Anaerobic Orbital Cellulitis: a Clinical and Experimental Study*

ANAEROBIC ORBITAL CELLULITIS: A CLINICAL AND EXPERIMENTAL STUDY*

BY Michael S. Jedrzyrski, MD (BY INVITATION), John D. Bullock, MD, Thomas W McGuire, MD (BY INVITATION), B. Laurel Elder, PhD (BY INVITATION), AND (BY INVITATION) J. David Bullock, Jr

INTRODUCTrION ORBITAL CELLULITIS IS A SERIOUS INFECTION WITH SIGHT- AND LIFE- threatening complications. Over the last few decades, as clinical bacteriologic methods have improved, a heightened awareness of the clinical importance of anaerobic bacteria in orbital cellulitis has developed. Anaerobic bacteria were once thought ofas "harmless" flora. However, because of increased clinical awareness and improved bacteriologic techniques, anaerobes are now known to cause serious infections throughout the body, including the orbit. 1-13 The largest reported series ofanaerobic orbital cellulitis are by Harris (a total of seven cases of subperiosteal abscesses involving anaerobes)5.6 and Brook (eight patients with anaerobic "periorbital cellulitis"). 1 In addition, there are numerous reports involving one or two patients.8-'2 The highlights of these cases are summarized in the following paragraphs. Bacterial orbital cellulitis, whether aerobic or anaerobic, is usually caused by an extension of a sinus infection, especially ethmoidal or maxillary sinusitis; direct inoculation of bacteria into the orbit from trauma, especially blunt trauma with orbital fractures; or the spread ofan infection from nearby structures such as the teeth or lacrimal sac.2-6,10,14-16 In each ofthese three routes, anaerobes have been shown to play a major role, especially Bacteroides, peptostreptococci, fusobacteria, Veillonella, propionibacteria, and eubacteria. 1,4-6,11,13 Orbital cellulitis may also be caused by hematogenous dissemination from a distant site.16 *From the Departments of Ophthalmology, Plastic Surgery, and Microbiology and Immu- nology, Wright State University School of Medicine, Dayton, Ohio.

