pelman, Weil, Laval, Sturman). In 1953 Callahan analyzed in detail his five cases of endophthalmitis which had occurred in 1,653 cataract extractions. At first the growth from preoperative conjunctival and lid margin smears of gram-negative bacteria had not been considered to be a contraindication. The operation had been postponed only when Streptococcus viridans and hemolyticus, Staphylococcus aureus and Diplococcus pneumoniae had been isolated. But after having lost two eyes in two cases from which gram-negative bacteria had been
obtained preoperatively, operation was also postponed for about three weeks in such cases. This precaution was followed by three cases of endophthalmitis caused by Proteus vulgaris; the patients had been operated on in spite of the fact that B. proteus had been isolated preoperatively. Crabb, Fielding and Ormsby emphasize that B. proteus is the principal agent among the gram-negative bacteria that is likely to cause postoperative panophthalmitis, because it commonly occurs in the conjunctival fornix in older persons. W e agree with this view because B. proteus has often been grown from preoperative conjunctival smears in our cases. Searching for allergic causes of uveitis, Binkhorst and van Ufford found sensitivity to bacterial allergens in a significant proportion of cases. The cutaneous test was most often positive to B. coli and B. proteus. In contrast with this, Bolletieri does not attribute significance to cutaneous reactions to proteus extracts because, according to him, they are nonspecific. One of the interesting features in our case is that the B. proteus did not enter the eye from without, through the exogenous route from the conjunctiva, but by means of endogenous metastasis, having been transported by the blood stream to the eye. In this way, panophthalmitis became the first apparent symptom of proteus sepsis and the pathogen was first isolated from the vitreous. According to Hippel even the most careful and detailed clinical and pathologic studies usually fail to detect the site of origin of metastatic purulent panophthalmitis. In most cases the bactériologie findings are defective and the pathogen is usually isolated from the enucleated eye. Also the primary focus is very difficult to find. In the order of frequency the following sites should be considered: teeth, tonsils, nasal sinuses (retention of pus), intestinal tract, genito-urinary tract. The male genito-urinary tract is un-
ENDOGENOUS PROTEUS
doubtedly an important etiologic source. In our case the diabetes and the severe phimosis increased the susceptibility to urinary infections. Metastatic panophthalmitis is a not uncommon complication of renal diseases. Weil, Laval and Sturman have described a case of Escherichia coli panophthalmitis from pyelonephritis, in which the pathogen could be isolated from the blood and urine and later from the pus obtained from a spontaneous perforation of the globe at the temporal limbal area. Sensitivity studies showed the micro-organism to be sensitive to Furadantin and tetracycline. The patient survived and the diagnosis was established by diagnostic intravenous pyelography, retrograde pyelography and finally by left nephrectomy. In the kidney multiple cortical abscesses, papillary necrosis, pyelonephritis and peripelvic abscess were found. Also Levine's case was one of E. coli metastatic panophthalmitis, with a pyonephrosis due to calculi as the primary focus. The pathogen could be isolated from both eyes and from the urine. While the bacteria causing panophthalmitis can be suppressed by the various antibiotics, B. proteus is sensitive to only a few of them. This accounts for the recent increase in interest in this pathogenic agent. In the usual doses chloramphenicol and tetracycline do not inhibit B. proteus. Gantrisin (sulfasoxazole) has proved to be the most potent agent, especially when applied locally, after corneal abrasion. The next in potency is neomycin. In cases of B. proteus panophthalmitis Callahan promptly punctured the chamber, collected aqueous for culture, rinsed the chamber with penicillin and streptomycin and also applied them subconjunctivally because, if administered parenterally, no efficient intraocular levels can be reached. Leopold has recommended the use of chloramphenicol (3.0 gm. in one dose) followed by 1.0 gm. doses at six-hour intervals.
PANOPHTHALMITIS
87
The local therapy in our case was similar to that recommended by Callahan. However, we punctured not only the chamber, but also the vitreous for diagnostic purposes, going on the assumption that the aqueous is usually sterile. This assumption was correct in our case, too, and it was only from the vitreous and the conjunctival discharge (which also came from the vitreous) that the B. proteus could be isolated. In response to the local therapy the panophthalmitic inflammatory phenomena markedly receded. However, the antibiotics administered locally and parenterally (penicillin, streptomycin, aureomycin) failed to combat sepsis. According to Topley acute sepsis seldom develops after excessive local reactions (pyonephrosis in our case). However, in spite of the relatively great therapeutic response in our case, an acute, fatal sepsis developed. SUMMARY
A case of endogenous panophthalmitis due to B. proteus sepsis is described. The first manifest symptom of sepsis was panophthalmitis. B. proteus (Proteus mirabilis, 0 : 2 8 , H : l ) was isolated in vivo from the conjunctival fornix and vitreous. The aqueous proved to be sterile. The B. proteus strain could be cultured from the blood, urine, duodenal juice and tonsils and, postmortem, from the spleen, gall bladder and kidney, as well. The source or sepsis, pyonephrosis, was revealed only by postmortem study. The proteus strain isolated proved to be sensitive to streptomycin and tetran. However, the arteriosclerotic and diabetic patient, aged 72 years, died of cardiovascular failure in spite of the proper antibiotic therapy. B. proteus more and more often causes exogenous postoperative panophthalmitis, but our case indicates that it may produce endogenous panophthalmitis as well. Frankel
Leo-u.
