Cerebral mucormycosis following open head trauma Case report RONALD J. |GNELZI, M.D., AND GARY D. VANDERARK, M.D. Neurosurgery Service, Denver General Hospital, University of Colorado Medical Center, Denver, Colorado
The authors describe a case of human cerebral mucormycosis following open head trauma and craniotomy, and discuss possible roles of steroids and antibiotic therapy in its pathogenesis. They suggest that the common usage of prolonged broad-spectrum chemoprophylaxis in head trauma may require critical review. KEYWORDS 9 cerebral mucormycosis steroids 9 antibiotics
EREBRAL mucormycosis is a rare phenomenon. To our knowledge, this is the first report of a case occurring after head trauma and craniotomy. In the majority of reported cases it has been associated with diabetic ketoacidosis; other predisposing factors include debilitation and antibiotic and steroid therapy. Mucormycosis infestation has not previously been described in the neurosurgical literature.
c
Case Report
This 6-year-old right-handed girl was thrown from a rapidly decelerating automobile and struck the pavement. She was in excellent health prior to the accident and not on medications; there was no familial or personal history of diabetes. Examination. The patient was decerebrate with fixed and dilated pupils. There was evidence of cerebrospinal fluid (CSF) leaking
J. Neurosurg. / Volume 42 / May, 1975
9 h e a d injury
9 craniotomy
9
from the wound site. Skull x-rays revealed a depressed skull fracture of the left frontal region without evidence of involvement of the small frontal sinuses. Operation. The patient was intubated and taken to the operating room where a rather extensive debridement of scalp, bone, and brain was performed. The dura was debrided and a patch of temporalis fascia was formed and sutured over the underlying dural defect. A basilar fracture was noted running across the superior orbital roof on the left to the cribriform fossa. The wound was then closed in layers and the patient was placed on the following intravenous medications: chloramphenicol, 350 mg three times daily, methicillin, 500 mg every 6 hours, and dexamethasone, 3 mg every 6 hours. Postoperative Course. The patient showed no further evidence of CSF leak and clinically remained in her preoperative state until the third day when she began to show some im593
R. J. Ignelzi and G. D. VanderArk provement. She continued to improve over the next few days to the point where she was able to communicate appropriately and move all extremities. On the fifth postoperative day the patient's mental status began to deteriorate. Cerebral angiography was performed, and a diagnosis of cerebral edema without focal mass was made. The patient was continued on antibiotics and steroids. On the eleventh postoperative day she had spiking fever. Pseudomonas was found in the urine and sputum; the organism was resistant to methicillin and chloramphenicol, but sensitive to garamycin which was then added to the treatment. The patient's condition continued to deteriorate and she again became decerebrate with fixed and dilated pupils. On the fourteenth postoperative day a large fluctuant mass developed in the area of the~scalp flap but not in the actual incisional line. This was needle aspirated but no organisms were seen on stain. She continued to have high spiking fevers despite the triple antibiotic therapy. A lumbar puncture revealed a leukocytosis of 500 with a predominance of polymorphic neutrophils, protein 100 mg, and glucose 105 mg%. Her peripheral white count at this point had risen to well over 40,000 with a predominance of polymorphic neutrophils. Stain and culture of the CSF were negative. The patient continued to have a fever and deteriorate neurologically. A repeat lumbar puncture 12 hours later revealed 4300 white blood cells, 90% polymorphic neutrophils, protein 235 mg, and glucose 75 mg%; many fungi with hyphae were seen on the stain and the cultures grew Zygomycetes mucor. A few hours later black drainage developed from the aspiration site and the wound edges., An extensive debridement of scalp and brain was performed. The brain and dura in the previously operated site appeared to be necrotic. Specimens taken from the various sites explored were stained and grew Zygomycetes mucor. Amphotericin B was given intravenously, 15 mg over 4 to 6 hours, and intrathecally, 15 mg every day. At this point the patient also developed hematuria and a workup revealed a hypocoagulable state with less than 10,000 platelets and a low normal fibrinogen level. The patient showed no response to the amphotericin B and her condition continued to deteriorate. She died on the 19th postoperative day. 594
Postmortem Examination. Findings included mucormycosis, massive edema, and necrosis of the left frontal, temporal, and parietal lobes (Fig. 1), and gangrene of the skin, scalp, and subcutaneous tissue, which on culture grew Zygomycetes mucor. Not only was the parenchyma of the brain involved, but there were also multiple areas of vasculitis and thrombosis with organisms in the walls of the vessels themselves (Fig. 2). Massive and diffuse hemorrhage appeared throughout the lungs, retroperitoneal space, spleen, pelvis, and bladder, consistent with hypocoagulation.
