Author: Baugher, Katherine M
Date published: February 1, 2011
Methicillin-resistant Staphylococcus aureus (MRSA) presents a host of clinical problems, including identification (commonly after initial treatment failure), increasing incidence, broadening drug resistance, and colonization resulting in its spread and recurrence. As the number of MRSA infections rises, the incidence of head and neck MRSA infections is also rising, as evidenced by a 16.3% increase in pediatric head and neck MRSA infections from 200 1 to 2006. ' Otologic infections were found most frequently (34%), with smaller percentages of sinonasal (28.3%) and oropharynx/neck (14.2%) infections.1
A range of monotherapy and combination therapies has been employed by physicians for the treatment of MRSA, some of which are often no longer effective. This study of three patients with MRSA otorrhea treated between 2007 and 2009, along with a literature review of the current treatment options and recommendations for MRSA otorrhea, highlights concepts that are of practical importance for anyone caring for patients with otorrhea.
Patient 1. A 56-year-old man presented with left otalgia and otorrhea 5 weeks after right (contralateral) total stapedectomy with oval window graft, tympanoplasty, and myringotomy tube placement. An old myringotomy tube was present on the left and had not been changed during the recent surgery. The patient had a history of chronic bilateral ear infections, cholesteatoma and mastoidectomy as a teenager, multiple myringotomy and tube placements, and ossicular reconstruction surgery 8 years previously. He had been free of infection in either ear at the time of his surgery.
When this patient presented with infection, his left tympanic membrane had a myringotomy tube in place, and the infection originated in his middle ear. Culture and sensitivity of the left ear fluid was obtained, and the patient was empirically started on ofloxacin drops. The fluid was suctioned from the ear canal and from the middle ear through the tube. Suction was repeated frequently until the otorrhea resolved. The culture revealed MRSA with drug sensitivities (table 1). Linezolid 600 mg twice daily for 10 days was prescribed, and his previous medication was discontinued.
Approximately 3 months later, the patient returned with bilateral otorrhea. Cultures and sensitivities were obtained with bilateral MRSA results identical to those from the previous culture. He was treated with linezolid 600 mg twice a day for 3 weeks and gentamicin drops three times a day. A week later the right ear was dry, while the left ear had a wet discharge. The linezolid course was continued for a total of 3 weeks, and gentamicin application to the left ear was continued for 1 more week. Follow-up cultures did not reveal MRSA. He has been free of MRSA infection for 22 months.
Patient 2. In 2007, a 67-year-old man underwent right tympanomastoidectomy. Two weeks after surgery, he complained of right otorrhea. His history included multiple ear surgeries and infections beginning in the 1980s, a mastoidectomy for cholesteatoma in 2001, and ossicular chain reconstruction in 2002.
The external auditory canal wall and eardrum were intact, but the infection involved the middle ear and ear canal. The mastoid was not tender, erythematous, or bulging. Culture revealed MRSA with the same sensitivities as Patient 1 and Patient 3 (table 1), and he began a 4-week course of vancomycin. Fluid was suctioned at 1- to 2-week intervals. A week after the completion of the vancomycin treatment, the patient's right ear was improved but not completely dry. He was started empirically on acetic acid drops. A second culture yielded MRSA along with Klebsiella pneumoniae.
Following the culture results, acetic acid was discontinued and a 4-week course of gentamicin drops three times daily was prescribed. At a 2-week follow-up visit, a prescription of trimethoprim/sulfamethoxazole (TMP/SMX) 1 60mg/800 mg twice daily for 6 weeks was added, which was later reduced to once daily because of constipation. The infection resolved following completion of the combination treatment. There has been no recurrence in the subsequent 22 months.
Patient 3. A 55-year-old woman was referred with right otorrhea and sensorineural hearing loss. She also complained of light-headedness and intermittent clicking noises in her right ear. Eight months previously, she had been hospitalized for streptococcal meningitis secondary to suppurative otitis media complicated by a cerebrovascular accident. Prior to her hospitalization, she had denied any history of ear infections, hearing loss, tinnitus, or vertigo. Computed tomography of this patient's temporal bones revealed right mastoiditis, and magnetic resonance imaging revealed a "mass" in her right internal auditory canal, along with mastoiditis. Previous treatment for her otorrhea had included 2 weeks of tobramycin/dexmethasone and a combination of ofloxacin drops and cefuroxime.