TR. AM. OPHTH. Soc. vol. LXXXIX, 1991 314 Bullock et al The bacteria most commonly recovered from purulent sinuses include Haemophilus influenzae, Streptococcus pneumoniae, other streptococci, Staphylococcus aureus, and non-spore-forming anaerobes such as Bacte- roides, peptostreptococci, fusobacteria, Veillonella, propionibacteria, and eubacteria. 17-21 Orbital cellulitis secondary to sinusitis is usually seen in children and young adults.5'6'14'16 The frequent recovery of anaerobes in cases of sinusitis should not be unexpected considering the gas composi- tion in purulent maxillary sinus secretions. Carenfelt and Lundberg22 have shown these secretions to have a Po2 of "0 or close to 0." Orbital cellulitis secondary to trauma with skin penetration is usually caused by S aureus. When blunt trauma causes an orbital fracture, the infection is usually due to the indigenous microflora of the involved sinus.23 A previously healthy sinus may become infected when hemorrhage, edema, or bone fragments obstruct its normal drainage5; blood in the sinus is thought to promote bacterial growth.15 In addition, an orbital wall fracture facilitates direct extension ofbacteria into the orbit. Several investigators2'3'6,7 have shown that odontogenic infections, which are often anaerobic, can spread to the orbit, producing an orbital cellulitis. There are several clinical characteristics of anaerobic orbital cellulitis that may help to differentiate it from orbital cellulitis caused by aerobes or facultative bacteria; these include gas production (which can be seen radiographically), foul-smelling discharge (which is caused by anaerobic bacterial production of short-chained fatty acids and volatile amines), and a polymicrobial Gram stain (rather than the typical single isolate most commonly seen with aerobic infections).24 The initial therapy in cases of suspected anaerobic orbital cellulitis is somewhat controversial. Nearly all anaerobic bacteria are sensitive to imipenem or to a combination ofbeta-lactam and beta-lactamase inhibitor such as ampicillin sodium-sulbactam sodium.24 Most anaerobes that cause sinusitis and orbital cellulitis are sensitive to penicillin, metronidazole, or chloramphenicol with the following exceptions: some Bacteroides species produce beta-lactamase, which splits open the beta-lactam ring in penicillin and related antibiotics, and some resistance to metronidazole and chloramphenicol has been found in the anaerobic gram-positive cocci.21,25 Cefoxitin sodium and clindamycin are also excellent agents against anaerobes, but their central nervous system (CNS) penetration is poor.26'27 Surgical drainage is required frequently. Complications of anaerobic orbital cellulitis include blindness,2-5"10"12 meningitis, 1-3 epidural abscess, "' subdural empyema,"l29 and frontal lobe cerebral abscesses. 1,9-12 Studies have shown that the majority of cerebral abscesses harbor anaerobic bacteria.9"12'28'29 The most common organ- Orbital Cellulitis 315 isms are Bacteroides, Peptostreptococcus, Fusobacterium, and Veillonella. Bacteria in general have a wide range ofresponses to oxygen depending upon the manner in which they oxidize substrates for energy.30 At one end of this spectrum are the strict aerobes, which carry out respiration only, the process in which the final electron acceptor in a series ofcoupled oxidation-reduction reactions is molecular oxygen. These bacteria must have oxygen to grow. At the other extreme are the obligate anaerobes, which are killed in the presence of oxygen. They produce energy by fermentation, whereby the final electron acceptor is an organic molecule, such as pyruvate, to form lactate. The largest number ofclinically significant bacteria, the facultative bacteria, are capable of either form of metabolism and thus can grow whether or not oxygen is present. Aerotol- erant anaerobes (which include most pathogenic anaerobes) are not killed by oxygen but simply may not replicate in its presence.31 Strict obligate anaerobes include organisms that constitute normal flora. A subset of anaerobic organisms are the "microaerophilic" organisms, which grow best at low oxygen tensions. 1,30,32 This term is used less frequently now than in the past, and many of these organisms recently have been re- classified in other anaerobic groups. "When organisms grow in the presence of oxygen, a number of enzy- matic reactions occur, resulting in the production of the superoxide radical, which, in high concentrations, is lethal to bacteria. In aerobes, facultative bacteria, and aerotolerant anaerobes, the enzyme superoxide dismutase prevents the accumulation of the superoxide ion: 202 + 2H + Superoxide 02 + H202 Dismutase superoxide radical hydrogen ion oxygen hydrogen peroxide Obligate anaerobes lack superoxide dismutase. Hydrogen peroxide, formed in the above reaction, is also lethal to bacteria. It is rapidly destroyed by the enzyme catalase, found only in aerobes and facultative bacteria. "30 "In addition to the oxygen concentration, the oxidation-reduction po- tential (Redox or Eh) of the culture medium or local environment is another critical factor in determining whether or not growth ofa bacterial inoculum will occur. For most media in contact with air, the Eh is about + 0.2 to + 0.4 V, an oxidizing state. Obligate anaerobes are unable to grow unless the Eh is less than -0.2 V. During growth of aerobic and/or anaerobic bacteria, there is a progressive decrease in the Eh of the medium or local environment. "0 This is one explanation for the common occurrence of "mixed infections," aerobes and anaerobes cultured from the same site.24 It is unclear whether the local oxygen tension or the Eh is 316 Bullock et al more important in establishing an anaerobic infection.33 In an anaerobic culture medium, oxygen is excluded and sulfhydryl-containing compounds (such as sodium thioglycolate), which capture oxygen radicals, may be added. Anaerobic infections are characterized by their bacteriologic complex- ity. Some studies, including many of the previously reported cases of anaerobic orbital cellulitis, indicate that an average ofthree to six different microbial species are found at the infected site, often including aerobes as well as anaerobes.5-711 24 This fact makes it very difficult to define the role of any one particular organism, which could be a pathogen or simply a commensal. Synergy or synergism refers to a "cooperative effort by two or more microbial species that produces a result that could not be achieved individually"30; for example, the consumption of local oxygen by aerobic organisms allowing anaerobes to flourish, or the production and extra- cellular release of virulence factors by one organism for the use of other bacteria growing at the same site. Synergy also may allow an organism in vivo to be resistant to an antibiotic while appearing to be sensitive to that antibiotic when tested in vitro.M Virulence factors allow an organism to cause and sustain infection, as well as to avoid the host's immune defenses.24 3536 The anaerobic bacteria that typically cause orbital cellulitis produce many of the same virulence factors as aerobes. These factors include adherence factors (for attachment to epithelial cells), capsular polysaccharides (to inhibit phagocytosis), succinic acid (to inhibit phagocytosis and intracellular killing), and en- zymes (which cause tissue disruption, promote the spread of infection, and destroy radicals, peroxides, and antibiotics) such as collagenase, hyaluronidase, fibrolysin, chondroitin sulfatase, phospholipase, superoxide dismutase, and beta-lactamase. Anaerobic infections are usually indigenous (ie, originating from the host's own flora). In order for such an infection to develop, certain systemic and/or local conditions need to be present. Systemic conditions that predispose to anaerobic infection do so either by altering the structure of local tissues or by altering the normal host inflammatory and immune responses. These include, but are not limited to, sickle cell anemia, uremia, diabetes mellitus, Sjogren's syndrome, and use of immuno- suppressive drugs.4 305 The role of systemic corticosteroids in anaerobic infections is controversial. Some investigatorsm15have stated that corticosteroids are a predisposing factor in anaerobic infections. This is not surprising, since an important immune defense against anaerobic bacteria is phagocytosis by inflammatory cells,24 and corticosteroids act to sup- press phagocytic function.37 However, infections caused by anaerobic Orbital Cellulitis 317 bacteria are not unusually common in patients taking corticosteroids.24 Local conditions that predispose to anaerobic infection do so by de- creasing the local oxygen tension and/or the Eh.29 30,' - These include tissue necrosis from trauma, surgery, or infection; anoxia from vascular injury, edema, aerobic infection, or shock; and the presence of a foreign body. A variety ofanimal models ofanaerobic infections have been created in numerous organ systems, including the lung,39,40 liver,4' subcutaneous tissue,42-46 abdomen,45 and heart.47A48 These animal models were used to characterize the infections produced, determine virulence factors, and compare efficacy ofantibiotic regimens. These studies noted the difficulty in producing anaerobic infections in healthy animals: relatively large inocula had to be used to produce infection, and the local environment had to be "primed." Priming has required the use ofan adjuvant or tissue injury. Adjuvants used in the past have included agar, barium sulfate, suture material, sterilized cecal contents or stool, gastric mucin, and even pieces of potato. Animal models of anaerobic conjunctivitis,49 keratitis,50 and endoph- thalmitis51,52 also have been produced in the past.

CLINICAL STUDY PATIENT 1 A 65-year-old woman was referred for right periorbital swelling, pain, and discharge. She was previously in good health except for mild arthritis, for which she occasionally took aspirin. Four days prior to consultation she tripped and fell, striking the right side of her face on the sidewalk. She was seen that day by her family physician, who referred her to an otolaryngologist. She was given a pre- scription for oral erythromycin. The following day she was seen by an ophthalmologist. Her examination apparently revealed right-sided periorbital edema so severe that her eyelids could be opened only a few millimeters. Her vision was light perception, and the pupil was barely reactive. Extraocular movements were markedly restricted in all directions, and there was a 3600 subconjunctival hemorrhage. A computed tomographic (CT) scan performed that day showed right proptosis, fractures ofthe medial walls ofboth the right orbit and maxillary sinus, a massive orbital hemorrhage, and blood in the right ethmoidal and maxillary sinuses. The ophthalmologist told her to continue taking her antibiotics and to use warm compresses. Three days later she was again seen by the ophthalmologist, who noted that her condition had worsened, and she was referred for consultation. On examination the patient had massive right proptosis, periorbital swelling, and erythema. Copious foul-smelling pus was draining from open wounds on her upper and lower eyelids (Fig 1) and right nostril. Her visual acuity was no light perception in the right eye, and the pupil was nonreactive. Extraocular muscle 318 BuUock et al

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FIGURE 1 Patient 1: Draining right orbital cellulitis due to Bacteroides intermedius and Peptostrep- tococcus micros. Orbital Cellulitis 319