Discussion
Mucormycosis is the most acutely fatal fungal infection known in man? Systemic involvement has a 50% mortality while cerebral involvement alone has over 80% mortality. TM The incidence of the disease is increasing and in particular the cephalic form is becoming more prevalentY The organism is ubiquitous, occurring in soil, decaying matter, as a laboratory contaminant, and in the nasal flora of man; it is considered a saprophytic organism? The systemic form with marked pulmonary involvement affects patients who are debilitated, have myeloproliferative diseases, and are receiving steroids. 15 In the cerebral form of mucormycosis, 70% of the cases are associated with diabetic acidosis? Both experimental and clinical evidence shows that not hyperglycemia, but rather the ketoacidosis, increases the host's susceptibility to the infestation? '2~The fungus usually enters the brain from the upper respiratory tract, paranasal sinuses, or orbit. Common clinical findings include steady pain and tenderness over the involved facial areas; black crusting and drainage of the nasal turbinates; proptosis with third, fourth, and sixth cranial nerve weakness; corneal anesthesia; and progressive mental deterioration? X-ray examination reveals a nodular thickening of the soft tissues lining the sinuses with spotty destruction of the walls, and absence of fluid levels. The frontal sinuses are frequently spared? ~ Possible initial neutropenia is followed by progressive marked leukocytosis; grossly reduced platelet counts under 10,000 are not uncommon. Cerebral spinal fluid analysis reveals findings consistent with a meningoencephalitis. The organism may not stain when the spinal fluid is examined; the J. Neurosurg. / Volume 42 / May, 1975
Cerebral mucormycosis following open head trauma absolute diagnosis rests on fresh smears of the involved tissue stained with 10% potassium hydroxide, biopsy revealing the invasive mycelia in their hypha form, and culture for exact identification of the fungus, x8 Pathologically the organism causes an intense inflammatory reaction in both meninges and brain. Thrombosis caused by the hyphae penetrating and growing into the walls and lumens of the vessels is a striking feature of the infection, and leads to ischemic infarction of the brain parenchyma, xl The disease has been associated with thrombosis of the internal carotid artery as late as 1 year after the initial infection? ~ Treatment consists of administration of amphotericin B and correction of the underlying systemic disorder, which, in most cerebral mucormycosis cases, is diabetic acidosis. Since amphotericin B is fungistatic, prolonged use is required to eradicate the infection, and this may lead to nephrotoxic problems/ Cases of this form of phycomycosis successfully treated with the above regimen have been reported? 7 Since our case is the first of its nature to be reported and lacked many of the common denominators associated with this infestation, a careful analysis of possible etiological factors was undertaken. The child had no personal or family history of diabetes mellitus and was acidotic at no time during her illness, unlike most patients with this disease. Although steroids have been implicated in promoting spreading of the fungus organism, 3 not one single case of mucormycosis occurred in the large series of reported central nervous system fungus infections in renal transplant patients on immunosuppressive therapy and steroids? 8 The mechanisms by which antibiotics may alter a host's resistance and increase susceptibility to fungal infections have been reviewed by Seelig. 19 These include elimination of the normal flora allowing overgrowth or superinfection with fungus by eliminating competing organisms; 21 increased invasion by the organism as a consequence of the conversion of the saprophytes to a more invasive form; and inhibiting both antibody synthesis and phagocytic activity, thus reducing the host's resistance to invasion. The overgrowth phenomenon has been written about extensively. 6 The increased invasiveness of fungi in patients on antibiotics has been shown, 8 and J. Neurosurg. / Volume 42 / May, 1975
Fie. 1. Gross specimen at autopsy' demonstrating massive edema and necrosis which is most marked in left frontal lobe.