17-19.
88
Ζ. L A F F E R S A N D S.
BOZSÖKY
REFERENCES
A b r a m s , H . L . : Septicemia due t o proteus v u l g a r i s : R e v i e w of the literature and report of a case cured by streptomycin. N e w E n g l a n d J. Med., 2 3 8 : 1 8 5 - 1 8 7 , 1948. Albrich, K.: A szembetegségek é s szemtünetek ö s s z e f ü g g e s e a szervezet e g y é b betegségével. Budapest, M a g y a r O r v o s i K ö n y v k i a d o Vâllalat, 1929. A r m s t r o n g , C. W . J., and L a m e r , A . E . : T h e effect of combination of antibiotics on P s e u d o m o n a s aeruginosa and P r o t e u s vulgaris in vitro and in v i v o . J. Lab. Clin. Med., 3 7 : 5 8 4 - 5 9 2 , 1951. Binkhorst, P . G., and v a n Ufford, W . J.: R e s u l t s obtained in the e x a m i n a t i o n of patients w i t h iridocyclitis and uveitis f o r allergy. A c t a allergologica, 1 4 : 4 7 0 - 4 8 5 , 1959. Bolletieri, D . : S u l valore della cutireasione con estratti di proteus c o m m u n e e di proteus X 19 nel trachoma. Boll. Ocul., 1 9 : 3 3 3 - 3 3 9 , 1940. R e f . : Zentralbl. f. Ophth., 4 6 : 1 6 3 , 1940. Burton, Α., and Waisbren, E . : T r e a t m e n t w i t h large doses of penicillin in a case of severe bacteremia due t o Proteus. A r c h . Int. Med., 9 1 : 1 3 8 - 1 4 1 , 1953. Callahan, A . : Effect of sulfonamides and antibiotics on panophthalmitis complicating cataract extraction. Α Μ Α A r c h . Ophth., 4 9 : 2 1 2 - 2 1 9 , 1953. Crabb, A . M., Fielding, I. L., and Ormsby, H . L. : Bacillus proteus endophthalmitis. A m . J. Ophth., 4 3 : 8 6 - 8 9 , 1957. Dobrzynski, Z. : P o s o c z n i a w y w o l a n a paleczka odmienca pospolitego ( B a c t . proteus v u l g a r i s ) P o l s k i tygod. lek., 1 2 : 1 7 8 3 - 1 7 8 4 , 1957. F a r a g o , F . : Bakteriologia és immunitâstan. M a g y a r orvosi K ö n y v k i a d o Târsulat. 1948. Goldbloom, Α . Α., and Golbey, M . : Case of acute cholangitis ( p o s t o p e r a t i v e ) due to proteus vulgaris sepsis treated w i t h aureomycin. A m . J. D i g e s t . Dis., 1 8 : 6 3 - 7 1 , 1951. H a n s o n , R. J., Karabatsos, N . , and H e r r o l d , R. D . : Species of the g e n u s proteus and s o m e urological implications. J. Urol., 7 9 : 1 0 1 6 - 1 0 1 7 , 1958. v o n Hippel, Ε . : Ein Fall von Iridocyclitis mit rezidivierendem H y p o p i o n mit anatomischem B e f u n d . A r c h . f. Ophth., 1 2 8 : 2 7 2 - 2 7 9 , 1932. Länyi, B . : Serological typing of proteus strains from infantile enteritis and other sources. A c t a Microbiol. H u n g . , 3 : 4 1 7 - 3 2 8 , 1956; Serological t y p i n g of proteus stains. Sensitivity to antibiotica. A c t a Microbiol. H u n g . , 4 : 4 4 7 - 4 5 7 , 1957. Levine, I.: Metastatic Bacillus coli panophthalmitis f r o m calculus pyonephrosis. A r c h . Ophth., 3 : 4 1 0 412, 1930. L u g o s s y , Gy.: Therapeutic experiments in endophthalmitis. A m . J. Ophth., 3 3 : 1 0 2 5 - 1 0 2 8 , 1950. N o r g a a r d , O., P e r c h , B., and Skadhauge, K. : Case of sepsis caused by proteus vulgaris. A c t a P a t h o l . Microbiol. Scand., 2 9 : 1 9 4 - 1 9 6 , 1951. P e r c h , B . : A c t a Pathol. Microbiol. Scand., 2 5 : 7 0 3 - 7 1 4 , 1948. Popova, S. Α . : Bacillus proteus vulgaris. V e s t . Oftal., 4 : 7 2 - 7 4 , 1 9 3 9 ; Zentralbl. f. Ophth., 4 4 : 6 1 1 , 1940. Spittel, J. Α., Martin, W . J., Geraci, J. E . , and N i c h o l s , D . R. : Bacteremia o w i n g to proteus Organism u s : A method of treatment. P r o c . Staff Meet. M a y o Clin., 2 9 : 2 2 5 - 2 2 8 , 1954. Stein, M. H., and Gechmann, E . : B l o o d stream! infection due t o proteus vulgaris and c a u s i n g t h r o m bocytopenic purpura: R e c o v e r y w i t h the use of chloramphenicol. N e w E n g l a n d J. Med., 2 5 2 : 9 0 6 - 9 0 8 , 1955. V e r r e y , F . : Clinique de l ' H u m e u r A q u e u s e Pathologique. Neuchâtel, Switzerland, D e l a c h a u x et N i e s t l é S.A., 1954. W e i l , V . J., Laval T., and Sturman, M.: Escherichia coli panophthalmitis from pyelonephritis. Α Μ Α A r c h . Ophth., 5 7 : 5 8 - 6 4 , 1957. Prikkel, A . és Fodor, Α . : B a k t e r i u m Mirabilis okozta sepsis. Orv. Hetil., 9 5 : 3 8 8 - 3 9 0 , 1954.