FIGURE 2 Patient 1: Axial CT scan showing proptosis, medial extraconal abscess, medial orbital wall fractures, and ethmoidal sinusitis. movements were absent on the right. She was febrile and obtunded. Cultures of the wounds were taken, and a Gram stain revealed both gram-positive cocci and gram-negative bacilli. The patient was admitted to the hospital, and intravenous cefuroxime, metronidazole, and tobramycin were administered. Her white blood cell count was 17,000/mm3 with 83% segmented neutrophils. A CT scan showed multiple orbit and sinus wall fractures, total opacification of the right ethmoidal sinus, fluid and gas in the right maxillary sinus, and an orbital abscess that communicated through a fracture in the orbital roofwith a large gas-containing frontal lobe brain abscess (Figs 2 and 3). The patient was taken to surgery, where she underwent drainage of the right orbit, debridement ofnecrotic tissue through the upper and lower eyelid wounds, drainage ofthe right frontal and ethmoidal sinuses and medial extraconal space via a Lynch incision, drainage ofthe right maxillary sinus via a Caldwell-Luc incision, formation ofa right nasoantral window, and neurosurgical drainage ofthe brain abscess via a frontal craniotomy. Histopathologic examination of the orbital tissues revealed neutrophils and necrotic debris in some areas (Fig 4) and collec- tions of plasma cells in other areas. Multiple cultures grew Bacteroides inter- 320 Bullock et al

FIGURE 3 Patient 1: Coronal CT scan showing right orbital abscess, which communicates through fracture in orbital roof with frontal lobe cerebral abscess. Note gas bubbles in frontal lobe abscess.

FIGURE 4 Patient 1: Photomicrograph of debrided orbital tissues showing neutrophils and necrotic debris (HPS, x400). Orbital Cellulitis 321

FIGURE 5 Patient 1: Photomicrograph ofdebrided orbital tissues showing both gram-positive cocci and gram-negative bacilli (Brown-Brenn, x 1000).

medius and Peptostreptococcus micros. A tissue Gram stain showed both gram- positive cocci and gram-negative bacilli (Fig 5). The patient did well postoperatively, with rapid improvement in periorbital swelling, fever, leukocytosis, and mental status. She was discharged after 6 weeks of cefuroxine and metronidazole therapy. At examination 12 months postoperatively, she remains no light perception with an amaurotic pupil, a residual exotropia, ptosis ofthe right upper eyelid, and retraction ofthe right lower eyelid (Fig 6).

PATIENT 2 A 54-year-old man was referred for right-sided periorbital swelling and inflammation. He was a homosexual and was positive for the HIV antibody. He had no history ofopportunistic infections. He had undergone tricuspid valve replacement with a prosthetic valve 7 years earlier. His medications included warfarin sodium (Coumadin), digoxin, and nifedipine. Three weeks prior to consultation a firm, nontender swelling ofthe right upper eyelid developed, for which he was given an intramuscular injection ofdeposteroid by another physician. He did not improve, and 2 days prior to consultation was seen by an ophthalmologist who diagnosed periorbital cellulitis and prescribed dicloxacillin sodium. After his condition worsened somewhat over the next 48 hours, the patient was referred. 322 BuUock et al

FiGURE 6 Patient 1: Twelve months postoperatively, patient has right upper eyelid ptosis, exotropia, and right lower eyelid retraction. Orbital CeUulitis 323

FIGURE 7 Patient 2: Axial CT scan showing right maxillary sinusitis.

At examination the patient had massive swelling, erythema, and fluctuance of the superomedial orbit, with marked swelling of the remainder of the upper and lower eyelids. There was minimal tenderness. The globe was displaced inferotem- porally. Visual acuity was 20/40, and there was no afferent pupillary defect. Extraocular muscle movements were limited. A needle was used to aspirate foul- smelling purulent material from the fluctuant area of the superonasal orbit. A Gram stain revealed gram-negative bacilli. The patient was admitted to the hospital and given intravenous ceftazidime and metronidazole. A CT scan revealed opacification of the right ethmoidal, frontal, and maxillary sinuses (Fig 7). There was destruction of the lateral walls of the frontal and ethmoidal sinuses, and adjacent to these areas there was a large abscess in the superomedial orbit (Fig 8). The cultures taken from the aspiration material grew Propionibacterium acnes, and the empiric antibiotics were replaced by intravenous cefuroxime. Surgery was delayed a few days while the patient's coagulation profile was normalized. He was then taken to surgery, where he underwent drainage of the orbit, removal of necrotic bone, and drainage of the frontal and ethmoidal sinuses via a Lynch incision, as well as drainage of the maxillary sinus via a Caldwell-Luc incision. The patient did well postoperatively with complete resolution of periorbital swelling. He received 4 weeks of intravenous cefuroxime postoperatively, followed by a course oforal cefuroxime. At examination 2 months postoperatively, he had a small residual right hypertropia. He was then lost to follow-up. 324 Bullock et al

FIGURE 8 Patient 2: Coronal CT scan showing right orbital cellulitis, frontal sinusitis, and bony defect in right superonasal orbit. Orbital Cellulitis 325

PATIENT 3 (PREVIOUSLY REPORTED AS PATIENT 5 IN REFERENCE 4) A 28-year-old man was referred for bilateral periorbital swelling and right-sided drainage. He was an alcoholic and had previously suffered a shrapnel injury to the right orbit and globe requiring enucleation and placement of an orbital implant. He was seen by another physician prior to consultation and was placed on prednisone for "right orbital inflammation." At examination he had severe right periorbital swelling and erythema, with a foul-smelling discharge from an open wound on the upper eyelid (Fig 9). There was also mild left periorbital swelling. Roentgenographic studies revealed a right frontal and ethmoidal sinusitis and loss of bone adjacent to the right frontal sinus (Fig 10). Cultures of the purulent drainage revealed Peptostreptococcus intermedius (Fig 11). He underwent surgical drainage ofa large orbital abscess and the ethmoidal and frontal sinuses and removal of necrotic bone through a Lynch incision. Intravenous penicillin was given, followed by oral penicillin. He did well postoperatively, with rapid resolution of periorbital swelling (Fig 12).