F~. 2. Photomicrographs of the same specimen at • (upper) and • (lower) magnification, revealing invasion of the vessel walls by the organism. The vessel wall shows macrophages with numerous large branching nonseptate hyphae characteristic of the lesion (lower). 595
R. J. Ignelzi and G. D. VanderArk abundant experimental evidence suggests that certain antibiotics may depress immunological defenses in the host. Chloramphenicol at the same low levels as those that suppress bacterial synthesis (50 ttg/ml) inhibits the synthesis of antibody in tissue culture; 2 antibiotics may also inhibit phagocytosis. In vivo and in vitro tests demonstrate that chloramphenicol and other broad-spectrum antibiotics decrease the ability of white cells to ingest foreign matter. 14'23 The degree to which antibiotics depress the host's immunological defenses is not known, but the possibility of this occurring must be remembered when these agents are used. References
1. Abramson E, Wilson D, Arky RA: Rhinocerebral phycomycosis in association with diabetic ketoacidosis. Ann Int Med 66:735-742, 1967 2. Ambrose CT, Coons AH: Studies on antibody production. J Exp Med 117:1075-1088, 1963 3. Baker RD, Schofield A, Elder TD, et al: Alloxan diabetes and cortisone as modifying factors in experimental mucormycosis (Rhizopus infection). (Abstract) Fed Proe 15:506-507, 1956 4. Bauer H, Ajello L, Adams E, et al: Cerebral mucormycosis: pathogenesis of the disease. Am J Med 18:822-831, 1955 5. Bergstrom L, Hemenway WG, Barnhart RA: Rhinocerebral otologic mucormycosis. Ann Otol Rhinol Laryngol 79:70-81, 1970 6. Blank H: Candida albicans. Frequent companion, occasional foe. Monogr Ther 2:1-6, 1957 7. Brummer DL, Chaves AD, Cugell DW, et al: Mucormycosis of the central nervous system associated with thrombosis of the internal carotid artery. J Pediatr 44:437-444, 1954 8. Campbell P J, Heseltine WW: An apparent growth stimulant for Candida albicans released from tetracycline-treated bacterial flora. J Hyg (Camb) 58:95-97, 1960 9. DeWeese DD, Schleuning AJ 2nd, Robinson LB: Mueormycosis of the nose and paranasal sinuses. Laryngoscope 75:1398-1405, 1965 10. Green WH, Goldberg HI, Wohl GT: Mucormycosis infection of the craniofacial structures. Am J Roentgenol Rad Ther Nucl Med 101:802-806, 1967 11. LaTouche C J, Sutherland TW, Telling M: Rhinocerebral mucormycosis. Lancet 2: 811-813, 1963
596
12. Martin FP, Lukeman JM, Ranson RF, et al: Mucormycosis of the central nervous system associated with thrombosis of the internal carotid artery. J Pediatr 44:437-444, 1954 13. McBride RA, Corson JM, Dammin GJ: Mucormycosis. Two cases of disseminated disease with cultural identification of rhizopus; review of the literature. Am J Med 28:832-845, 1960 14. Nicol TI, Sewell A: Effect of sulphonamides on the phagocytic activity of the reticuloendothelial system. Nature 184:1241-1242, 1959 15. Parkhurst GF, Vlahides GD: Fatal opportunistic fungus disease. JAMA 202:279-281, 1967 16. Prockop LD, Silva-Hunter M: Cephalic mucormycosis (phycomycosis). A case with survival. Arch Neurol 17:379-385, 1967 17. Sandier R, Tallman CB, Kearny DG, et al: Successfully treated rhinocerebral phycomycosis in well controlled diabetes. N Engl J Med 285:1180-1182, 1971 18. Schneck SA: Neurology and neuropathology of immunosuppressive therapy and acquired immunological deficiency. Res Publ Assoe Res Nerv Ment Dis 49:293-304, 1971 19. Seelig MS: Mechanisms by which antibiotics increase the incidence and severity of candidiasis and alter the immunological defenses. Bacteriol Rev 30:442-459, 1966 20. Sheldon WH, Bauer H: The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med 110:845-852, 1959 21. Smits BJ, Prior AP, Arblaster PG: Incidence of candida in hospital in-patients and the effects of antibiotic therapy. Br Med J 1:208-210, 1966 22. Taylor CG, Alexander RE, Green WH, et al: Mucormycosis (phycomycosis) involving the maxilla. Report of a case with survival. Oral Surg 27:806-822, 1969 23. Zalman MV, Frasinel N, Neagoe N: Phagocytose des staphylocoques pathogenes sous l'action des antibiotiques. Arch Roam Pathol Exp Microbiol 22:919-928, 1963
This work was supported in part by National Institutes of Health Grant GM 20309-02. Address reprint requests to: Ronald J. Ignelzi, M.D., Division of Neurosurgery, Veterans Administration Hospital, 3350 LaJolla Village Drive, San Diego, California 92161.
