Clostridial myositis (Proceedings)

Clostridial myositis results from rapidly progressive necrosis of muscle from infection with clostridial organisms, often with fatal consequences. The majority of equine cases are secondary to intramuscular injections or as a result of direct contamination of deep wounds with bacterial growth in an anaerobic environment. Infection results in local inflammation often with severe pain and swelling, and can progress to a state of systemic inflammatory response (SIRs) with fever, depression, tachycardia, progressive toxemic shock, disseminated intravascular coagulation (DIC) and death. There is often rapid progression, and even with early and aggressive therapy, in severe cases, a guarded to poor prognosis should be given.

Malignant edema, clostridial myositis/cellulitis/fascitis and gas gangrene are a continuum of conditions due to infection of the subcutis, fascia and/or muscle. There is often fulminant tissue necrosis, with disintegration of tissue and serosanguinous exudate with bubbles of gas or free gas caused by infection with gas producing anaerobic clostridial organisms.

Clinical signs

In peracute cases animals may be found recumbent or dead. Painful muscular swellings, often with crepitus may be felt. The overlying skin may initially be hot and inflamed, but becomes progressively cool and insensitive. If systemic toxemia occurs the horse will become profoundly depressed and show signs of SIRs (tachycardia, tachypnea, fever and leukocytosis or leukopenia).

The extent of tissue necrosis and surrounding edema can be observed ultrasonographically. A distinction between edema and cellulitis can sometimes be difficult. Edema is characteristically located in the subcutaneous tissue, dissects along tissue planes, is anechoic, and loculated in appearance. Cellulitis usually appears as an echogenic, homogeneous thickening of the subcutaneous tissues, also dissecting along tissue planes. Sometimes hypoechoic pockets are seen in an area of cellulitis, but loculations are typically not seen. In anaerobic infections gas shadowing is often observed.

Aspiration of nonclotting, malodorous fluid (with or without gas) is typical. Volatile fatty acids are produced by many anaerobes including Clostridium spp. Gram-stain can provide a presumptive diagnosis of clostridial myositis with the detection of large Gram-positive rods, with ("paper-clip appearance") or without spores. Anaerobic (and aerobic) culture is also recommended.

Clinicopathological changes are non-specific. Muscle enzyme activities are usually moderately elevated, but often not to the extent expected for degree of myonecrosis present. Changes typical of septic-toxic conditions include leukocytosis or leukopenia, often with elevation of the band neutrophil count and fibrinogen concentration. There may be hyperproteinemia with a long standing walled off abscess, but more typically hypoproteinemia occurs due to exudative losses into the necrotic tissue. With the development of toxic shock there is hemoconcentration, azotemia and often coagulopathies with thrombocytopenia and DIC. In ~ 1/3 of cases there autoimmune mediated anemia secondary to antigen formation against red blood cells due to cross reaction with clostridial antigens.

The pathogens

Clostridium perfringes, C. septicum, C. chauvoei, C. fallax, C. sordelli and C. novyi are the principal pathogens. They are large Gram-positive, obligatory anaerobic rods that are ubiquitous in the soil and environment. They are also commensals of the skin, oral cavity and intestinal tract. Clostridia form spores, which allows the organism to survive until germination and growth can occur. Germination of spores and vegetative growth occurs in suitable anaerobic conditions. Clostridial organisms liberate potent exotoxins. Some organisms release these toxins continually during the growth of the organism, while others release the toxin during death.

Treatment

Intravenous penicillin-G (20,000 to 60,000 IU/kg q 2-4 h IV, then at a reduced dose for several weeks) is the historically recommended treatment for clostridial infections. Although penicillin treatment, with and without surgical fenestration, has resulted in survival, mortality with gas gangrene is unacceptably high. Experimentally, penicillin is a poor antibiotic choice, being non-curative with frequent relapse and death. In a murine C. perfringes gas gangrene model, clindamycin, metronidazole, rifampin and tetracycline were all more effective than penicillin, which had survival rates no different than untreated controls. Protein synthesis inhibitor- antimetabolite antibiotics such as tetracycline and chloramphenicol suppressed clostridial toxin production, while C. perfringes alpha toxin production continued in the presence of penicillin. Based on treatment of about 30 cases (at Ohio State University and Auburn University) tetracycline and metronidazole are now our standard treatments for clostridial myositis, being inexpensive, safe and anecdotally more efficacious. We currently recommend oxytetracycline (6.6 mg/kg IV, q 12-24h in 500 ml 0.9 % NaCl) and metronidazole (20 mg/kg PO q 6h, or 15 mg/kg IV q 6hrs). The daily cost is ~$16/d, compared to $360/d for 60,000 IU q 4h penicillin-G potassium. Anecdotal evidence suggests that this alternative therapy is safe and as efficacious, if not more so than penicillin, and certainly more economic. Long-term antibiotic therapy is essential, and horses are discharged on metronidazole and doxycycline (20 mg/kg q 12h) for a total of about 20 days of antibiotic therapy.