LAFFERS,
PROTEUS M.D.,
A N D S.
Budapest, CASE
PANOPHTHALMITIS* BOZSOKY,
M.D.
Hungary w a s diagnosed a s metastatic panophthalmitis o r i g i nating f r o m sepsis. I n order t o identify the pathogenic agent, t o find the origin o f the sepsis and t o determine the therapeutic methods to be employed the f o l l o w i n g e x aminations w e r e m a d e : A b o u t 0.3 ml. o f yellow-tinted, fibrinous aqueous humor w a s obtained b y puncturing the c h a m ber w i t h a n A m s l e r needle and w a s replaced b y 20,000 u. o f penicillin. A subsequent uveal puncture with an A m s l e r needle yielded a minimum amount of semisolid pus. T h e bulging f o r n i x o f the conjunctiva w a s incised and p u s similar to that found in the uvea w a s obtained. A f t e r the sample w a s taken and m o s t o f the pus drained off, the probe entered a cavity which pointed in the direction o f the internal rectus muscle. A strip o f g a u z e soaked in penicillin and streptomycin w a s inserted and 100,000 u. o f penicillin and 0.25 g m . o f streptomycin w e r e injected s u b conjunctivally. Conjunctival, aqueous and uveal specimens w e r e taken f o r bactériologie study. Blood w a s obtained f o r hémoculture. Treatment consisted o f 1,000,000 u. o f penicillin, 1.0 g m . streptomycin, strophoside and Germicid suppository, the latter t o combat fever. A f t e r h a v i n g instituted this therapy, clinical and laboratory study w a s continued. T h e diagnostic opinion w a s sepsis and jaundice. T h e sepsis presumably originated f r o m the bile ducts. U r i n a l y s i s : specific gravity 1,024, albumin + , U B G slightly i n creased, sugar 1.9-percent, acetone negative, sediment 4 0 t o 60 leukocytes. L i v e r function t e s t s : thymol 13 u., U c k o + - ( - + > serum bilirubin 12.7 m g . percent. Internal medical examination. T h e heart w a s normal i n size and sound. P u l m o n a r y emphysema w a s present. T h e liver w a s palpable s i x cm. below the right costal m a r g i n ; i t s m a r g i n w a s acute, not tender. T h e r e w a s sacral edema and marked jaundice. Opinion. T h e sepsis orginates presumably from the bile ducts but t h e results o f urinalysis suggest that t h e urogenital tract should a l s o be suspected as a potential source o f infection. U r o l o g i e study s h o w e d the kidney areas free, t h e prostate moderately enlarged and glandular. N o tumor w a s palpable. T h e residue w a s 2 0 0 ml. T w o days after admission the results f o r the bactériologie and serologic examination o f the aqueous, vitreous and conjunctiva w e r e a s f o l l o w s : T h e aqueous w a s sterile. F r o m the vitreous and conjunctiva a g r a m - n e g a t i v e bacterium, s h o w i n g the same morphology, had been g r o w n , which w a s being identified. T h e strain w a s susceptible to streptom y c i n and tetran, moderately sensitive t o chlorocid, resistant to aureomycin, penicillin and ultraseptyl ( s u l f a t h i a z o l e ) . S e r o l o g i c findings:
REPORT
