Critical Care Medicine

Head and Neck Infections

Head and Neck Infections

Cervical fascial space infections; retropharyngeal abscess; danger space Infection; Ludwig's angina; Lemierre's syndrome; prevertebral space infection; lateral pharyngeal space infection; submandibular space infection; parapharyngeal infection; prevertebral abscess; quinsy; septic jugular thrombophlebitis; pharyngomaxillary space infection; necrotizing mediastinitis; Fusobacterium necrophorum bacteremia; epiglottitis; peritonsilar abscess; rhinocerebral mucormycosis; invasive fungal sinusitis; Cavernous sinus thrombosis

1. Description of the problem

What every clinician needs to know

Infections of the head and neck carry a significant risk of morbidity and mortality due to the potential for involvement of crucial neurovascular structures, spread to the central nervous system or compromise of the upper airway. Serious infections usually originate as common, typically benign infections such as superficial soft tissue infections, sinusitis, otitis, pharyngitis or dental infections that progress into deeper fascial compartments.

Maintaining a high index of suspicion is essential to making the diagnosis as these infections are uncommon, initial clinical findings may be subtle, and differentiating them from their more benign counterparts can be difficult. Early identification and treatment is important as progression to irreversible complications or death can be rapid.

Immunosuppressed patients may have a subtler presentation and are at risk for infection with a broader array of organisms. Particularly important is rhinocerebral mucormycosis.

Septic cavernous sinus thrombosis is a rare but serious complication of facial cellulitis or sinusitis.

Cervical fascial space infections: The fascial planes of the head and neck form a complex geography of discrete potential spaces, many of which contain crucial neurovascular structures. These fascial layers generally provide an effective barrier to the spread of infection. Occasionally common infections such as sinusitis, otitis, pharyngitis and dental infections can progress to involve these potential spaces, which then act as conduits for spread to deeper structures such as the carotid sheath, the mediastinum and the central nervous system.

Serious complications include: upper airway obstruction, septic jugular thrombophlebitis, mediastinitis, epidural abscess, cranial nerve palsies, and carotid artery rupture.

The clinical syndrome, potential complications and management are based on which anatomical compartment is affected. Five compartments are of particular importance:

  1. The submandibular spaceis the area inferior to the tongue and bounded laterally and anteriorly by the mandibular bone. Infection of this space, often referred to as Ludwig's angina, is prone to cause upper airway occlusion, as tongue swelling can be a prominent feature.

  2. The lateral pharyngeal spaceis shaped like an inverted cone located on the lateral neck, with its base being the skull and its apex at the hyoid bone. It is divided into an anterior and posterior compartment by the styloid process and attached muscles. The posterior compartment contains several vital neurovascular structures, including the ninth through 12th cranial nerves, the carotid sheath and the cervical sympathetic trunk. The deep layer of the cervical fascia, together with the esophagus anteriorly and the vertebral bodies posteriorly, create three potential spaces, which can be thought of conceptually as cylinders of varying length spanning from the base of the skull to various depths of the thorax.

  3. The retropharyngeal space (the most anterior of the three) traverses from the base of the skull to the superior mediastinum and is bounded anteriorly by the pharynx and esophagus and posteriorly by the alar layer of the deep cervical fascia. Complications of infection of this space are related to the potential for spread to the mediastinum.

  4. The danger space(the middle of the three) extends from the base of the skull to the diaphragm. It is bounded anteriorly by the alar fascia and posteriorly by the prevertebral fascia. Necrotizing mediastinitis is the most serious complication.

  5. The prevertebral space(the most posterior of the three) extends from the base of the skull all the way to the coccyx. It is defined anteriorly by the prevertebral fascia and posteriorly by the vertebral bodies.

Epiglottitis: Acute adult epiglottitis is distinct from epiglottitis in children in that in adults oropharyngeal symptoms are more prominent, progression is slower and airway obstruction is less common. Early in its course it can be difficult to differentiate from pharyngitis.

Clinical features

Cervical fascial space infections:Specific manifestations are based on which anatomical location is affected. Some features common to most cervical fascial compartment infections include:

  • Signs of systemic toxicity including fever are generally present; however, in immunosuppressed individuals or those who have received antibiotics these signs may be absent.

  • Because infection occurs deep in the subcutaneous tissues, superficial signs of inflammation, including erythema and induration, may be minimal or absent. Pain and tenderness in the absence of these findings may be a clue to suggest deeper infection.