J. Neurosurg. / Volume 42 / May, 1975
The authors describe a case of human cerebral mucormycosis following open head trauma and craniotomy, and discuss possible roles of steroids and antibiotic therapy in its pathogenesis. They suggest that the common usage of prolonged broad-spectrum chemoprophylaxis in head trauma may require critical review. KEYWORDS 9 cerebral mucormycosis steroids 9 antibiotics
EREBRAL mucormycosis is a rare phenomenon. To our knowledge, this is the first report of a case occurring after head trauma and craniotomy. In the majority of reported cases it has been associated with diabetic ketoacidosis; other predisposing factors include debilitation and antibiotic and steroid therapy. Mucormycosis infestation has not previously been described in the neurosurgical literature.
c
Case Report
This 6-year-old right-handed girl was thrown from a rapidly decelerating automobile and struck the pavement. She was in excellent health prior to the accident and not on medications; there was no familial or personal history of diabetes. Examination. The patient was decerebrate with fixed and dilated pupils. There was evidence of cerebrospinal fluid (CSF) leaking
J. Neurosurg. / Volume 42 / May, 1975
9 h e a d injury
9 craniotomy
9
from the wound site. Skull x-rays revealed a depressed skull fracture of the left frontal region without evidence of involvement of the small frontal sinuses. Operation. The patient was intubated and taken to the operating room where a rather extensive debridement of scalp, bone, and brain was performed. The dura was debrided and a patch of temporalis fascia was formed and sutured over the underlying dural defect. A basilar fracture was noted running across the superior orbital roof on the left to the cribriform fossa. The wound was then closed in layers and the patient was placed on the following intravenous medications: chloramphenicol, 350 mg three times daily, methicillin, 500 mg every 6 hours, and dexamethasone, 3 mg every 6 hours. Postoperative Course. The patient showed no further evidence of CSF leak and clinically remained in her preoperative state until the third day when she began to show some im593
R. J. Ignelzi and G. D. VanderArk provement. She continued to improve over the next few days to the point where she was able to communicate appropriately and move all extremities. On the fifth postoperative day the patient's mental status began to deteriorate. Cerebral angiography was performed, and a diagnosis of cerebral edema without focal mass was made. The patient was continued on antibiotics and steroids. On the eleventh postoperative day she had spiking fever. Pseudomonas was found in the urine and sputum; the organism was resistant to methicillin and chloramphenicol, but sensitive to garamycin which was then added to the treatment. The patient's condition continued to deteriorate and she again became decerebrate with fixed and dilated pupils. On the fourteenth postoperative day a large fluctuant mass developed in the area of the~scalp flap but not in the actual incisional line. This was needle aspirated but no organisms were seen on stain. She continued to have high spiking fevers despite the triple antibiotic therapy. A lumbar puncture revealed a leukocytosis of 500 with a predominance of polymorphic neutrophils, protein 100 mg, and glucose 105 mg%. Her peripheral white count at this point had risen to well over 40,000 with a predominance of polymorphic neutrophils. Stain and culture of the CSF were negative. The patient continued to have a fever and deteriorate neurologically. A repeat lumbar puncture 12 hours later revealed 4300 white blood cells, 90% polymorphic neutrophils, protein 235 mg, and glucose 75 mg%; many fungi with hyphae were seen on the stain and the cultures grew Zygomycetes mucor. A few hours later black drainage developed from the aspiration site and the wound edges., An extensive debridement of scalp and brain was performed. The brain and dura in the previously operated site appeared to be necrotic. Specimens taken from the various sites explored were stained and grew Zygomycetes mucor. Amphotericin B was given intravenously, 15 mg over 4 to 6 hours, and intrathecally, 15 mg every day. At this point the patient also developed hematuria and a workup revealed a hypocoagulable state with less than 10,000 platelets and a low normal fibrinogen level. The patient showed no response to the amphotericin B and her condition continued to deteriorate. She died on the 19th postoperative day. 594
Postmortem Examination. Findings included mucormycosis, massive edema, and necrosis of the left frontal, temporal, and parietal lobes (Fig. 1), and gangrene of the skin, scalp, and subcutaneous tissue, which on culture grew Zygomycetes mucor. Not only was the parenchyma of the brain involved, but there were also multiple areas of vasculitis and thrombosis with organisms in the walls of the vessels themselves (Fig. 2). Massive and diffuse hemorrhage appeared throughout the lungs, retroperitoneal space, spleen, pelvis, and bladder, consistent with hypocoagulation.