S z . J., a man, aged 72 years, w a s brought t o the Department o f Ophthalmology o f the Institute o f Rheumatology and Medical H y d r o l o g y b y ambulance o n D e c e m b e r 2 9 , 1959, w i t h the diagnosis o f retrobulbar inflammation, O . S . T h e patient w a s in poor condition and g a v e vague, uncertain answers to our questions. H e told u s h e had had frequent episodes o f chills and high fever during the past t w o weeks. T w o days before admission h e developed pain and blindness i n the left e y e though the vision o f that e y e had been g o o d before. H i s doctor g a v e h i m a penicillin injection. T h e n e x t d a y an ophthalmologist w a s consulted and the patient w a s immediately hospitalized. A relative told u s that the patient had recently been o n a diabetic diet. O n examination, the patient w a s found t o be in a very poor condition and had obviously lost much weight. T h e tongue w a s dry and coated. T h e skin and sclera s h o w e d an intense y e l l o w color. T h e left l e g w a s thicker than the right. T h e right ankle w a s e x t r e m e l y tender. T h e r e w a s an enormous scrotal hernia. T h e sensorium w a s normal. P u l s e rate 96 in o n e minute, blood pressure 150 m m . H g , systolic, 90 mm. H g , diastolic. Ocular findings. V i s i o n w a s : R e a d s fingers at four meters, photosensitivity w a s lost. N o correction w a s attempted because of h i s poor condition. T h e right e y e w a s normal. Sclerotic blood v e s sels were found in the eyegrounds and fine degeneration in the macula. T h e left e y e s h o w e d edema, s w e l l i n g and redness of both eyelids, more marked in the upper. A s a result o f exophthalmos, there w a s a constant three to four-mm. space between the palpebral m a r g i n s and the left e y e could not be closed. T h e conjunctiva showed strong injection, Chemosis and circular overlapping o f the cornea. I n the upper conjunctival fold the conjunctival sac s h o w e d a y e l l o w translucence, corresponding t o an accumulation o f pus. Ciliary injection, corneal opacity, a v e r y deep c h a m ber, fibrinous aqueous w i t h a three-mm. hypopyon in the inner lower area and a dirty green iris w e r e found. T h e pupil w a s moderately dilated, round, c e n tral and did not respond t o light. I n the area o f t h e pupil the iris circularly adhered t o the anterior surface o f the lens. T h e r e w a s a thick membrane of exudate in the area o f the pupil. N o pink g l o w could be obtained. T h e deeper structures o f the eye could not be visualized. T h e eyeball w a s s o f t to palpation, protruded and w a s looking downward. T h e ocular m o v e m e n t s w e r e greatly restricted. O n the basis o f the examinations the condition * F r o m the State Institute o f R h e u m a t o l o g y and Balneology. 83
84
Ζ. L A F F E R S A N D S. B O Z S Ô K Y TOTAL PROTEIN
Serum Aqueous
(mg.%) A S O 6400 60 3100 120
Staph. 1.0/ml. 0.5/ml.
Brucella 4 2
MlDDLEBROOKDUBOS
4 2
CRP
1024 512
Cytologic study o f a smear made of the aqueous (fig. 1) showed many leukocytes, lymphocytoid and monocytoid cells, at sites iris pigment, as well as microphages, macrophages and phagocytosing bacteria. T h e cellular morphology w a s extremely variable. T o locate the primary focus, a throat swab, duodenal juice and urine w e r e sent for bactériologie study. Other laboratory findings. Blood count: erythrocytes, four million ; leukocytes 24,000 ; hemoglobin, 12-percent. Differential count: juveniles, one-perc e n t ; stabs, eight-percent; polymorphonuclears, 87percent, lymphocytes, four-percent. T h e r e w a s toxic granulation. Blood sugar, 338 m g . percent. A n E C G and chest X - r a y films showed no substantial alterations. T h e n e x t day the patient felt better. T h e swelling of the eyelid and conjunctiva, as well as t h e protrusion, w a s diminished. H e could close his eyes. P u l s e rates w a s 100/min., body temperature 37.7°C. Antibiotics (penicillin, s t r e p t o m y c i n ) , insulin, vitamins, infusion and cardiaca were given. H e continued t o make good progress on the third and four days, too. T h e jaundice diminished but the temperature remained around 3 8 ° C . and the blood pressure dropped from 150 mm. H g , systolic, and 100 mm. H g , diastolic, t o 100/65 mm. H g , in spite of the administration o f analeptics. T h e pulse
Fig.