  • A thorough examination of the cranial nerves should always be performed as cranial nerve palsies, which may be subtle, may be the only finding suggestive of a more severe infection that requires urgent intervention.

Submandibular space (Ludwig's angina):Infection typically results from spread of infection from the submandibular molars. Other potential routes of infection include trauma to the floor of the mouth, including fractures of the mandible or puncture by a foreign body, invasion of tumors or spread from contiguous lymphadenitis.

Typical signs/symptoms:fever/chills, mouth/dental pain, neck stiffness, dysphagia, drooling and muffled "hot potato" voice. Trismus is notably absent, which can help differentiate this from infection of the lateral pharyngeal space. Lymphadenopathy is typically absent. Patients may lean forward and tilt their head up to maintain an open airway (the "sniffing position"), which is an ominous sign of impending airway compromise.

Physical exam: The hallmark of this infection is symmetrical, tender, brawny swelling of the submandibular area, often described as "woody" edema. Swelling of the tongue may be prominent (potentially leading to airway compromise).

Lateral pharyngeal space: Infections can occur as a result of spread from a variety of primary sites, including: pharyngitis, tonsillitis, dental caries, parotitis, cervical lymphadenitis or infection of other deep neck spaces. In adults the most common sources are dental infections and peritonsillar abscess.

Symptoms of the initial inciting infection are often minor (i.e. toothache, sore throat) and may have resolved days to weeks before manifestations of the lateral pharyngeal space infection appear.

Typical signs/symptoms: trismus, dysphagia, lateral neck pain, fever.

Physical exam: Swelling over the angle of the jaw. Neck pain is increased with lateral flexion to the contralateral side. Infections of the anterior compartment have more prominent signs and symptoms. Posterior compartment infection may be difficult to diagnose clinically as trismus, dysphagia and visible swelling are often absent. Fever without localizing symptoms may be the only sign. Vocal cord paralysis, lateral deviation of the tongue on extension, or ipsilateral Horner's syndrome may occur with cranial nerve and sympathetic nerve involvement.

Suppurative jugular thrombophlebitis (Lemierre's syndrome)is a severe complication of infection of the posterior compartment. Pain, trismus, and obvious swelling are often absent. Induration posterior to the sternocleidomastoid may be a clue to the diagnosis. Sign/symptoms of metastatic foci of infection (pleuritic chest pain from lung abscess) can suggest the diagnosis.

Rarely, infection of the posterior compartment can cause arteritis and aneurysm of the carotid artery. Rupture is often preceded by small "herald bleeds," which may present as ecchymosis of the neck or bleeding from the oropharynx, nose or ears.

Retropharyngeal space:In adults infection of the retropharyngeal space is typically the result of oropharyngeal trauma (such as choking on a chicken bone that pierces the posterior pharynx) or iatrogenic due to instrumentation of the oropharynx (nasogastric tube, endoscopy, endotracheal tube).

Typical signs/symptoms:odynophagia, dyspnea and neck stiffness. Pleuritic chest pain suggests spread to the mediastinum.

Physical exam: Swelling of the posterior pharynx. Signs of tamponade (elevated JVD) may indicate spread to the pericardium.

Danger space: Infection typically occurs as a result of spread from contiguous spaces (retropharyngeal). Other than symptoms of the inciting infection (sore throat, odynophagia) symptoms of mediastinitis and tamponade suggest the diagnosis.

Prevertebral space: Back/neck pain. Fever is present in only half of cases. Neurologic deficits or radiculopathy. Cord compression from epidural abscess may present as paralysis, indicating the spinal level of involvement.

Peritonsillar abscess: Can occur in any age group but most common in young adults. Most often a complication of acute tonsillitis.

Typical signs/symptoms: Presents similar to submandibular space infection: fever, sore throat, dysphagia, drooling and muffled voice. It differs in that trismus is often present, and submandibular swelling is absent.

Physical exam:usually unilateral swelling of the anterior pillar and soft palate. Swelling of the middle or lower aspect of the tonsil. Cervical lymphadenopathy.

If evidence of systemic inflammatory response (fever, elevated WBC) persists after abscess drainage or rupture it may indicate that infection has spread to the lateral pharyngeal space. This more commonly occurs when infection involves the middle or lower portion of the tonsil.