Discussion
Mucormycosis is the most acutely fatal fungal infection known in man? Systemic involvement has a 50% mortality while cerebral involvement alone has over 80% mortality. TM The incidence of the disease is increasing and in particular the cephalic form is becoming more prevalentY The organism is ubiquitous, occurring in soil, decaying matter, as a laboratory contaminant, and in the nasal flora of man; it is considered a saprophytic organism? The systemic form with marked pulmonary involvement affects patients who are debilitated, have myeloproliferative diseases, and are receiving steroids. 15 In the cerebral form of mucormycosis, 70% of the cases are associated with diabetic acidosis? Both experimental and clinical evidence shows that not hyperglycemia, but rather the ketoacidosis, increases the host's susceptibility to the infestation? '2~The fungus usually enters the brain from the upper respiratory tract, paranasal sinuses, or orbit. Common clinical findings include steady pain and tenderness over the involved facial areas; black crusting and drainage of the nasal turbinates; proptosis with third, fourth, and sixth cranial nerve weakness; corneal anesthesia; and progressive mental deterioration? X-ray examination reveals a nodular thickening of the soft tissues lining the sinuses with spotty destruction of the walls, and absence of fluid levels. The frontal sinuses are frequently spared? ~ Possible initial neutropenia is followed by progressive marked leukocytosis; grossly reduced platelet counts under 10,000 are not uncommon. Cerebral spinal fluid analysis reveals findings consistent with a meningoencephalitis. The organism may not stain when the spinal fluid is examined; the J. Neurosurg. / Volume 42 / May, 1975
Cerebral mucormycosis following open head trauma absolute diagnosis rests on fresh smears of the involved tissue stained with 10% potassium hydroxide, biopsy revealing the invasive mycelia in their hypha form, and culture for exact identification of the fungus, x8 Pathologically the organism causes an intense inflammatory reaction in both meninges and brain. Thrombosis caused by the hyphae penetrating and growing into the walls and lumens of the vessels is a striking feature of the infection, and leads to ischemic infarction of the brain parenchyma, xl The disease has been associated with thrombosis of the internal carotid artery as late as 1 year after the initial infection? ~ Treatment consists of administration of amphotericin B and correction of the underlying systemic disorder, which, in most cerebral mucormycosis cases, is diabetic acidosis. Since amphotericin B is fungistatic, prolonged use is required to eradicate the infection, and this may lead to nephrotoxic problems/ Cases of this form of phycomycosis successfully treated with the above regimen have been reported? 7 Since our case is the first of its nature to be reported and lacked many of the common denominators associated with this infestation, a careful analysis of possible etiological factors was undertaken. The child had no personal or family history of diabetes mellitus and was acidotic at no time during her illness, unlike most patients with this disease. Although steroids have been implicated in promoting spreading of the fungus organism, 3 not one single case of mucormycosis occurred in the large series of reported central nervous system fungus infections in renal transplant patients on immunosuppressive therapy and steroids? 8 The mechanisms by which antibiotics may alter a host's resistance and increase susceptibility to fungal infections have been reviewed by Seelig. 19 These include elimination of the normal flora allowing overgrowth or superinfection with fungus by eliminating competing organisms; 21 increased invasion by the organism as a consequence of the conversion of the saprophytes to a more invasive form; and inhibiting both antibody synthesis and phagocytic activity, thus reducing the host's resistance to invasion. The overgrowth phenomenon has been written about extensively. 6 The increased invasiveness of fungi in patients on antibiotics has been shown, 8 and J. Neurosurg. / Volume 42 / May, 1975
Fie. 1. Gross specimen at autopsy' demonstrating massive edema and necrosis which is most marked in left frontal lobe.