1
(Laffers and B o z s o k y ) . A q u e o u s s h o w i n g phagocytes.
smear,
rate w a s 120/min. I n the morning o f the fifth d a y chills developed, the limbs w e r e cold and moist and cyanosed. T h e pulse rate w a s 120/min., the pulse w a s weak, blood pressure 60 m m . H g , and the fever 38.1°C. T h e chills ceased within a f e w minutes in response to t w o ampules of steralgin. T o combat the severe collapse an intravenous noradrenaline drip infusion w a s started, combined w i t h H o s t a c y c l i n (aureomycin, 2 5 0 m g . in four h o u r s ) , vitamins and cardiaca. S o m e laboratory tests w e r e done or repeated in the meantime. T h e r e w a s n o sugar o r acetone in the urine, the blood sugar w a s 144 m g . percent. N P N : 108 m g . percent. U r e a N : 52 m g . percent. Liver function tests: U c k o + + + + , total bilirubin 8.8 m g . percent, direct 6.9 m g . percent, indirect 1.9 m g . percent. T h e leukocyte count w a s 10,000/cu. mm. A W a s s e r m a n n test w a s negative. O n the second d a y of incubation a g r a m - n e g a t i v e bacterium, s h o w i n g propertie- identical to that g r o w n from the eye, g r e w from the hémoculture taken on December 30th. T h e same bacterium strain could be g r o w n from the urine, duodenal juice and throat swab. T h e strain proved to be B . proteus mirabilis, with an antigenic structure of 0 : 2 8 , H : l . ( W e express our thanks to D r . B. Lânyi for identifying the strain and for determining its antigenic structure.) S e r u m from the patient showed an Ο agglutination of 1:128, and a Η agglutination of 1:512 with the proteus strain isolated. O n the basis o f the laboratory findings and the results of physical examinations ( t h e size o f the liver had decreased considerably), it w a s suggested that renal failure had been joined by an imminent hepatargic coma, and therefore the patient w a s transferred to the Department o f Medicine N o . 2. T h e r e treatment w a s continued as before and w a s supplemented with sodium thiosulfate, adrenal cortical hormone and A C T H . O n the seventh d a y o f admission the patient developed a severe collapse, with cardiovascular failure due to arteriosclerosis, and died. T h e jaundice, the enlarged and tender liver s u g gested a sepsis due to cholangiohepatitis, originating f r o m cholelithiasis. I n support o f this v i e w w e r e t h e increase o f the mostly direct serum bilirubin, the positivity o f the tests f o r liver function and the fact that m o r e than 50 percent o f N P N w a s urea. U r i n a r y retention and the urinary sediment indicated renal involvement. T h e diabetes w a s mild throughout and caused n o trouble. S e v e n days after admission the pathogen could be identified ( B . proteus) and on the basis o f sensitivity tests adequate therapy could be instituted. H o w e v e r , the primary focus, the original site o f the sepsis, could be detected only post mortem. Postmortem findings. A stone, about the size o f a pigeon's e g g , w a s found in the gall bladder, w h o s e wall w a s thickened and w h i c h contained w h i t e mucous bile. T h e left kidney w a s enlarged, several abscesses of pea and bean size w e r e visible on and in it. T h e renal pelvis w a s filled w i t h viscous pus. M o s t of the renal pyramids showed necrosis. T h e r e w a s a
ENDOGENOUS PROTEUS large, bean-sized stone in the ureter, about five cm. from the pelvis, causing dilatation of the ureter, with several decubital ulcers in the mucosa o f the d i s tended area. T h e left eyeball w a s soft and flaccid. In place of vitreous, dense y e l l o w i s h - g r a y pus w a s found. A pinhead-sized perforation w a s detected near the insertion of the internal rectus muscle and around it a small bean-sized preformed cavity with very viscous pus on its wall. T h e postmortem analysis indicated pyonephrosis of the left side as a complication of nephrolithiasis, leading to sepsis, with the metastatic inflammation of the left eye as an uncommon complication ( D r . Fodor). A t autopsy specimens were taken from the gall bladder, spleen and renal abscess under sterile c o n ditions for culture study. B. proteus of the antigenic structure already mentioned g r e w f r o m all three specimens. H i s t o l o g i c changes in the eye are shown in F i g u r e 2 . In the H u n g a r i a n literature P r i k k e l and F o d o r have described a lethal sepsis caused by P r o t e u s mirabilis. T h e strain w a s isolated f r o m three different sites—wound serum, cerebrospinal fluid and cerebral abscess. DISCUSSION
The pathogenic significance of B. proteus has been increasing since the advent of antibiotics, especially in the urologie practice (Hanson, et al.). However, proteus sepsis is still uncommon. In his survey published in 1948 Abrams mentions 52 cases in the world literature. In 1951, Norgaard, et al., reported one more case. In 1954, seven cases were described by Spittel, et al., and, in 1957, Dobrzynski described one case. Under the age of 40 years, proteus sepsis is usually otogenic, over this age it tends to be of urogenital origin. It is not always possible to locate the source of the sepsis in vivo. For example, in Dobrzyski's case, it was only during postmortem study that the primary focus (a lung abscess) could be identified. The prognosis is most unfavorable, the proteus strains usually being resistant to antibiotics. According to Abrams, 64.6 percent of the published cases were fatal. On the basis of animal experiments and in vitro studies, Armstrong and Lamer have recommended the use of combinations of antibiotics in the treatment of proteus sepsis.