Stridor, cyanosis, and tachypnea imply impending upper airway obstruction from laryngeal edema, which is more common when infection is bilateral.

Epiglottitis:

Typical signs/symptoms:sore throat, odynophagia, and fever (variable). Features that may help distinguish from benign pharyngitis include muffled voice, stridor and inability to handle oral secretions.

Physical exam:tenderness over the anterior neck, especially over the hyoid bone, may be a distinguishing feature.

Septic cavernous sinus thrombosis:Typically presents with fever, retro-orbital headache and unilateral periorbital edema that progresses to bilateral involvement. Initially it may be difficult to distinguish from orbital or periorbital cellulitis. Later symptoms include diplopia and extraocular muscle paralysis. Bilateral involvement strongly suggests the diagnosis. Mental status changes may occur. On physical exam proptosis, ptosis and extraocular muscle paralysis are the most common findings.

Rhinocerebral mucormycosis: Occurs in patients with particular forms of immunosuppression, most commonly patients with hematologic malignancies with chemotherapy-induced neutropenia, and poorly controlled diabetics. Other risk factors include long-tem steroid use, solid organ transplant and advanced AIDS.

Typical signs/symptoms: Initially the patient may present with sinus pain and congestion, but symptoms are typically mild. Progression to orbital cellulitis or brain abscess presents with proptosis, ophthalmoplegia, chemosis, blindness and mental status changes.

Physical exam: Tenderness over the maxillary or frontal sinus. Black necrotic lesions may be visible on the mucosa of the nasal cavity or soft palate.

Key management points

Infections are generally polymicrobial, include anaerobes, and reflect the normal resident flora of adjacent mucocutaneous surfaces. Empiric antibiotics chosen with these considerations in mind should be initiated as soon as infection is suspected.

When possible cultures should be obtained to guide definitive antibiotic therapy; however, antibiotic therapy should not be delayed if cultures cannot be immediately obtained.

CT scan with IV contrast is the imaging modality of choice and should be performed urgently in any case where deep head and neck infection is suspected. MRI is a valid alternative if it is readily available.

Surgical drainage is often required in addition to antibiotics. Early involvement of surgical consultants (ENT, neurosurgery) should be sought even if immediate surgical intervention is not deemed necessary, as progression of infection may be rapid.

All patients suspected of having rhinocerebral mucormycosis should have urgent ENT exam with nasopharyngeal laryngoscopy with biopsy of any abnormalities. CT of the sinuses should be performed.

2. Emergency Management

Cervical fascial space infections: Once stabilized, CT scanning will help to determine if surgical intervention is necessary.

Airway management: Although most cases can be managed with antibiotics and close monitoring of respiratory status, often endotracheal intubation may be required to prevent complete upper airway obstruction.

Signs of impending airway compromise include: tachypnea, dyspnea, stridor and use of the accessory muscles. Patients may lean forward with nose tilted up (the "sniffing position") in order to maintain their airway.

Especially in submandibular space infections, where the risk of airway obstruction is highest, it is recommended to have a low threshold for intubation. Once signs of impending airway compromise manifest, fiberoptic-guided nasotracheal intubation may be required, as soft tissue swelling and friability and the potential for laryngospasm can make blind oral intubation unsafe.

In cases of complete airway obstruction during attempted intubation an emergent tracheostomy may become necessary, so supplies and personnel trained in this procedure should be readily available.

Epiglottitis: Maintaining patency of the upper airway is the most important consideration in the emergent management of adult acute epiglottitis. Adults have larger, more rigid upper airways than children, making them less prone to obstruction and making the need for intubation less common. Laryngoscopy should be performed to help inform this decision.

Patients presenting with signs of impending airway compromise (stridor, cyanosis, severe dyspnea) or who have greater than 50% occlusion of the laryngeal space should have an endotracheal tube placed. Patients lacking these symptoms and with less than 50% occlusion can often be monitored in an ICU setting without immediate intubation.

Rhinocerebral mucormycosis is a surgical emergency as early and aggressive surgical debridement is necessary to prevent spread of infection to crucial neurovascular structures. Antifungal therapy should be started as soon as the diagnosis is suspected.

3. Diagnosis

Cervical fascial space infection: The diagnosis is usually suspected based on the previously described clinical findings. In most cases imaging is necessary to confirm the diagnosis and decide on the need for surgical therapy. CT scan with IV contrast is the imaging modality of choice and should be performed urgently on all patients in whom the diagnosis is suspected.