PATIENT 4 (PREVIOUSLY REPORTED, IN PART, AS PATIENT 20 IN REFERENCE 4) A 15-year-old boy had had frontal headaches for 4 to 5 days when severe redness, chemosis, and proptosis of the left eye developed. The patient had sickle cell anemia but denied prior trauma or sinus disease. An otolaryngologist admitted him to the hospital with a diagnosis of left orbital cellulitis and then attempted to drain the orbit through a small stab incision in the inferonasal aspect of the left orbit. A small amount ofpurulent material was obtained and a Penrose drain was placed, but the patient's condition worsened. The Gram stain showed gram- positive cocci and gram-negative bacilli. A CT scan revealed a left orbital abscess and left frontal, ethmoidal, and maxillary sinusitis (Figs 13 and 14). The patient wsa then seen in consultation. Visual acuity was 20/20 in the normal right eye and hand movements in the left eye. The left globe was essentially frozen owing to massive proptosis, and the left pupil was nonreactive (Fig 15). The patient underwent drainage of the left orbital abscess and ethmoidal and frontal sinuses through a Lynch incision, drainage of the left maxillary sinus via a Caldwell-Luc incision, and formation of a left nasoantral window. Cultures of the purulence grew a Bacteroides species, a microaerophilic streptococcus, Strep- tococcus pneumoniae, and Streptococcus pyogenes. He was treated with penicillin and metronidazole and was discharged 19 days postoperatively. At follow-up examination 4 months later, the patient's visual acuity was 20/40 in the left eye; a moderate ptosis of the left upper eyelid and a keloid in the area of the previous incision were evident.

PAIENTS 5 AND 6 Two additional patients are summarized in Table I as patients 5 and 6. Patient 5 has been previously reported as patient 3 in references 2 and 3 and as patient 11 in reference 4. Patient 6 has been previously reported as patient 4 in references 2 and 3. 326 Bullock et al

FIGURE 9 Patient 3: Draining right orbital abscess due to Peptostreptococcus intermedius. Orbital Cellulitis 327

FIGURE 10 Patient 3: Orbital tomography showing destruction ofright superomedial orbital bone. Note right orbital prosthetic implant.

FIGURE 11 Patient 3: Photomicrograph ofdebrided orbital tissues showing gram-positive cocci in chains (Peptostreptococcus intermedius) (Brown-Brenn, x 1000). 328 Bullock et al

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EXPERIMENTAL STUDY

MATERIALS AND METHODS Bacteroidesfragilis, Bacteroides intermedius, and Peptostreptococcus micros were obtained in thioglycolate broth from Compunet Clinical Labo- ratories, Dayton, OH. The concentration of these "initial stocks" was approximately 108 to 109 organisms/ml, calculated by matching a McFar- land Turbidity Standard. Forty-eight male and female Dutch Belted rabbits (Lepus europaeus), aged 2 to 3 months and weighing from 1 to 2 kg, were used in this study. The animals were kept in an approved animal facility with food and water ad libitum. Dutch Belted rabbits were selected because of their relatively large eyes, which are similar to human eyes in appearance, and because of the ease of handling the animals. Preinjection ocular examinations revealed that all rabbits had clear media and normal-appearing orbits. Fifteen selected rabbits were immunosuppressed with methylprednisolone acetate, 10 mg/kg intramuscularly (Depo-Medrol, Upjohn), 72 hours prior to bacterial injection. Thirty minutes before bacterial injection all rabbits were anesthetized with ketamine hydrochloride, 40 mg/kg 330 Bullock et al

FIGURE 14 Patient 4: Axial CT scan showing left proptosis, orbital cellulitis, and maxillary sinusitis.

intramuscularly (Vetalar, Parke-Davis) and 2 to 3 drops oftopical propara- caine hydrochloride (Alcaine, Alcon). Priming and injections were performed on one side only, selected randomly. A pediatric lid speculum was placed between the lids. A 1.5-ml volume ofbacteria was injected via the superior conjunctival fornix into the intraconal space, using a 20-gauge, 1-inch needle. The rabbits were divided into five groups, containing both immunosuppressed and immunocompetent animals. Group 1, consisting of eight rabbits, received injections of sterile thioglycolate broth or bacteria in broth. The injections were prepared as follows: for single-organism injections (B fragilis, B intermedius, or P micros), 1 part "initial stock" was mixed with 1 part thioglycolate broth. For injection ofboth B intermedius Orbital Celulitis 331

FIGURE 15 Patient 4: Coronal CT scan showing left orbital cellulitis and ethmoidal and maxillary sinusitis.

and P micros, 1 part ofeach "initial stock" was added to 2 parts broth, thus giving approximately the same number of bacteria per injection. Group 2, consisting of eight rabbits, received injections using fresh autologous blood (obtained from an ear vein) as an adjuvant. The injections were prepared with equal parts of sterile thioglycolate broth and fresh autologous blood (for sterile injections), equal parts of"initial stock" and fresh blood (for single-organism injections), or 1 part B intermedius initial stock with 1 part P micros initial stock and 2 parts fresh autologous blood (for the mixed injection). Group 3, consisting of 19 rabbits, received injections of sterile 0.5% semisolid agar in thioglycolate broth, or bacteria "initial stock" (singly or in combination) mixed with semisolid agar (final agar concentration = 332 Bullock et al

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iwQ- Orbital Cellulitis 333 0.5%, warmed to 37°C prior to injection). Group 4, consisting ofsix rabbits, received a "priming" injection of2 ml of fresh autologous blood intraorbitally, followed 48 hours later by an injection ofa mixture of 1 part B intermedius initial stock, 1 part P micros initial stock, and 2 parts thioglycolate broth. Group 5, consisting of seven rabbits, were "primed" by producing local thermal necrosis prior to injections. After a local anesthetic (0.5 ml of2% lidocaine HCI, Abbott) was given, thermal tissue damage was achieved by administering cautery to the orbit (via the superior conjunctival fornix) with a Malis Bipolar Coagulator (CMC-1, Codman). The coagulator was set at a current of 4 A for 3 seconds' duration. Four sites per orbit were cauterized. Immediately following cauterization each rabbit received an injection of broth, or bacteria in broth, prepared as for group 1. Following the injections the animals were returned to their cages. To verify the viability and purify the each inoculum, the "initial stocks," thioglycolate broth, and semisolid agar were cultured. Clinical examination of the rabbits began 2 days postinjection and continued every other day thereafter. The rabbits were examined for signs of orbital cellulitis: proptosis, chemosis, exudate, lid swelling, and decreased extraocular motility. Asymmetry between the injected and noninjected sides was very helpful in noting subtle signs. A positive result was given when these signs were present in significant severity, and a negative result when questionable or absent. Photographs were taken at least every 4 days. After 3 weeks the clinically positive animals were sacrificed with an intravenous injection of Euthanasia T-61 solution (Hoechst-Roussel). An exenteration of the affected orbit was performed and purulent material was examined by Gram stain and aerobic and anaerobic cultures. Tissues from selected rabbits were placed in 10% phosphate-buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin-phylox- ine-safranin (HPS) and Brown-Brenn (a tissue Gram stain). This study was conducted in accordance with the Association for Re- search in Vision and Ophthalmology resolution on the use of animals in research.

