Vancomycin therapy and the progression of methicillin-resistant Staphylococcus aureus vertebral osteomyelitis.

Abstract: Vancomycin therapy is the standard treatment for methicillin-resistant Staphylococcus aureus (MRSA), the most common cause of vertebral osteomyelitis, an increasingly frequent complication of nosocomial bacteremia. We report five recent cases suggesting that, while giving the appearance of success by conventional clinical and laboratory criteria (eg, resolution of fever and leukocytosis), vancomycin monotherapy may in fact be insufficient to prevent or reverse the progression of hematogenous MSRA vertebral osteomyelitis. A review of the literature and possible therapeutic alternatives are also discussed.

Key Words: Nosocomial bacteremia, Staphylococcus aureus, vancomycin, vertebral osteomyelitis

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Vertebral osteomyelitis is increasingly being reported as a complication of nosocomial bacteremia. (1) Staphylococcus aureus, often methicillin-resistant (MRSA), is the most common cause of vertebral osteomyelitis. (2) Intravascular catheter-related nosocomial bacteremia is an important source of MRSA vertebral osteomyelitis. (1) Vancomycin is the standard treatment for MRSA bacteremia. (3) Prolonged treatment courses (4 to 6 weeks) are recommended if a secondary focus of infection, such as osteomyelitis, is suspected. (3) We have recently encountered five patients with MRSA bacteremia who developed vertebral osteomyelitis and epidural phlegmon, or abscess with spinal cord compression and neurologic sequelae, despite intravenous (IV) vancomycin therapy. All five MRSA isolates were susceptible to vancomycin with a minimum inhibitory concentration (MIC) less than or equal to 1 [micro]g/mL. Vancomycin monotherapy of MRSA bacteremia may not prevent the development of, and may not be the optimal therapy for MRSA bacteremic vertebral osteomyelitis.

Case Reports

Patient 1:

An 88-year-old male patient developed complete heart block and had a permanent pacemaker placed in the left subclavian position. Two weeks later he developed fever, chills and flucturance of the pacemaker pocket and presented to our hospital. He denied neck pain, weakness, or skin infections. He had no history of staphylococcal infections, osteomyelitis, or valvular heart disease. On examination the patient was in no distress. Temperature was 100.7[degrees]F, respiratory rate of 17 breaths/min, blood pressure of 162/90 mm Hg and pulse of 72 beats/min. Head and neck examination was normal, with no neck stiffness or tenderness. Lungs were clear on auscultation. Heart examination showed no murmur, gallop, or rub. The pacemaker pocket was erythematous, tender, and flucturant. Neurologic examination was normal. Laboratory tests showed white blood cell count (WBC) of 19,300/m[m.sup.3] with 80% segmented neutrophils, 10% banded neutrophils, and 10% lymphocytes. Serum urea nitrogen was 15 mg/dL and serum creatinine was 0.9 mg/dL. Two sets of blood cultures and a culture of the pacemaker pocket aspirate grew MRSA susceptible to vancomycin with an MIC of 1 [micro]g/mL (MicroScan, Dade MicroScan, West Sacramento, CA). A transthoracic echocardiogram showed no valvular vegetations or regurgitant flow. The pacemaker and the intracardiac wires were removed and the patient received six weeks of IV vancomycin via a peripherally inserted central venous catheter (PICC). A trough serum vancomycin level was 14 [micro]g/mL. The patient defervesced in 48 hours and remained afebrile throughout the remainder of the hospital course. Elevated WBC normalized after four days of therapy. A new permanent pacemaker was placed in the right subclavian position after four weeks of vancomycin therapy. On day 35 of vancomycin therapy the patient complained of moderately severe neck pain on movement and at rest. Neurologic examination was normal and there was no cervical spine tenderness. Radiograph of the cervical spine showed advanced degenerative changes but no bone destruction. No computed tomographic (CT) scan of the cervical spine was performed. A soft cervical collar and acetaminophen with codeine were prescribed, with improvement in neck pain. The patient was discharged home after the completion of vancomycin therapy. He was able to walk but continued to complain of neck pain. No fever was reported at home. Three weeks later he had a sudden onset of quadriparesis and was brought to the hospital. The patient was awake and alert. Vital signs showed temperature of 99.7[degrees]F, pulse of 76 beats/min, blood pressure of 142/73 mm Hg and respiratory rate of 22 breaths/min. Physical examination demonstrated complete quadriplegia. Both old and new pacemaker sites showed no evidence of infection. Lungs were clear to auscultation and cardiac examination showed no murmur, rub, or gallop. Abdomen was soft and flat. Complete blood cell count showed WBC of 25,400/m[m.sup.3] with 88% segmented neutrophils and 12% lymphocytes. Chemical profile was unremarkable. Two sets of blood cultures subsequently grew MRSA with MIC to vancomycin of 1 [micro]g/mL. A CT scan of the cervical spine showed a nearly complete destruction of C6 and C7 vertebrae with epidural and retropharyngeal abscess, and spinal cord compression. Chest radiograph was clear. Vancomycin and ceftriaxone were administered intravenously, and an emergency surgery was arranged, but the patient suffered a cardiopulmonary arrest and could not be resuscitated. Permission for a postmortem examination was denied by the family.