There are no diagnostic laboratory findings. WBC is often elevated, but absence of leukocytosis does not eliminate the diagnosis.

Blood cultures should be sent routinely and are variably positive depending on which compartment is infected. Superficial cultures of nasopharyngeal surfaces do not reflect the microbiology of deeper infected sites and are generally not helpful. If surgical drainage is undertaken, cultures of aspirated material should be sent to guide definitive antibiotic therapy.

Blood cultures positive for Fusobacterium suggest Lemierre's syndrome and should be followed up with a CT scan of the neck.

Peritonsillar abscess: The diagnosis is generally made clinically. If drainage is pursued samples of aspirated material should be sent for culture.

Epiglottitis: The definitive diagnosis of epiglottitis is made by direct visualization of the epiglottis. Findings include swelling and erythema of the epiglottis, aryepiglottic folds and arytenoid cartilage. The classic "cherry red" epiglottis seen in childhood epiglottiitis is uncommon in adults.

Plain films of the neck can be helpful in suggesting the diagnosis. Typical radiographic findings include the "thumb sign" (enlarged epiglottis), and thickened aryepiglottic folds. On X-ray the ratio of epiglottis or aryepiglottic fold width to third cervical vertebrae width of greater than 0.5 or greater than 0.35 respectively has a high sensitivity for the diagnosis.

Cultures to be sent include blood cultures and swab of the epiglottis (although this should be done only in intubated patients, as it can precipitate edema and airway obstruction).

Rhinocerebral mucormycosis: The diagnosis is suspected based on the typical clinical findings described above. CT scan of the sinus should be performed and will generally show thickening or opacification of the maxillary sinus.

Biopsy specimens should always be sent for fungal culture in addition to pathology as histology of sinus biopsy showing tissue invasion with broad, "ribbon-like", non-septate hyphae can establish the diagnosis of a fungal infection, but the specific fungus can be determined only by growing the organisms in culture. This may have important implications for treatment.

Septic cavernous sinus thrombosis: Imaging with either IV contrast-enhanced CT scan or MRI with gadolinium is necessary to definitively establish the diagnosis.

4. Specific Treatment

Cervical fascial space infections (with the exception of prevertebral space): Antibiotics should include coverage of beta-lactamase-producing oral gram-positive cocci (viridans streptococci) and oral anaerobes. With the widespread prevalence of methicillin-resistant Staphylococcus aureus (MRSA), most experts recommend empiric MRSA coverage, especially if risk factors are present (IVDU, high prevalence of MRSA in the community, known MRSA colonization, end-stage kidney disease, recent exposure to broad spectrum antibiotics, or with nosocomial infection). Initially antibiotics should be given IV. Once signs of infection are improving the patient can be transitioned to oral antibiotics to complete the full course of therapy.

Typical antibiotic regimens:

Ampicillin/Sulbactam 3 g IV every 6 hours (or other extended-spectrum penicillin/beta-lactamase inhibitor combination) OR

Ceftriaxone 2 g IV daily PLUS metronidazole 500 mg every 6-8 hours OR

Quinolone (i.e. levofloxacin 750 mg IV daily) plus clindamycin 600 mg IV every 8 hours

PLUS MRSA coverage with:

Vancomycin IV 15 mg/kg every 12 hours OR

Daptomycin 6 mg/kg IV daily OR

Linezolid 600 mg IV every 12 hours

MRSA coverage should be changed to nafcillin 2 g IV every 4 hours if methicillin-sensitive staph is isolated as the causative organism.

Immunosuppressed patients or patients at risk for hospital-acquired infection (i.e. in the hospital for more than 48 hours before infection, or hospitalized within the last 90 days) should also be covered for resistant gram-negative rods. Specific antibiotic choice should be based on the local antibiogram in consultation with an infectious disease specialist. Commonly a carbapenem (such as meropenem 1 g IV every 8 hours) will be effective.

Antibiotic duration and the need for surgical drainage or other adjuvant therapy depends on the anatomic site and presence of complications. In uncomplicated infection antibiotics should be continued for 2-3 weeks, with duration based on resolution of symptoms.

Lemierre's syndrome: Antibiotics should be continued for 4-6 weeks.

Prevertebral infections: Infections complicated by discitis or vertebral osteomyelitis should be treated for 6-8 weeks.

Need for surgery?