PANOPHTHALMITIS
85
F i g . 2 (Laffers and Bozsoky). Site of scleral perforation, s h o w i n g numerous leukocytes.
In their seven cases, Spittel and his associates employed a combination of streptomycin and Oxytetracycline and lost none of their patients. In this country, Lânyi has studied in detail the pathogenicity of proteus strains, having analyzed about 1,600 proteus strains from various sources biochemically and for antigenic structure. H e has found that most of the proteus strains isolated from pathologic processes (enteritis, urogenital infections, and so forth) belonged to the antigen groups 0 : 3 , 6, 10, 13, 26 and 28. As is known, Perch makes distinction between 49 O-groups and 110 types. In our case the pathogen showed the 0 : 2 8 , H : l antigenic pattern. Its pathogenicity is indicated by the fact that the patient's serum showed an Ο titer of 1:128 and a Η agglutination titer of 1:512 against it. A detailed evaluation of the serologic evidence for blood and aqueous will be discussed elsewhere. Many pathogens (bacteria, viruses, protozoa) may cause endophthalmitis or panophthalmitis. They may invade the eye through wounds caused by injury or at ocular operation (for example, after cataract
86
Ζ. L A F F E R S A N D S. B O Z S Ô K Y
extraction), or eventually by endogenous metastasis. In the monograph by Verrey the pathogens producing endophthalmitis are grouped as follows : 1. Pathogens that may equally cause exogenous and endogenous endophthalmitis. To this group belong the pneumococci, staphylococci, gonococci, the influenza bacillus of Pfeiffer, the coli-type bacilli and the blastomycetae. The latter three play no important role. 2. Exclusively metastatic endophthalmitis is produced among others by Mycobacterium tuberculosis, Treponema pallidum, meningococcus, Bacillus leprae, pestis, leptospira, and so forth. 3. Some bacteria produce or are involved in exogenous endophthalmitis only. In this group belong Proteus vulgaris and B. pyocyaneus. In the ophthalmologic literature of the past few years the number of reports on gram-negative bacteria causing exogenous panophthalmitis (mainly following cataract extraction) has been increasing. A s early as 1939, Popova described the case of a man, aged 65 years, in whom B. proteus vulgaris had caused postoperative panophthalmitis after cataract extraction. In 1945, Leopold reported on a case of panophthalmitis caused by Pseudomonas aeruginosa, a gram-negative bacterium. B. coli has often been reported as the cause of panophthalmitis (Glover, Pelman, Weil, Laval, Sturman). In 1953 Callahan analyzed in detail his five cases of endophthalmitis which had occurred in 1,653 cataract extractions. At first the growth from preoperative conjunctival and lid margin smears of gram-negative bacteria had not been considered to be a contraindication. The operation had been postponed only when Streptococcus viridans and hemolyticus, Staphylococcus aureus and Diplococcus pneumoniae had been isolated. But after having lost two eyes in two cases from which gram-negative bacteria had been
obtained preoperatively, operation was also postponed for about three weeks in such cases. This precaution was followed by three cases of endophthalmitis caused by Proteus vulgaris; the patients had been operated on in spite of the fact that B. proteus had been isolated preoperatively. Crabb, Fielding and Ormsby emphasize that B. proteus is the principal agent among the gram-negative bacteria that is likely to cause postoperative panophthalmitis, because it commonly occurs in the conjunctival fornix in older persons. W e agree with this view because B. proteus has often been grown from preoperative conjunctival smears in our cases. Searching for allergic causes of uveitis, Binkhorst and van Ufford found sensitivity to bacterial allergens in a significant proportion of cases. The cutaneous test was most often positive to B. coli and B. proteus. In contrast with this, Bolletieri does not attribute significance to cutaneous reactions to proteus extracts because, according to him, they are nonspecific. One of the interesting features in our case is that the B. proteus did not enter the eye from without, through the exogenous route from the conjunctiva, but by means of endogenous metastasis, having been transported by the blood stream to the eye. In this way, panophthalmitis became the first apparent symptom of proteus sepsis and the pathogen was first isolated from the vitreous. According to Hippel even the most careful and detailed clinical and pathologic studies usually fail to detect the site of origin of metastatic purulent panophthalmitis. In most cases the bactériologie findings are defective and the pathogen is usually isolated from the enucleated eye. Also the primary focus is very difficult to find. In the order of frequency the following sites should be considered: teeth, tonsils, nasal sinuses (retention of pus), intestinal tract, genito-urinary tract. The male genito-urinary tract is un-