Wound fenestration

Fenestration of emphysematous regions to allow oxygenation of the anaerobic necrotic environment and drainage of exudates is generally recommended. Extensive skin sloughing may occur if skin viability is lost. Often limb wounds result in massive swelling, with the entire leg expanding to 3 times its normal diameter. The massive swelling of tissues causes pressure necrosis and loss of vascular supply to overlying skin, resulting in skin sloughing. Differentials include staphylococcus limb cellulitis. With neck infections, edema fluid and sometimes dissemination of the infection spreads ventrally resulting in pectoral, thoracic and even limb edema. If the head is held low due to neck pain or depression severe head edema can occur often resulting in airway obstruction. Tracheostomy may be required. Cold hosing or cold packing of the surrounding tissue can help with the resolution of edema.

Case one: 2 year-old Standardbred filly

History

The filly was the third out of five horses vaccinated for influenza and rhinopneumonitis in the left cervical musculature from a 5-dose vial by the owner 5 days previously. The day after vaccination, the filly was depressed, and a 15 cm diameter mass marked the vaccination site. The RDVM administered flunixin, phenylbutazone and procaine penicillin-G (20,000 IU/kg IM, q 12 h for 4 d). Severe swelling of the head causing nasal passage occlusion occurred after 48 hours and the filly was unable to raise her head. The RDVM inserted a nasopharyngeal tube and gave an antihistamine, DMSO in 5 LRS, gentamicin (6.6 mg/kg IV, q 24 h for 2 d) tetanus toxoid and antitoxin (1500 IU IM). The filly ate and drank until the day of referral. The RDVM thought the head swelling was due to an allergic reaction and due to its severity advised referral with subsequent euthanasia likely.

Physical examination

The filly was markedly depressed. The head was twice its normal size. Tissue swelling occluded the left nasal passage and obscured both orbits rendering the horse non-visual. The filly was disoriented, moved reluctantly with low head carriage and showed weakness (toe dragging, truncal sway and knuckling). Oral mucous membrane color (mmc) was dark pink with a normal refill time of <2 seconds. The vulval mmc was a normal pink. T= 100° F, HR = 42 bpm, RR = 42bpm. The ventral neck was diffusely swollen, but no focal pain or crepitus were palpable.

Assessment and case management

Primary problems identified were: marked facial swelling with airway obstruction, weakness, depression, pain and history of neck swelling from IM vaccination. The horse was systemically stable with normal vital parameters. Hyperemic oral mmc was likely due to venous congestion and lymphatic obstruction from facial swelling. Causes of swelling included: diffuse cellulites or myositis extending from the vaccination site, dependent edema from head positioning or unrelated angioedema.

Facial ultrasonographic evaluation was consistent with edema. Aspiration of ultrasonographically imaged fluid from a well-defined emphysematous abscess at the vaccination site dorsal to C3-C4 revealed malodorous serosanguinous exudate. Gram stain and aerobic/anaerobic culture were performed. With local anesthesia, the abscess was lanced and a Penrose drain was placed. The culture was negative, possibly due to the previous antibiotic therapy. Although the head edema was severe, normal vital signs suggested minimal toxemia and thus a better prognosis.

To assess the upper airway, endoscopy was performed. The head was elevated 50 cm and after a 20 second view of the pharynx the filly recoiled backwards, dog-sat for one minute, then collapsed in lateral recumbency. Vital signs remained normal, but due to severe nasal and pharyngeal edema, prophylactic tracheostomy was performed. The filly remained immobile and hypo-responsive to audible and tactile stimuli for 2 hours. Differentials requiring exclusion were fractured cervical vertebrae, osteomyelitis, meningitis, increased intracranial pressure (ICP), or acute toxic or bacterial shower from abscess disruption.