Examination revealed a right anterior tympanic membrane perforation with mild otorrhea. The ear was totally deaf. The patient was started empirically on a 10-day course of tobramycin/dexmethasone drops and levofloxacin 750 mg daily. The levofloxacin was stopped when culture results identifying MRSA were received, and she began TMP/SMX 160 mg/800 mg twice daily for 2 weeks. Sensitivities are listed in table 1 . Two weeks from the initial referral, the patient underwent a right tympanomastoidectomy with planned staged reconstruction and myringotomy.
Two months after the surgery, the patient developed right otorrhea and initially was started on a 1 0-day course of tobramycin/dexmethasone drops, and levofloxacin 750 mg daily for 1 week, while awaiting her culture results. The graft was intact. Frequent suction was used to keep the ear as free of purulence as possible. The results demonstrated MRSA with the aforementioned susceptibilities. Her previous medications were discontinued, and she was started on 2 weeks of linezolid 600 mg twice daily and gentamicin drops, three times a day. Her otorrhea resolved, but 3 days after completing the course of antibiotics she developed otorrhea, otalagia, and imbalance. Linezolid 600 mg twice a day and gentamicin drops three times daily for 1 month were prescribed.
Three months later she developed thick, clear otorrhea and a new anteroinferior perforation. Cultures and sensitivities were identical to previous cultures. The therapy initially included sulfacetamide drops three times a day for 3 weeks, and linezolid 600 mg twice a day for 1 month. She continued the course of prescribed sulfacetamide drops, and the otorrhea resolved.
Two months later, this patient's right ear began to drain again, and she noted mild imbalance. She was started on linezolid 600 mg twice daily for the next month along with gentamicin, three drops three times daily, for presumed MRSA otorrhea, but the culture was negative for MRSA and grew only normal skin flora.
Approximately 1 year after she underwent tympanomastoidectomy, she presented to the office with right mastoiditis. A culture revealed no organisms other than normal skin flora. She was started on ciprofloxacin 500 mg twice daily and ofloxacin drops. A week later, she was taken to the operating room, where she underwent a right revision mastoidectomy, drainage of purulence, and removal of a right mastoid titanium plate. MRSA was not present at the time, and the patient has remained free of MRSA infection and otorrhea from any other cause for 21 months.
In light of the increasing incidence of MRSA otorrhea and the rising resistance to common MRSA treatments, familiarity with current and anticipated treatment options is vital for expethent otolaryngologic treatment.
The current nomenclature divides MRSA into two types: healthcare-associated (HA-MRSA) and community-acquired (CA-MRSA). Initially, MRSA was responsible for nosocomial infections and referred to as HA-MRSA.2 Risk factors for nosocomial MRSA include prolonged hospitalization, care in an intensive care unit, prolonged antimicrobial therapy, surgical procedures, and close proximity to a patient infected or colonized with MRSA.3 In the past decade, CA-MRSA has been isolated in the outpatient setting, in young, healthy individuals without any healthcare association.4 CAMRSA has been associated with soft-tissue infections and necrotizing pneumonia,4 as well as less multidrug resistance than HA-MRSA2 but higher growth rates.5 The Centers for Disease Control and Prevention (CDC) requires all of the following to establish a diagnosis of CA-MRSA6-.
LA culture obtained either outpatient or within 48 hours of hospital admission;
2. No history of MRSA infection or colonization;
3. No history of hospitalization, dialysis, surgery, or admittance to a nursing home, skilled nursing facility, or hospice within one year; and