Submandibular space: In most cases surgery is not necessary. If fluctuance is appreciated or if fever persists despite antibiotics, surgical drainage may be indicated.

Lateral pharyngeal space: Anterior compartment infections often involve abscess formation, and early surgical drainage can prevent spread to other cervical fascial compartments. Posterior compartment infections, including complicated infections such as Lemierre's syndrome, usually do not produce drainable fluid collections and can often be managed with antibiotics alone without surgery. Surgical ligation of the jugular vein is indicated only if infection fails to resolve on IV antibiotics. "Herald bleeds" indicating imminent carotid artery aneurysm rupture require immediate surgical intervention.

Retropharyngeal space: If infection has not spread to the mediastinum, surgery is usually not required. Necrotizing mediastinitis requires urgent surgical drainage.

Prevertebral space: It is controversial whether drainage of prevertebral space infections is beneficial. In most cases neurologic symptoms can be used to guide the decision for surgery. Patients without neurological deficits who can be monitored with frequent MRI can be managed conservatively with IV antibiotics, although neurosurgical consultation should be obtained early to monitor clinical and radiographic progression. Worsening of neurological deficits while on antibiotics is an indication for surgical intervention.

Other treatment considerations

In Lemierre's syndrome the utility of anticoagulation has not been established and it is generally not recommended.

Difficulty with swallowing makes aspiration pneumonia a risk (especially in prevertebral space infections). Swallowing evaluation should be performed before allowing oral intake.

Peritonsillar abscess and epiglottitis: Empiric antibiotic regimens should include coverage of group A strep, penicillin-resistant strep pneumonia, Haemophilus influenzae, and MRSA.

Typical antibiotic regimens:

Ceftriaxone 2 g IV every 24 hours PLUS vancomycin IV 15 mg/kg every 12 hours

Quinolone (i.e. levofloxacin 750 mg IV daily) PLUS vancomycin

Rhinocerebral mucormycosis: These organisms are not sensitive to azole or echinocandid antifungals. Amphotericin B is the treatment. A lipid formulation of amphotericin B is recommended to decrease the potential for side effects, including acute renal failure and electrolyte abnormalities.

Aggressive surgical debridement is essential. Often multiple surgeries are required.

Cure of infection is contingent on reversal of the underlying immunodeficiency (i.e. decrease immunosuppresive meds, correct DKA, reverse neutropenia with granulocyte colony-stimulating factor).

Septic cavernous sinus thrombosis: Empiric IV antibiotic regimens should be chosen based on the suspected origin of infection (cellulitis vs. sinusitis). Regimens should include coverage for MRSA and streptococci. Anaerobic coverage should be included if a sinus source is suspected.

The benefit of anticoagulation is unclear but it may be indicated in patients with early unilateral disease. Glucocorticoids may help decrease cranial nerve dysfunction and should be considered.

Drugs and dosages

Note: (!) = required dose adjustment for decreased renal function

Dosing of IV antibiotics used in treatment of head and neck infection:

Ampicillin/sulbactam 3 g every 6 hours(!)

Pipercillin/tazobactam 3.375 g every 8 hours(!)

Ceftriaxone 2 g every 24 hours(!)

Clindamycin 600 mg every 8 hours

Metronidazole 500 mg every 6-8 hours

Levofloxacin 750 mg every 24 hours(!)

Vancomycin 15 mg/kg every 12 hours(!)

Daptomycin 6 mg/kg every 24 hours(!)

Linezolid 600 mg every 12 hours

With daptomycin a baseline CPK should be checked and monitored weekly as rhabdomyolisis is a potential side effect.

With linezolid CBC should be checked every few days as thrombocytopenia is a potential side effect. Other side effects include peripheral neuropathy and optic neuritis.

Dosing of PO antibiotics used after patient stabilized and ready for discharge:

Amoxicillin/clavulanate 875 mg twice daily (!)

Metronidazole 500 mg 3 times a day

Levofloxacin (same as IV dosing)(!)

Oral options for coverage of MRSA:

Co-trimoxazole (Bactrim) 2 DS tabs twice daily (!)

Clindamycin 450 mg every 6-8 hours

Linezolid (same as IV dosing)

Minocycline 100 mg twice daily

Patients whose infections are not resolving on IV antibiotics may require surgical intervention.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Most of the infections discussed here should show progress towards resolution within 3-5 days (rhinocerebral mucormycosis is an exception). Patients with serious bacterial head and neck infections who survive the immediate complications (airway obstruction, etc.) should make a complete recovery within several weeks.