RESULTS Cultures of all "sterile" media were negative. Cultures of all "initial stocks" were positive only for the primary organism. The injection vol- umes (1.5 or 2.0 ml) were well tolerated by the rabbits, as were the various "priming" procedures-blood drawing and injection, and cautery. Immediately after injection the eyes were proptotic. The orbits in which 334 Bullock et al

FIGURE 16 Lateral view of rabbit 18 days after injection with both Bacteroides intermedius and Pep- tostreptococcus micros in semisolid agar, showing left orbital cellulitis. orbital cellulitis did not develop returned to their normal appearance within 2 to 3 days. In the positive cases, evidence of orbital cellulitis was usually present by day 3 or 4, with increasing severity through day 21, when the animals were sacrificed. The signs of infection most commonly present were eyelid swelling, proptosis, exudate, decreased extraocular movements, and chemosis (Figs 16 and 17). None of the rabbits died during the pre-euthanasia course of this study. Table II summarizes the experimental results. No signs oforbital cellulitis developed from injections of sterile broth, agar, or blood (top row of Table II, groups 1, 2, 3). None of the infected rabbits in groups 1, 2, or 4 (thioglycolate broth, fresh blood, or 48-hour-old blood), whether immunosuppressed or immunocompetent, had significant orbital cellulitis. In group 3 (semisolid agar), orbital cellulitis developed in all rabbits injected with B fragilis, P micros, and B intermedius combined with P micros. Orbital cellulitis developed in one ofthree rabbits injected with B intermedius in semisolid agar; this rabbit was immunocompetent. In group 5 (cautery), signs of orbital cellulitis developed in all rabbits, including the two that received sterile broth; however, it seemed to be milder in the two receiving sterile broth than in those injected with bacteria. Orbital Cellulitis 335

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FIGURE 17 Frontal view of rabbit in Fig 16, showing left proptosis.

TABLE II: RESULTS OF EXPERIMENTAL STUDY Group no. 1 2 3 4 5 Condition of orbit Intact Intact Intact 48-Hour Thermal nec- blood rosis Media Broth Fresh blood Agar Broth Broth Bacteria None 0/2 0/1* 0/4 NDt 2/2 (0/1) (0/1) B fragilis 0/2 ND 5/5 ND ND B intermedius 0/1 1/2 ND 1/1 (0/1) (0/1) (0/1) P micros 0/1 ND 1/1 (0/1) (2/2) P intermedius and 0/2 212 0/4 3/3 P micros (0/2) (0/1) (2/2) (0/2) *Top entry represents immunocompetent rabbits. Entry in parentheses represents rabbits immunosuppressed with methylprednisolone acetate, 10 mg/kg. Numerator ofeach entry is number of rabbits with clinically significant orbital cellulitis, and denominator is number of rabbits injected with each particular preparation. tNot done. 336 BuUock et al

FIGURE 18 Photomicrograph oforbital tissues from rabbit in Figs 16 and 17, showing pseudoeosinophils and necrotic debris (HPS, x 400).

At autopsy and orbital dissection, an orbital abscess was uniformly present in positive cases. The necrotic material could often be found extending back into the orbit behind the globe. These tissues were examined microscopically. Postmortem Gram stains and cultures were positive for the injected organism(s) in all subgroups except those rabbits in group 5 that received sterile thioglycolate broth. Cultures of the exudate from these two animals revealed Pseudomonas aeruginosa. Histopathologic study with the HPS stain revealed areas of pseudoeosinophils (equivalent to human neutrophils53), necrotic debris, and plasma cells (Fig 18). The Brown-Brenn stain revealed clumps of bacteria present in all specimens studied (Fig 19).

DISCUSSION The clinical cases herein presented include examples ofall three routes of infection in anaerobic orbital cellulitis. The infection of patient 1 was clearly related to trauma, with bacteria, presumably from the ethmoid sinus, being inoculated into the orbit through a medial wall fracture. Direct inoculation also may have played a part in patient 3. In patient 2, the infection may have been secondary to bacterial dissemination from his Orbital Cellulitis 337