ENDOGENOUS PROTEUS
doubtedly an important etiologic source. In our case the diabetes and the severe phimosis increased the susceptibility to urinary infections. Metastatic panophthalmitis is a not uncommon complication of renal diseases. Weil, Laval and Sturman have described a case of Escherichia coli panophthalmitis from pyelonephritis, in which the pathogen could be isolated from the blood and urine and later from the pus obtained from a spontaneous perforation of the globe at the temporal limbal area. Sensitivity studies showed the micro-organism to be sensitive to Furadantin and tetracycline. The patient survived and the diagnosis was established by diagnostic intravenous pyelography, retrograde pyelography and finally by left nephrectomy. In the kidney multiple cortical abscesses, papillary necrosis, pyelonephritis and peripelvic abscess were found. Also Levine's case was one of E. coli metastatic panophthalmitis, with a pyonephrosis due to calculi as the primary focus. The pathogen could be isolated from both eyes and from the urine. While the bacteria causing panophthalmitis can be suppressed by the various antibiotics, B. proteus is sensitive to only a few of them. This accounts for the recent increase in interest in this pathogenic agent. In the usual doses chloramphenicol and tetracycline do not inhibit B. proteus. Gantrisin (sulfasoxazole) has proved to be the most potent agent, especially when applied locally, after corneal abrasion. The next in potency is neomycin. In cases of B. proteus panophthalmitis Callahan promptly punctured the chamber, collected aqueous for culture, rinsed the chamber with penicillin and streptomycin and also applied them subconjunctivally because, if administered parenterally, no efficient intraocular levels can be reached. Leopold has recommended the use of chloramphenicol (3.0 gm. in one dose) followed by 1.0 gm. doses at six-hour intervals.
PANOPHTHALMITIS
87
The local therapy in our case was similar to that recommended by Callahan. However, we punctured not only the chamber, but also the vitreous for diagnostic purposes, going on the assumption that the aqueous is usually sterile. This assumption was correct in our case, too, and it was only from the vitreous and the conjunctival discharge (which also came from the vitreous) that the B. proteus could be isolated. In response to the local therapy the panophthalmitic inflammatory phenomena markedly receded. However, the antibiotics administered locally and parenterally (penicillin, streptomycin, aureomycin) failed to combat sepsis. According to Topley acute sepsis seldom develops after excessive local reactions (pyonephrosis in our case). However, in spite of the relatively great therapeutic response in our case, an acute, fatal sepsis developed. SUMMARY
A case of endogenous panophthalmitis due to B. proteus sepsis is described. The first manifest symptom of sepsis was panophthalmitis. B. proteus (Proteus mirabilis, 0 : 2 8 , H : l ) was isolated in vivo from the conjunctival fornix and vitreous. The aqueous proved to be sterile. The B. proteus strain could be cultured from the blood, urine, duodenal juice and tonsils and, postmortem, from the spleen, gall bladder and kidney, as well. The source or sepsis, pyonephrosis, was revealed only by postmortem study. The proteus strain isolated proved to be sensitive to streptomycin and tetran. However, the arteriosclerotic and diabetic patient, aged 72 years, died of cardiovascular failure in spite of the proper antibiotic therapy. B. proteus more and more often causes exogenous postoperative panophthalmitis, but our case indicates that it may produce endogenous panophthalmitis as well. Frankel
Leo-u.
17-19.
88
Ζ. L A F F E R S A N D S.