The filly's immobility enabled rapid lumbosacral CSF collection for cytology, which was normal. No evidence of cervical vertebral canal stenosis, osteoarthritis, osteomyelitis or fracture was observed radiographically, but a second abscess over C5-C6 was seen. External evidence of this abscess was undetectable, but 500 ml of pungent gas and 200 ml of serosanguinous fluid was aspirated by ultrasound guidance prior to drainage and placement of two more Penrose drains.

The CBC revealed a mild leukocytosis (11.4 X 109cells/L; normal < 10.6) with a mature neutrophilia and monocytosis consistent with infection, inflammation or a stress leukogram. Elevation of the acute phase protein fibrinogen (985 mg/dL; normal < 422) and the presence of reactive lymphocytes were attributed to the myonecrotic abscesses.The rapid progression of systemic signs and abscess formation after intramuscular injection with identification of large, gas producing Gram-positive rods lead to the presumptive diagnosis of clostridial myositis.

Oxytetracycline (6.6 mg/kg IV, q 24 h in 500 ml 0.9 % NaCl) and metronidazole (20 mg/kg PO q 6 h) was commenced. Analgesia was provided by butorphanol (0.01 mg/kg IV q 4 h for 72 h) and phenylbutazone (2.2 mg/kg IV then PO, q 12 h).

The filly was transported to a heavily bedded stall. The head was elevated 30° and hourly cold packing was performed to reduce facial edema. The filly was unresponsive for 2 more hours, and then she suddenly stood, drank water and looked for food! The collapse and immobility was attributed to severe pain from compression of the second abscess by head elevation during endoscopy.

Except for 30 minutes q 2h, the head was elevated by tethering the horse via a padded halter to an overhead wire. By day 2, 60 % of the edema had resolved. The eyes were visible with normal papillary light response, menace, and no corneal uptake of fluorescein stain. The filly was still depressed and moved stiffly but was markedly improved. Meningitis was considered unlikely as CSF cytology, cell count and protein were normal and culture was subsequently negative.

By afternoon of the second day, only 10 % of the facial edema remained. The tracheostomy tube was removed. The neck was evaluated by ultrasound daily. The fenestrated area was hot-packed and wounds were flushed with 1% providone iodine q 8 hrs.

The filly was treated with oxytetracycline and metronidazole for one week in the hospital, and then discharged on metronidazole and doxycycline (10 mg/kg PO, q 12h) for 5d.

The filly made an uneventful recovery and commenced training after one month.

Take Home Message: It is important to identify and drain all abscesses. Multiple abscesses may exist but may not be externally discernable. Ultrasonography and radiology can be used to identify loculations of fluid and gas. Identification of large Gram-positive rods and the presence of pungent gas within abscesses are highly suggestive of clostridial infection, allowing for appropriate therapy prior to the results of culture and sensitivity. The absence of systemic signs even in the presence of marked tissue damage provides a better prognosis.

Case Two: 4-year-old Spotted Saddle Horse.

History

Intramuscular flunixin meglumine had been administered over the left shoulder 2 weeks previously, with subsequent abscess development. Recently, progressive lethargy and hematuria had developed. The horse was treated with procaine-penicillin for 4 days prior to admission.

Diagnostic procedures and findings

The horse was depressed, with T = 101.5 ° F, PR = 80 bpm, RR = 56 bpm. MMC was pale pink with a CRT of < 2 sec. The urine was discolored (brown/red). Urinalysis was consistent with hemoglobinuria or myoglobinuria. No casts were observed, but the USG = 1.014. Ultrasonographic examination of the left shoulder revealed multiple pockets of fluid, one of which was large enough to drain. Culture of the fluid revealed large Gram-positive rods consistent with Clostridial species.