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FIGURE 19 Photomicrograph oforbital tissues from rabbit in Fig 16 and 17, showing gram-positive cocci and gram-negative bacilli (Brown-Brenn, x 1000). prosthetic tricuspic valve. P acnes infections have been associated with prosthetic cardiac valves.' Sinus involvement was seen in all six of the patients. In patient 4, an underlying sinusitis was most likely the cause of the orbital cellulitis, since no other local factors were present. In the other five cases it is difficult to assess whether the sinusitis led to the orbital cellulitis or was a consequence of the underlying infectious process. In patients 5 and 6, a previous odontogenic infection and subsequent extraction was the underlying cause of the orbital cellulitis. All six patients had orbital abscesses, the most serious form of orbital cellulitis.14 Systemic factors that may have contributed to the severity of these anaerobic infections included HIV infection in patient 2 (sinusitis has been recognized to be a common problem in AIDS patients, presumably owing to deficits in humoral immunity54), corticosteroid use in patients 2 and 3, alcoholism in patient 3, sickle cell anemia in patient 4, and uremia in patient 5. Local conditions included trauma, vascular injury, and edema in patient 1 (her aspirin use may have caused increased bleeding and subsequent pressure necrosis of the orbital tissues); trauma and foreign body in patient 3; and dental extractions in patients 5 and 6. The aforementioned nonspecific clues to anaerobic infection were present in all six patients. All six had foul-smelling pus. Patients 1, 4, and 5 338 Bullock et al showed a polymicrobial Gram stain, and patient 1 showed gas production in the frontal lobe brain abscess imaged by computerized tomography. These clues were helpful in the proper choice of an antibiotic regimen in patients 1, 2, 3, and 4. Patient 5 was already receiving the proper antibiotics before the culture specimen was available, and in patient 6 the proper antibiotics were apparently started too late in the clinical course. The previously noted complications of anaerobic orbital cellulitis were seen in this series and included blindness and meningitis (patient 5), blindness and frontal lobe cerebral abscess (patient 1), and death due to subdural empyema (patient 6). Patients 1 through 5 all responded to one or more ofthe following antibiotics: clindamycin, metronidazole, or penicillin. In patient 6, although the microaerophilic Streptococcus was sensitive to clindamycin in vitro, this antibiotic was very poor CNS penetration.27 The polymicrobial nature of these anaerobic infections is illustrat- ed by patient 1 (two anaerobes cultured), patient 2 (Gram stain revealed gram-negative bacilli, culture revealed P acnes, a gram-positive bacillus), patient 4 (two anaerobes and two aerobes cultured), and patient 5 (three different organisms noted on the Gram stain). In the experimental portion ofthe study, an animal model ofanaerobic orbital cellulitis was produced reliably in rabbits. The model is similar clinically, histopathologically, and bacteriologically to its human counter- part. The bacteria used are members of the genera Bacteroides and Peptostreptococcus. Bacteroides is a member of the group "non-spore- forming anaerobic gram-negative bacilli," which includes Bacteroides and Fusobacterium.24,30,32'55 Bacteroides organisms are found as normal flora in the upper respiratory, gastrointestinal, and female genital tracts. The major infections caused by Bacteroides are intra-abdominal, CNS, oral, upper respiratory (including sinusitis), pleuropulmonary, pelvic, endocar- dial, ear, skin, bone, and sepsis. Bacteroides organisms commonly produce beta-lactamase but generally are sensitive to metronidazole, clindamycin, chloramphenicol, and cefoxitin sodium. Bacteroides bacteria reportedly cause approximately 12% of anaerobic ocular infections.56 B fragilis is the most clinically important species in terms of the frequency and severity of infections, and most early experimental studies of anaerobic infections involved B fragilis. For these reasons we chose to utilize this organism in our model. B intermedius is one species in the B melaninogenicus group, named for the pigmented colonies seen in vitro. It was chosen for the animal model because it was cultured from patient 1, and it has been noted by others as a cause oforbital cellulitis.6 It is a more fastidious organism than B fragilis. Peptostreptococcus is part ofthe group of"anaerobic gram-positive coc- Orbital CeUulitis 339 ci," which includes the genera Peptococcus and peptoStreptoCOCCUS.24,30,32,55 Peptostreptococci are part of the normal flora of the upper respiratory tract (including sinuses), gastrointestinal tract, and female genital tract. They are isolated frequently from clinical specimens and are involved in infections ofthe sinuses, soft tissues, ear, female genitourinary tract, head and neck, CNS, abdomen, lung, bones, and joints, as well as sepsis. They commonly produce gas. They tend to be sensitive to penicillin, clindamycin, cephalosporins, vancomycin, and imipenem. However, approximately 10% are resistant to metronidazole, and resistance to chloramphenicol has been reported. P micros was chosen because of its documented involvement in orbital cellulitis5'6"11 and the recovery of this organism in patient 1. Sterile preparations of the various media were injected to ensure that they would not cause orbital inflammation, which would mimic an orbital cellulitis. We found that the rabbits tolerated all sterile media well; even orbits that were injected with semisolid agar returned to their preinjection appearance within a few days, although the proptosis lasted longer than when broth or fresh blood was injected. We first investigated whether or not an infection could be established by injecting a large number of bacteria in broth (group 1) into the orbit. This simple approach was not effective, probably because the broth was absorbed quickly by the healthy orbital tissues, enabling the rabbit's immune defenses to eliminate the injected bacteria before an infection could occur. The next group ofrabbits (group 2) was injected with bacteria in fresh blood. This was an attempt to mimic the conditions in patient 1, who had orbital and sinus hemorrhages prior to development of the orbital cellulitis. This approach also failed, probably because the fresh blood contained oxygen and a large number of leukocytes, which may have killed many of the bacteria. In addition, the blood was resorbed quickly by the healthy orbital tissues. In order to overcome the problem of rapid reabsorption of media and bacteria, we utilized semisolid agar and found a high degree of success in creating infection by injecting the bacteria with 0.5% agar (group 3). This adjuvant acts to "prime" the local environment by setting up a "safe haven" for the bacteria to begin replicating, thus mimicking an area of necrotic or devitalized tissue. This semisolid agar is easily produced in any laboratory that manufactures its own media. It is liquid enough to mix with broth and inject through a 20-gauge needle yet apparently solid enough to form a slowly resorbed "pocket" when injected into the soft tissues of the orbit. The histopathologic findings and features of these infections were similar to those of patient 1. 340 Bullock et al To overcome the problems of using fresh blood, a 2-ml volume of autologous blood was injected 48 hours before the bacteria were injected (group 4). Infections could not be established with this technique. Appar- ently, the blood was resorbed too quickly or was infiltrated with protec- tive inflammatory cells by the time the bacteria were injected. Immunosuppression of the animals with methylprednisolone had no apparent effect on the development of an anaerobic orbital cellulitis. In groups 1, 2, and 4 we were unable to establish an infection regardless of the animal's immune status. In group 3, we were able to establish an infection in nearly all the animals whether immunosuppressed or immunocompetent, and there was no apparent difference in their severity or clinical course. In addition, of those animals that received B intermedius in semisolid agar, the immunosuppressed rabbit failed to become clinically infected, and the only rabbit in this group to have an orbital infection was immunocompetent. Under the assumption that actual tissue damage might be required to establish an anaerobic infection, cautery was used to produce thermal necrosis. An orbital cellulitis (with positive cultures) was produced with this technique; however, signs of orbital inflammation unavoidably occurred even when only sterile broth was injected. Thus, it was difficult to tell how much of the orbital inflammation was due to the cautery alone and how much was due to the anaerobic infection. In addition, the orbits that received cautery followed by an injection of sterile broth eventually became infected with Pseudomonas. Although we did not culture Pseu- domonas from those orbits that received cautery and anaerobic bacteria, superinfection by other bacteria is possible in these thermally damaged orbits.