Patient 2:

A 45-year-old male patient with a history of poorly controlled insulin-requiring diabetes mellitus presented to his private physician's office complaining of a two-week history of "boils" in his groin that had spontaneously drained purulent material. He had subjective fever, chills, and mild abdominal discomfort. Evaluation in the emergency room revealed a temperature of 101.5[degrees]F. The patient was obese and had a nondraining, nonfluctuant carbuncle in the perineal area. Abdominal examination and the remainder of the physical examination were normal. WBC was 17,800/m[m.sup.3]. A nonfasting blood glucose level was 155 mg/dL. Renal and hepatic function tests were within normal limits. Chest radiograph and abdominal ultrasound were normal. A CT scan of the pelvis was normal except for nonspecific soft tissue swelling in the area of the carbuncle. IV levofloxacin, 500 mg daily, was begun, and the patient was admitted to the hospital. Temperature increased to 103.5[degrees]F. Infectious diseases consultation was requested. Physical examination was unchanged. IV vancomycin 1,250 mg every 12 hours and piperacillin/tazobactam 4.5 g intravenously every 6 hours were added. The patient defervesced over the next 24 hours. Admission blood cultures were reported as growing MRSA in two sets. Vancomycin MIC was 1 [micro]g/mL. On day 3 of the hospitalization, the carbuncle was incised and drained. The Gram stain of the operative culture revealed Gram-positive cocci in clusters, but the culture revealed no growth. Erythrocyte sedimentation rate (ESR) was 50 mm/h. Transthoracic echocardiogram showed no valvular vegetations or regurgitant flow. Patient complained of a mild mid-thoracic back pain and a triple-phase technetium bone scan was performed. It showed only degenerative changes in the cervical and thoracic spine. Piperacillin/tazobactam and levofloxacin were discontinued. A PICC line was inserted and the patient was discharged to complete a 14-day course of IV vancomycin. Vancomycin trough level was 12 [micro]g/mL. After 10 days of vancomycin therapy, ESR decreased to 38 mm/h. Vancomycin therapy was extended to 21 days total. After 21 days of vancomycin therapy the patient remained afebrile, and the area of surgical incision was healed. The PICC line was removed, and vancomycin was discontinued. Several days before the completion of vancomycin therapy, the patient again developed back pain. He did not report this to his physicians, but consulted a chiropractor who reviewed the report of the bone scan "to be sure that there was no infection in his back." The patient then had several chiropractic treatments. The day after his last dose of vancomycin, he complained of sudden onset of bilateral leg weakness and numbness and was unable to ambulate. He presented to the emergency department where he had no fever, but was found to have paraplegia and a sensory level compatible with an upper thoracic level spinal cord defect. Body size precluded magnetic resonance imaging. A myelogram suggested a T4 epidural abscess. IV vancomycin 1,500 mg every 12 hours, ceftazidime 2 g intravenously every 8 hours, rifampin 600 mg orally every 12 hours, and dexamethasone 10 mg intravenously every 6 hours were administered. On the evening of the third hospital day the patient was taken to the operating room by a team of neurosurgeons and thoracic surgeons. Acute and chronic vertebral osteomyelitis of T4, T5, and T6 vertebrae with spinal cord compression by the collapsed vertebrae was found. The involved vertebrae were debrided and fused. Admission blood cultures and operative bone cultures grew MRSA with vancomycin MIC of 1 [micro]g/mL. The isolate was also susceptible to rifampin and trimethoprim/sulfamethoxazole. Ceftazidime was discontinued and trimethoprim/sulfamethoxazole 160/800 mg orally twice daily was added. The patient had gradual neurologic improvement after a prolonged period of physical rehabilitation. Vancomycin was given for 56 days and trimethoprim/sulfamethoxazole and rifampin were continued for 12 months. The patient was able to ambulate with assistance and had no evidence of recurrence of infection after twelve months.