4. No permanent catheter or other device that passes through the skin and into the body.
The antibiotic profile is also commonly referred to for MRSA designation, typically indicating clindamycin susceptibility as CA-MRSA.7 Distinguishing between CA-MRSA and HA-MRSA is not always straightforward, since colonization might have been present over a period of time, thus obscuring the source.2,4
Common MRSA algorithms categorize separate treatment options for mild to moderate or severe infections, along with consideration of whether a patient has healthcare risk factors.4 An algorithm by the American Academy of Pediatrics for CA-MRSA infections qualifies patients with mild infection as afebrile and previously healthy, those with moderate infections as febrile and previously healthy, and those with severe infections as toxicappearance, immunocompromised, or limb-threatening and requiringhospitalization. The treatment of moderate infections can follow the recommendations for mild or severe infections at the discretion of the clinician.8
Mild to moderate infections
TMP/SMX and clindamycin are the most commonly used first-line agents for mild to moderate CA-MRSA otorrhea.9 TMP/SMX remains an effective monotherapy and maintains high susceptibility rates,1" 'a although combination therapy has been recommended.14 Combinations of TMP/SMX with gentamicin, polymyxin B/neomycin/hydrocortisone, or ofloxacin have proven effective in MRSA otorrhea treatment.12 However, the high incidence of resistance to aminoglycosides and quinolones may cause such combinations to be unpredictable.15 Additionally, higher rates of TMP/SMX resistance have been found in patients infected with HIV, not surprisingly, due to the use of TMP/SMX for Pneumocystitis prophylaxis.
Given the low resistance rates to rifampin and its successful use in combination therapy,111517 a study of TMP/SMX and rifampin might be useful for acute otitis media with otorrhea.12 TMP-SMX has been recommended as a first-line treatment for MRSA after tympanostomy-tube placement along with tobramycin/ dexmethasone and chloramphenicol drops.18 However, we remain cautious about using ototoxic drops when the eardrum is not intact.
Literature reports indicate increasing clindamycin resistance in the United States1,12,19 and even higher resistance in Korea and Taiwan, where the highest rates of CA-MRSA are reported (table 2).15,20 22 The SENTRY Antimicrobial Surveillance Program determined that only 20.8% of all MRSA isolates in the United States (1997-1999) were susceptible to clindamycin.13 Geographical regions in which CA-MRSA isolates demonstrate >10 to 15% resistance to clindamycin necessitate replacing empiric clindamycin treatment with TMP/ SMX 814 or another antibiotic. Because of the rising resistance, clinical trials of clindamycin and rifampin combination therapy for otorrhea may be a worthwhile consideration. Infections that have failed treatment with clindamycin or TMP/SMX can be treated with vancomycin or linezolid.14,23
A global, multicenter study in 2004 reviewed susceptibilities of MRS A isolates to fluoroquinolone treatment, showing the lowest susceptibility in North America, where ciprofloxacin and levofloxacin demonstrated <6% susceptibility.24 Interestingly, the use of ciprofloxacin and levofloxacin has been associated with MRSA infection occurrence, and studies propose that their use increases the risk of infection or colonization with MRSA via an undetermined mechanism.25 The usefulness of fluoroquinolone treatment now seems to be very limited because of the prevalence of resistant strains.12,14,15,18,23
Recent publications reveal the usefulness of acetic acid and other cleansing agents for use as monotherapy or combination therapy for MRSA otitis.2'' Aural cleansing with diluted acetic acid was shown to be a more desirable choice for the treatment of chronic MRSA suppurative otitis media than intravenous vancomycin or teicoplanin, having similar efficacy and treatment duration.27 Burow's solution was found to be effective for treatment of MRSA and intractable chronic ear infections,26,28 as well as reducing granulation tissue.26 Fusidic acid (widely used in Europe but not available in the United States) was reportedly a very effective topical and parenteral therapy,20,21,29 with currently reduced usefulness in Europe due to high levels of resistance from its widespread use as a monotherapy.29 Fusidic acid susceptibility remains very high in other parts of the world.15 Typically, fusidic acid is combined with rifampin to help avoid resistance.30
Moderate to severe infections