SUMMARY In this article we have reviewed the clinical and bacteriologic aspects of anaerobic orbital cellulitis and have presented six patients to illustrate these points. Physicians who treat patients with orbital cellulitis should have a high index of suspicion for possible instances involving anaerobes, so that appropriate management can be started early. To investigate this problem further, we created an animal model of anaerobic orbital cellulitis. This model may be useful in future studies of the pathogenesis and treatment of this serious and often devastating disease. Orbital Cellulitis 341

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DISCUSSION DR ROBERT G. SMALL. I am pleased to discuss this paper by Doctors Jedrzynski and Bullock and associates. Doctor Bullock is an authority on orbital cellulitis. His paper on orbital cellulitis associated with dental extraction presented to this Society in 1984 generated considerable interest and discussion. The present paper adds an important dimension to our knowledge of orbital cellulitis: the role of anaerobic bacteria. The authors' dramatic photographs underline the severity of this entity. Immediate and expert intervention by the ophthalmologist is necessary to prevent blindness or death. The authors have developed an experimental model in the rabbit in which anaerobic orbital cellulitis can be regularly produced. This model adds to our understanding ofthe pathogenesis and treatment of anaerobic orbital abscess and should be useful in future studies. This paper helps the clinician diagnose and treat orbital cellulitis with suspected anaerobic orbital abscess. This disease occurs in patients debilitated by disease or trauma, often with delayed or inadequate treatment. Computed tomography shows fluid and gas in the paranasal sinuses. Urgent surgical drainage ofthe sinuses and orbit produces foul-smelling pus, which, with a polymicrobial Gram stain, suggests anaerobic infection. Since anaerobes take 3 to 5 days to identify on culture, appropriate antibiotics such as metronidazole, clindamycin, imipenem- cilastatin, and ampicillin-sulbactam are started immediately. Several questions occurred to me as I studied this paper. The authors state that anaerobic infections are commonly mixed rather than the result of infection by a single organism, and yet four of the six patients had anaerobic cellulitis in which only a single organism grew on culture. How does this relate to anaerobic orbital abscesses? Patients 5 and 6 had infections by a single organism, microaerophilic Streptococcus, but microaerophilic streptococci are not considered to be anaerobes by some authorities. This paper suggests that although anaerobic orbital cellulitis is a recognized entity, it is not particularly common. Most patients with orbital infection do not develop abscesses, and most orbital abscesses are not anaerobic. From a semantic point of view, anaerobic orbital cellulitis cannot be diagnosed unless pus is obtained from the orbit for examination and culture. Then one is dealing with an anaerobic orbital abscess. Can this be put in perspective by saying orbital cellulitis is common, orbital abscess is less common, and anaerobic orbital abscess is rare? Anaerobes are not virulent unless special circumstances such as trauma, debil- ity, or dental extraction permit them to grow in the orbit. Four ofthe six patients had delays of 5 days to 1 month until aggressive treatment by the authors was instituted. This suggests that delayed or inadequate treatment also plays a role in anaerobic orbital infection. Once established, however, anaerobic orbital infection is a particularly dangerous entity. Will the authors comment on this? 344 BuUock et al Why was cefuroxime used in patient 2 for Propionibacterium acnes? Infectious disease specialists here would have chosen penicillin G. All six patients had sinus and orbital infection, and all patients had sinus and orbital surgery. Most anaerobes that cause orbital abscess are found in the normal flora ofthe mouth and pharynx. Can we conclude that anaerobic orbital cellulitis is a sinus infection that extends to the orbit? Anaerobic bacteria commonly found with other bacteria in chronic sinusitis are not considered virulent. Anaerobes are less often encountered in acute sinusitis. Thus, special conditions must be necessary for anaerobes from the sinuses to infect the orbit. The upper teeth, anatom- ically close to the maxillary sinus, provide another entry for autoinoculation ofthe patient's anaerobic flora. Doctor Bullock's earlier paper points out the well- established association ofdental extraction with orbital cellulitis, and two patients reported in that paper had anaerobic infection. Anaerobic orbital cellulitis is somewhat analogous to mucormycosis ofthe orbit. Both are rare. Neither organism is virulent, and both require special predisposing conditions to gain a foothold in the orbit. Both conditions are usually first seen by an otolaryngologist as pansinusitis. Both have high morbidity and mortality, and both require urgent orbital and sinus surgery. I wonder if Doctor Bullock did the sinus surgery himself. I am more comfort- able with an otoryngologist present in this situation. In orbital cellulitis, there is danger ofcavernous sinus thrombosis. This did not occur in the present series, and yet brain abscess, frontal osteomyelitis, meningitis, and subdural empyema did occur. Is there any reason why anaerobic orbital cellulitis does not produce cavernous sinus thrombosis? The animal experiments are particularly interesting. In one animal model, 15 rabbits were given one dose of methylprednisone acetate 72 hours prior to bacterial inoculation. Is this adequate for immunosuppression? For humans to be immunosuppressed, prolonged treatment with steroids is necessary. The fact that it was necessary to use either agar or thermal injury to produce anaerobic cellulitis in the rabbits is in keeping with the clinical findings that tissue disruption, trauma, or some other favorable local orbital condition must be present to enable anaerobic bacteria to multiply in orbital tissues. Thus, anaerobic bacteria are not virulent in the uncompromised healthy orbit. Can the authors tell us how they might use the animal model in future studies? Thank you for the opportunity to discuss this excellent paper. DR DAN B. JONES. I commend the authors on a superb paper. I have always had a passion for studies on anaerobic ocular infections. I have a few minor points to add. One is that you did not mention the techniques utilized for attempted recovery of anaerobic bacteria in these cases. As you are aware, these organisms may be extremely difficult to isolate. In two cases, you apparently recognized gram-negative organisms in direct smears of material but failed to isolate gram- negative bacteria in culture. Use of Sabouraud's broth is a simple and practical method which does not require special systems for incubation. However, contamination of the medium is difficult to assess. The ideal method is to inoculate an Orbital Cellulitis 345 agar plate, such as Schaedler's or brucella agar, which can be placed into