The majority of patients with rhinocerebral mucormycosis survive if their underlying immunodeficiency is corrected; however, there is often significant disfigurement related to the aggressive debridement necessary for cure. Patients who remain immunosuppressed (i.e. refractory hematologic malignancy) often die of progressive fungal disease.

Failure to respond to IV antibiotics as evidenced by persistent fever or worsening symptoms should prompt the following considerations:

1. Is there infection with a resistant organism that is not being treated with the current antibiotic regimen?

-- Consider adding MRSA or resistant gram-negative rod coverage.

2. Is there a focus of infection that requires surgical drainage?

-- CT scan if not already done, with drainage/culture of any identified abscesses.

3. Has the patient developed a secondary complication (such as aspiration pneumonia) that requires alternate antibiotic therapy?

Peritonsillar abscess: Once the acute infection has resolved tonsillectomy should be considered to prevent relapse. Until that can be done, prophylactic antibiotics should be considered.

Rhinocerebral mucormycosis: Patients should have close outpatient monitoring, including repeat CT or MRI, to make sure disease is not progressing. Secondary antifungal prophylaxis with oral posaconazole should be continued as long as neutropenia persists.

Epidemiology

Serious infections of the head and neck are uncommon in the post-antibiotic era, with estimated annual incidence rates ranging from less than 1 to 30 per 100,000 persons, depending on the site of infection. Of the deep neck space infections, peritonsillar abscess is the most common. Although rates of epiglottitis in children have decreased markedly since the introduction of routine vaccination for type b Haemophilus influenzae, rates in adults have remained stable. Rhinocerebral mucormycosis occurs almost exclusively in immunosuppressed patients. With the increased prevalence of immunosuppression (due to increased number of solid organ and stem cell transplantations), rates have increased.

What's the evidence?

Description of the problem

Chow, AW, Hall, JB, Schmidt, GA, Wood, LDH. "Life threatening infections of the head, neck and upper respiratory tract". Principles of Critical Care. McGraw Hill. 1998.

Parhiscar, A, Har-El, G. "Deep neck abscess: a retrospective review of 210 cases". Ann Otol Rhino Laryngol. 2001. pp. 1051.

Marr, KA, Carter, RA, Crippa, F. "Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients". Clin Infect Dis.. 2002. pp. 909.

Emergency management

Andreassen, UK, Baer, S, Nielsen, TG. "Acute epiglottitis - 25 years experience with nasotracheal intubation, current management policy and future trends". J Laryngol Otol.. 1992. pp. 1072.

Wolf, M, Strauss, B, Kronenberg, J. "Conservative management of adult epiglottitis". Laryngoscope. 1990. pp. 183.

Franz, TD, Rasgon, BM, Quesenberry, CP. "Acute epiglottitis in adults. Analysis of 129 cases". JAMA.. 1994. pp. 1358.

Boscolo-Rizzo, P, Da Mosto, MC. "Submandibular space infection: a potentially lethal infection". Int J Inf Dis.. 2009. pp. 327.

Diagnosis

Rana, RS, Moonis, G. "Head and neck infection and inflammation". Radiol Clin N Am. 2011. pp. 165-82.

Hurley, MC, Heran, MK. "Imaging studies for head and neck infections". Infect Dis Clin N Am.. 2007. pp. 305.

Reynolds, SC, Chow, AW. "Life-threatening infections of the peripharyngeal and deep fascial spaces of the head and neck". Infect Dis Clin N Am. 2007. pp. 557-76.

Specific treatment

Brook, I. "Microbiology and principles of antimicrobial therapy for head and neck infections". Infec Dis Clin N Am.. 2007. pp. 355.

Rega, AJ, Aziz, SR, Ziccardi, VB. "Microbiology and antibiotic sensitivities of head and neck space infections of odontogenic origin". J Oral Maxillofasc Surg. 2006. pp. 1377.

Chen, KC, Chen, JS, Kuo, SW. "Descending necrotizing mediastinitis: A 10-year surgical experience in a single institution". J Thorac Cardiovasc Surg.. 2008. pp. 191.

Reynolds, SC, Chow, AW. "Severe soft tissue infections of the head and neck: A primer for the critical care physician". Lung. 2009. pp. 271-9.

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