BOZSÖKY
REFERENCES
A b r a m s , H . L . : Septicemia due t o proteus v u l g a r i s : R e v i e w of the literature and report of a case cured by streptomycin. N e w E n g l a n d J. Med., 2 3 8 : 1 8 5 - 1 8 7 , 1948. Albrich, K.: A szembetegségek é s szemtünetek ö s s z e f ü g g e s e a szervezet e g y é b betegségével. Budapest, M a g y a r O r v o s i K ö n y v k i a d o Vâllalat, 1929. A r m s t r o n g , C. W . J., and L a m e r , A . E . : T h e effect of combination of antibiotics on P s e u d o m o n a s aeruginosa and P r o t e u s vulgaris in vitro and in v i v o . J. Lab. Clin. Med., 3 7 : 5 8 4 - 5 9 2 , 1951. Binkhorst, P . G., and v a n Ufford, W . J.: R e s u l t s obtained in the e x a m i n a t i o n of patients w i t h iridocyclitis and uveitis f o r allergy. A c t a allergologica, 1 4 : 4 7 0 - 4 8 5 , 1959. Bolletieri, D . : S u l valore della cutireasione con estratti di proteus c o m m u n e e di proteus X 19 nel trachoma. Boll. Ocul., 1 9 : 3 3 3 - 3 3 9 , 1940. R e f . : Zentralbl. f. Ophth., 4 6 : 1 6 3 , 1940. Burton, Α., and Waisbren, E . : T r e a t m e n t w i t h large doses of penicillin in a case of severe bacteremia due t o Proteus. A r c h . Int. Med., 9 1 : 1 3 8 - 1 4 1 , 1953. Callahan, A . : Effect of sulfonamides and antibiotics on panophthalmitis complicating cataract extraction. Α Μ Α A r c h . Ophth., 4 9 : 2 1 2 - 2 1 9 , 1953. Crabb, A . M., Fielding, I. L., and Ormsby, H . L. : Bacillus proteus endophthalmitis. A m . J. Ophth., 4 3 : 8 6 - 8 9 , 1957. Dobrzynski, Z. : P o s o c z n i a w y w o l a n a paleczka odmienca pospolitego ( B a c t . proteus v u l g a r i s ) P o l s k i tygod. lek., 1 2 : 1 7 8 3 - 1 7 8 4 , 1957. F a r a g o , F . : Bakteriologia és immunitâstan. M a g y a r orvosi K ö n y v k i a d o Târsulat. 1948. Goldbloom, Α . Α., and Golbey, M . : Case of acute cholangitis ( p o s t o p e r a t i v e ) due to proteus vulgaris sepsis treated w i t h aureomycin. A m . J. D i g e s t . Dis., 1 8 : 6 3 - 7 1 , 1951. H a n s o n , R. J., Karabatsos, N . , and H e r r o l d , R. D . : Species of the g e n u s proteus and s o m e urological implications. J. Urol., 7 9 : 1 0 1 6 - 1 0 1 7 , 1958. v o n Hippel, Ε . : Ein Fall von Iridocyclitis mit rezidivierendem H y p o p i o n mit anatomischem B e f u n d . A r c h . f. Ophth., 1 2 8 : 2 7 2 - 2 7 9 , 1932. Länyi, B . : Serological typing of proteus strains from infantile enteritis and other sources. A c t a Microbiol. H u n g . , 3 : 4 1 7 - 3 2 8 , 1956; Serological t y p i n g of proteus stains. Sensitivity to antibiotica. A c t a Microbiol. H u n g . , 4 : 4 4 7 - 4 5 7 , 1957. Levine, I.: Metastatic Bacillus coli panophthalmitis f r o m calculus pyonephrosis. A r c h . Ophth., 3 : 4 1 0 412, 1930. L u g o s s y , Gy.: Therapeutic experiments in endophthalmitis. A m . J. Ophth., 3 3 : 1 0 2 5 - 1 0 2 8 , 1950. N o r g a a r d , O., P e r c h , B., and Skadhauge, K. : Case of sepsis caused by proteus vulgaris. A c t a P a t h o l . Microbiol. Scand., 2 9 : 1 9 4 - 1 9 6 , 1951. P e r c h , B . : A c t a Pathol. Microbiol. Scand., 2 5 : 7 0 3 - 7 1 4 , 1948. Popova, S. Α . : Bacillus proteus vulgaris. V e s t . Oftal., 4 : 7 2 - 7 4 , 1 9 3 9 ; Zentralbl. f. Ophth., 4 4 : 6 1 1 , 1940. Spittel, J. Α., Martin, W . J., Geraci, J. E . , and N i c h o l s , D . R. : Bacteremia o w i n g to proteus Organism u s : A method of treatment. P r o c . Staff Meet. M a y o Clin., 2 9 : 2 2 5 - 2 2 8 , 1954. Stein, M. H., and Gechmann, E . : B l o o d stream! infection due t o proteus vulgaris and c a u s i n g t h r o m bocytopenic purpura: R e c o v e r y w i t h the use of chloramphenicol. N e w E n g l a n d J. Med., 2 5 2 : 9 0 6 - 9 0 8 , 1955. V e r r e y , F . : Clinique de l ' H u m e u r A q u e u s e Pathologique. Neuchâtel, Switzerland, D e l a c h a u x et N i e s t l é S.A., 1954. W e i l , V . J., Laval T., and Sturman, M.: Escherichia coli panophthalmitis from pyelonephritis. Α Μ Α A r c h . Ophth., 5 7 : 5 8 - 6 4 , 1957. Prikkel, A . és Fodor, Α . : B a k t e r i u m Mirabilis okozta sepsis. Orv. Hetil., 9 5 : 3 8 8 - 3 9 0 , 1954.