CBC revealed anemia (PCV = 13%), marked leukocytosis (49.6 x 109/L) with a left shift (2.5 x 109/ L band neutrophils). The fibrinogen concentration was slightly elevated at 548 mg/dL. Serum biochemical evaluation revealed azotemia (creatinine = 4.7 mg/dL and BUN = 97 mg/dL), hyponatremia (128 mEq/L), hypochloremia (82 mEq/L), hyperglobulinemia (5.4 mg/dL), hyperbilirubinemia (10.4 mg/dL) and increased activities of liver enzymes (AST, ALP, GGT, SDH) and muscle enzymes (CPK).

Coomb's test was negative. Cross matching with two blood donors was performed. Major cross match was compatible, minor was incompatible.

Assessment of laboratory findings

The neutrophilia with left shift, hyperfibrinogenemia and hyperproteinemia were consistent with the observed abscessation. The anemia was likely immune mediated due to antibody formation against red blood cell surface antigens. Autoimmune hemolytic anemia is a rare complication reported secondary to antigen stimulation from Clostridium spp., Staphylococcus spp., Streptococcus spp., viral and parasitic infections as well as secondary to neoplasia or drug induction. The resulting hemolysis led to hemoglobinuria. Urinary pigments can lead to renal damage by causing renal tubule obstruction and reduction in renal blood flow. The azotemia with isosthenuria confirms renal damage with impaired tubular concentrating ability. The elevated bilirubin was due to hemolysis.

Treatment

Whole blood transfusion (6 liters), dexamethasone (20 mg IV Q 24h for 9 days), LRS at 2 x maintenance (120 ml/kg/d for 3 days, then 60ml/kg/d for 1 d), oxytetracycline (6.6 mg/kg IV, q 12h in 250 ml 0.9 % NaCl x 9 d) and metronidazole (20 mg/kg PO q 6 h x 8d) were administered.

The horse responded to therapy with the PCV increasing to 22% after the transfusion and resolution of the pigmenturia and azotemia after intravenous fluid therapy. A second episode of hemolysis occurred after 6 days of hospitalization (hemolysed serum, red urine, elevated heart rate, and azotemia-creatinine = 2.8mg/dL). Intravenous fluids were required for 24 hours. The horse was discharged to the care of the RDVM on doxycycline (10mg/kg PO q 12h x 7 d) and dexamethasone (20mg PO q 24h x 5d). The PCV was 18%, and the leukocytosis was slowly resolving (22.3 x 109/L). The prognosis was still guarded due to the risk of further episodes of hemolysis and renal damage.

Take home message: Autoimmune hemolytic anemia is a rare complication of Clostridial spp. infections.

Case Three: 2-year-old Standardbred filly

History

The filly was referred for severe edema and swelling of the cervical and head regions, following intramuscular flunixin meglumine and phenylbutazone injections four days previously.

Assessment and case management

The severe head swelling had resulted in severe nasal edema, and the filly presented in respiratory distress, requiring immediate tracheostomy. Ultrasound examination did not reveal any discrete abscesses, and both jugular veins appeared patent, although deep to 10cm of edema fluid. An aspirate of this fluid was obtained for cytology, Gram-stain and culture. Clostridial cellulites was suspected.

Blood results showed a moderate increase in band neutrophils (0.7 x 109/L) and elevated fibrinogen (798 mg/dL), indicating inflammation. Mild dehydration was present with mild azotemia and electrolyte abnormalities.

Treatment

Although no bacteria were observed on the Gram-stain Clostridial spp. were suspected so oxytetracycline and metronidazole were administered for 4 days. A cephalic catheter was required due to the inaccessibility of the jugular veins, and risk of inducing phlebitis from access through infected tissue. Patency of the cephalic catheter was maintained with a slow infusion of LRS. Phenylbutazone was also administered.

Culture of the aspirate from the neck grew Staphylococcus aureus/intermedius, which was resistant to gentamicin, tetracycline and tribrissen. It was sensitive to amikacin, ceftiofur, chloramphenicol, enrofloxacin and penicillin. Potassium penicillin (20, 000 IU/kg IV q 6h) and enrofloxacin (2.5mg/kg IV q12h) were administered and the horse was released to the care of the referring veterinarian.

Take home message

Not all fulminant myositis/cellulites cases are due to clostridial organisms. Staphylococcus aureus can produce similar clinical findings and antibiotic therapies may be vastly different. Gram-stains are often helpful stall side, but culture and sensitivity should always be performed.