F~. 2. Photomicrographs of the same specimen at • (upper) and • (lower) magnification, revealing invasion of the vessel walls by the organism. The vessel wall shows macrophages with numerous large branching nonseptate hyphae characteristic of the lesion (lower). 595
R. J. Ignelzi and G. D. VanderArk abundant experimental evidence suggests that certain antibiotics may depress immunological defenses in the host. Chloramphenicol at the same low levels as those that suppress bacterial synthesis (50 ttg/ml) inhibits the synthesis of antibody in tissue culture; 2 antibiotics may also inhibit phagocytosis. In vivo and in vitro tests demonstrate that chloramphenicol and other broad-spectrum antibiotics decrease the ability of white cells to ingest foreign matter. 14'23 The degree to which antibiotics depress the host's immunological defenses is not known, but the possibility of this occurring must be remembered when these agents are used. References
1. Abramson E, Wilson D, Arky RA: Rhinocerebral phycomycosis in association with diabetic ketoacidosis. Ann Int Med 66:735-742, 1967 2. Ambrose CT, Coons AH: Studies on antibody production. J Exp Med 117:1075-1088, 1963 3. Baker RD, Schofield A, Elder TD, et al: Alloxan diabetes and cortisone as modifying factors in experimental mucormycosis (Rhizopus infection). (Abstract) Fed Proe 15:506-507, 1956 4. Bauer H, Ajello L, Adams E, et al: Cerebral mucormycosis: pathogenesis of the disease. Am J Med 18:822-831, 1955 5. Bergstrom L, Hemenway WG, Barnhart RA: Rhinocerebral otologic mucormycosis. Ann Otol Rhinol Laryngol 79:70-81, 1970 6. Blank H: Candida albicans. Frequent companion, occasional foe. Monogr Ther 2:1-6, 1957 7. Brummer DL, Chaves AD, Cugell DW, et al: Mucormycosis of the central nervous system associated with thrombosis of the internal carotid artery. J Pediatr 44:437-444, 1954 8. Campbell P J, Heseltine WW: An apparent growth stimulant for Candida albicans released from tetracycline-treated bacterial flora. J Hyg (Camb) 58:95-97, 1960 9. DeWeese DD, Schleuning AJ 2nd, Robinson LB: Mueormycosis of the nose and paranasal sinuses. Laryngoscope 75:1398-1405, 1965 10. Green WH, Goldberg HI, Wohl GT: Mucormycosis infection of the craniofacial structures. Am J Roentgenol Rad Ther Nucl Med 101:802-806, 1967 11. LaTouche C J, Sutherland TW, Telling M: Rhinocerebral mucormycosis. Lancet 2: 811-813, 1963
596
12. Martin FP, Lukeman JM, Ranson RF, et al: Mucormycosis of the central nervous system associated with thrombosis of the internal carotid artery. J Pediatr 44:437-444, 1954 13. McBride RA, Corson JM, Dammin GJ: Mucormycosis. Two cases of disseminated disease with cultural identification of rhizopus; review of the literature. Am J Med 28:832-845, 1960 14. Nicol TI, Sewell A: Effect of sulphonamides on the phagocytic activity of the reticuloendothelial system. Nature 184:1241-1242, 1959 15. Parkhurst GF, Vlahides GD: Fatal opportunistic fungus disease. JAMA 202:279-281, 1967 16. Prockop LD, Silva-Hunter M: Cephalic mucormycosis (phycomycosis). A case with survival. Arch Neurol 17:379-385, 1967 17. Sandier R, Tallman CB, Kearny DG, et al: Successfully treated rhinocerebral phycomycosis in well controlled diabetes. N Engl J Med 285:1180-1182, 1971 18. Schneck SA: Neurology and neuropathology of immunosuppressive therapy and acquired immunological deficiency. Res Publ Assoe Res Nerv Ment Dis 49:293-304, 1971 19. Seelig MS: Mechanisms by which antibiotics increase the incidence and severity of candidiasis and alter the immunological defenses. Bacteriol Rev 30:442-459, 1966 20. Sheldon WH, Bauer H: The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med 110:845-852, 1959 21. Smits BJ, Prior AP, Arblaster PG: Incidence of candida in hospital in-patients and the effects of antibiotic therapy. Br Med J 1:208-210, 1966 22. Taylor CG, Alexander RE, Green WH, et al: Mucormycosis (phycomycosis) involving the maxilla. Report of a case with survival. Oral Surg 27:806-822, 1969 23. Zalman MV, Frasinel N, Neagoe N: Phagocytose des staphylocoques pathogenes sous l'action des antibiotiques. Arch Roam Pathol Exp Microbiol 22:919-928, 1963
This work was supported in part by National Institutes of Health Grant GM 20309-02. Address reprint requests to: Ronald J. Ignelzi, M.D., Division of Neurosurgery, Veterans Administration Hospital, 3350 LaJolla Village Drive, San Diego, California 92161.
J. Neurosurg. / Volume 42 / May, 1975