Treatment options for moderate to severe MRSA infections, including otorrhea, encompass a group of highly effective anti-MRSA agents. Vancomycin is recommended as the first-line agent for severe MRSA, as culture sensitivities remain extremely high (table 2) 15.20-22 However, as evidenced by the current study, vancomycin is not an infallible agent even if culture sensitivities indicate susceptibility. Along with the standard parenteral administration, vancomycin can be used successfully as a topical preparation or in combination with naficillin, rifampin, or gentamicin, which are recommended when vancomycin monotherapy is unsuccessful.14,31'33 The combinations of rifampin or gentamicin with vancomycin are synergistic and useful in treatment of severe infections.15,34
Although vancomycin has been the gold standard for severe MRSA infections, resistance to vancomycin has been growing.30 This rise has been attributed to the transfer of vancomycin resistance from vancomycinresistant enterococci.34'36
For vancomycin-resistant infections, a group of highly effective drugs are used sparingly to retain high susceptibility for severe infections. Linezolid is considered equivalent to vancomycin,15,22 has an oral formulation,23 and is the only antibiotic in this group approved for children.14 An in vitro study examining linezolid combination therapy found that the addition of rifampin was additive in rifampin-sensitive MRSA strains, whereas gentamicin and vancomycin caused decreases in efficacy.37
Although linezolid is generally well tolerated, with the most common side effect being diarrhea,8 there have been reports of peripheral neuropathy, thus limiting its use in most cases to no more than 4 weeks in adults and 2 weeks in children.14,34 Vitamin B6 can be used to prevent and treat linezolid-induced thrombocytopenia, anemia, and leukopenias associated with extended administration.8,38
In vitro studies have shown extremely promising results for daptomycin, which allows for a shorter treatment duration than vancomycin.1*39'40 The efficacy of quin upristin/dalfopristin is also comparable to vancomycin in treating skin and soft-tissue infections.41 However, it is not as successful in complete eradication and has a high rate of adverse drug reactions, such as infusion site pain, which can occur in as many as 68% of patients.42
Other agents useful for vancomycin failure include teicoplanin and tigecycline.15,43 Teicoplanin is not available in the United States and has a mechanism of action similar to that of vancomycin.36 Its advantages are that it is generally well tolerated, lacks the renal monitoring required for the potential nephrotoxic effects of vancomycin, and may be administered intramuscularly.34,36 A phase III randomized, double-blinded study comparing tigecycline and vancomycin for the treatment of complicated MRSA skin and soft-tissue infections found clinical cure to be similar, but with almost double the incidence of nausea and vomiting with tigecycline versus vancomycin.44
Interesting MRSA treatments are in various stages of animal or clinical testing. The first cephalosporins ef fective against MRSA, ceftobiprole and ceftaroline, look very promising, with ceftobiprole showing effectiveness similar to that of vancomycin and linezolid. Dalbavancin, iclaprim, oritavancin, and telavancin have all done well in trials, with success rates similar to those of the comparator. Several antibody therapies are also in clinical trials that might provide immunity to MRSA infections in the future.34 With new drug options, trials of various types of combination therapies are ongoing and should continue in an effort to protect the efficacy of important drugs.
In summary, MRSA otorrhea can be treated successfully using combination therapy based on individual culture sensitivities and/or a current knowledge of local strains. Recommended first-line treatments are combination therapies, including TMP/SMX for mild to moderate infections and vancomycin or linezolid for more severe infections. High rates of resistance to fluoroquinolones and clindamycin make them inferior choices as empiric treatment for suspected MRSA. Cost-effective treatments, including acetic acid and fusidic acid, can be used effectively in combination therapy. There is a group of highly effective drugs recommended for use in the most severe cases, including vancomycin-resistant infections. Otolaryngologists should be familiar not only with current options but also emerging advances for the treatment of this potentially serious infection.
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Katherine M. Baugher, MS; Troy Sommers Hemme, DO; Mary Hawkshaw, RN5 BSN, CORLN; Robert T. Sataloff, MD, DMA, FACS
From the Department of Otolaryngology- Head and Neck Surgery, Philadelphia Collegeof Osteopathic Medicine (Ms. Baugher and Dr. Hemme), and the Department of Otolaryngology-Head and Neck Surgery, Drexef University College of Medicine (Ms. Hawkshawand Dr. Sataloff), Philadelphia.
Corresponding author: Robert T. Sataloff, MD, DMA, FACS, 1721 Pine St., Philadelphia, PA 19103. E-mail: firstname.lastname@example.org