a heat- sealed biobag containing a gas generator. The plates can be easily examined within the biobag and contamination can be readily recognized as bacterial growth separate from the inoculation sites. I am also concerned about the selection of a second generation cephalosporin antibiotic for treatment oforbital cellulitis possi- bly caused by anaerobic organisms. A recommendation for initial treatment of orbital cellulitis secondary to paranasal sinusitis in adults is nafcillin and chloramphenicol. Alternative agents for suspected anaerobic infection are penicillin G and clindamycin. I understand your frustration over the difficulty of producing an animal model ofanaerobic infections. As you are aware, streptococcus is commonly encountered in polymicrobial orbital cellulitis and sinusitis. This organism may be a co-factor in anaerobic infections. I would be interested in whether or not the concurrent inoculation of streptococcus in your animal model would produce progressive anaerobic infection. I again commend you on an excellent paper. DR LEONARD Apt. My comment has to do with the choice of drug therapy. Since many of the Bacteriodes species (especially Bfragilis) are resistant to penicillin G and to the cephalosporins, and inasmuch as many cases ofanaerobic infection also involve aerobic gram-positive organisms, clindamycin commonly has been considered the initial drug of choice. This viewpoint is popular with the infectious disease specialists at UCLA, including Doctor Finegold, our expert on anaerobic infections. Clindamycin has the advantage ofbeing effective against most anaerobic micro- organisms (including B fragilis), as well as the gram-positive organisms that often also are present in anaerobic infections. Most anaerobic infections that result from trauma are polymicrobial. In listening to the presentation this morning (I realize it is an abbreviation of the entire study), I got the impression that cindamycin did not play a prominent part in the therapy. If this is so, may I ask the authors why? DR MICHAEL S. JEDRZYNSKI. I would like to thank Doctors Small, Jones, and Apt for their comments. I'll start out with Doctor Small's discussion. It is interesting that four of our six patients grew out only one organism on culture. However, two ofthese had more than one organism on their Gram stain; evidently we missed some organisms on culture. Nonetheless, the Gram stains were still very helpful in raising our suspicion that an anaerobic infection was present. Regarding the issue of microaerophilic Streptococcus: the classification of these bacteria has been in flux in the last few years. We think that, although microaerophilic streptococci certainly are not strict anaerobes, we feel they are probably best grouped with anaerobic bacteria in general. The American Society for Microbiology as well as several major infectious disease textbooks continue to list the microaerophilic streptococci with the other anaerobes. Certainly I agree that anaerobic orbital cellulitis is rare. However, without 346 BuUock et al improving culture techniques for anaerobic organisms I think they are going to become a more noted cause of orbital cellulitis. We agree that delayed and/or inadequate treatment is an important factor in these infections. Many of our patients were treated inappropriately at first. Some were given steroids, others were not given the right antibiotics, and these factors increased the risk and severity of the infections. Cefuroxime was used in our second patient because the Gram stain revealed gram-negative rods and, propionibacteria are gram-positive rods. They tend to hold on to the Gram stain very well, so the chance ofgetting an artificial decolor- ization is low. Thus, we kept the cefuroxime "on board" to cover the possibility ofa gram-negative organism being present that we didn't grow on culture. Cefurox- ime will cover propionibacteria fairly well, although we agree that penicillin is a better choice. You asked ifanaerobic orbital cellulitis is due to a sinus infection which extends to the orbit. It probably is. We could study this further by using our animal model. Since rabbits have sinuses, we could establish a sinusitis and see if it leads to orbital cellulitis. As for the surgeon on the cases: Doctor Bullock performed all the sinus surgery by himself. The neurosurgeon drained the brain abscess in the first patient. Why doesn't anaerobic orbital cellulitis produce cavernous sinus thrombosis? I'm not sure. There have probably been 30 to 40 cases of anaerobic orbital cellulitis reported in the literature and as far as we know none of these caused a cavernous sinus thrombosis, although many caused other infections in the CNS. I think it is because the cavernous sinus is such a vascular structure and, thus, too well oxygenated. This does not give the anaerobes a chance to establish an infection. Regarding our immunosuppression of the rabbits, I believe that our protocol is adequate. It is equivalent to giving an average adult 700 mg of Depomedrol. Doctor Bullock has done a number of studies involving bacterial and fungal infections in rabbits (Nocardia asteroides and PseudaUescheria boydii) in which he was unable to establish infections in immunocompetent rabbits, but immunosuppression by our protocol caused death from overwhelming infection. In the future, this animal model could be used in further studies of the pathogenesis of anaerobic orbital cellulitis. It could also be used to study various treatment regimens, including new antibiotics or hyperbaric oxygen. We agree with Doctor Jones that in these patients it is important to find out about their risk factors. Many of them have risk factors that we do not always associate with certain infections. We also agree with Doctor Jones that the culture techniques used in these cases are very important. We specifically ask for anaerobic cultures, and we send these specimens in special anaerobic transport containers. We also agree that cefuroxime alone is not the best agent for anaerobes. Probably the best drugs against anaerobes are imipenem or a combination of a beta-lactam and a beta-lactamase inhibitor such as ampicillin and sulbactam. Anaerobes are generally always sensitive to these. There have been reported cases Orbital Cellulitis 347 of resistance to chloramphenicol, clindamycin, and metronidazole by anaerobes. Doctor Jones asked whether or not Streptococcus would be important in establishing these infections. During the pilot phase of our animal studies we attempted to create such a mixed infection using S aureus and B fragilis. These rabbits all died within 24 hours; thus, we concluded that the mixed infections were too fulminant. This is why we restricted our research to only anaerobic infections. Doctor Apt asked about cindamycin. We agree that cindamycin is an excellent drug against anaerobes. The problem with it is that it has poor CNS penetration, and three ofour patients had CNS involvement. Our sixth patient, who died from a subdural empyema, was on cindamycin. It probably was started too late in his clinical course, after his CNS was involved. Thank you again for your attention.