Patient 3:

A 69-year-old patient was admitted for elective reversal of colostomy. He had a history of diverticulitis and pelvic abscess with mixed enteric flora (no MRSA), requiring a Hartmann procedure. Past medical history was positive for mild hypertension and noninsulin-requiring diabetes mellitus for the last 4 years controlled with glipizide. Piperacillin/tazobactam was given perioperatively. Postoperatively the patient developed fever and left arm septic phlebitis at the site of a peripheral IV line. Blood cultures grew MRSA susceptible to vancomycin (MIC 1 [micro]g/mL), trimethoprim/sulfamethoxazole, rifampin, tetracycline, clindamycin, and linezolid. Vancomycin 1 g intravenously every 12 hours was started and piperacillin/tazobactam discontinued. Left arm swelling, induration, and tenderness persisted, and a Doppler ultrasound showed left cephalic vein thrombus. On day 4 of vancomycin, surgical incision and drainage of the left arm antecubital fossa abscess as well as excision of the left cephalic vein were performed. Operative cultures grew MRSA with the same susceptibilities. The patient defervesced over the next three days. Vancomycin levels were 20 [micro]g/mL peak and 9.1 [micro]g/mL trough. On day 13 of vancomycin therapy, C-reactive protein level was 14 mg/dL and ESR was 96 mm/h. The patient remained afebrile with normal WBC counts. On day 21 of vancomycin therapy the patient complained of cervical pain and was given celecoxib orally with good relief. X-ray of the cervical spine showed mild degenerative changes. On day 28 of vancomycin C-reactive protein level decreased to 11 mg/dL and ESR decreased to 89 mm/h. Infectious diseases consultant recommended completing six weeks of vancomycin therapy. On day 32 of vancomycin therapy, neck pain recurred and was treated with a heating pad, celecoxib, and cyclobenzaprine. Neurologic evaluation was normal. Pain secondary to degenerative spine disease was diagnosed and physical therapy and ultrasound treatments were prescribed. On day 36 of vancomycin therapy, ESR increased to 112 mm/h but C-reactive protein level decreased to 6.1 mg/dL. Pain worsened, and on day 37 of vancomycin a CT scan of the cervical spine showed destruction of C3 and C4 vertebrae with a narrowing of the spinal canal. Magnetic resonance imaging (MRI) showed C3 and C4 osteomyelitis with associated extensive epidural and paraspinal phlegmon. Shortly after the MRI the patient developed quadriplegia. Blood cultures obtained at this point revealed no growth. C3 and C4 anterior corpectomy with C2 to C5 iliac crest bone graft with anterior arthrodesis was performed. An epidural phlegmon, but no abscess, was found. The dura was pulsatile and was not entered at surgery. Operative cultures grew MRSA with the same susceptibilities as previous isolates. Postoperatively, patient remained quadriplegic and was treated with vancomycin and rifampin 600 mg orally daily for 56 days. Transthoracic echocardiogram showed no valvular vegetations or regurgitant flow. There has been no evidence of infection recurrence after the completion of therapy.

Patient 4:

A 71-year-old female patient was admitted to the hospital with bilateral leg weakness. She had a history of essential hypertension and a cerebrovascular accident. There was no history of fever, chills, headache, or skin rash. Vital signs, including temperature, were normal. Physical examination showed bilateral leg weakness with decreased reflexes. MRI of the lumbar spine without IV contrast showed an L4-L5 posterior bulging disk and unremarkable vertebral bodies. CT scan of the head and MRI scan and magnetic resonance angiography of the head showed only old white matter disease. Chest radiograph was normal. Transthoracic echocardiography showed no vegetations or regurgitant blood flow. Complete blood count, urinalysis, and chemistry profile were normal. A preliminary diagnosis of Guillain-Barre syndrome was made. A right femoral venous catheter was placed and a course of plasmapheresis sessions initiated. The patient was discharged to a physical rehabilitation facility to continue plasmapheresis, but after eight days she developed fever of 103[degrees]F and chills, and was transferred back to the hospital. Physical examination was positive for bilateral leg weakness and a right inguinal venous catheter with a small amount of purulence at the insertion site. WBC was 17,000/m[m.sup.3]. Serum creatinine was 0.7 mg/dL. Urinalysis was normal. Blood cultures were drawn and the catheter was removed and cultured. Vancomycin 1 g intravenously every 12 hours was started. The patient defervesced over the next 24 hours and remained afebrile thereafter. WBC count decreased to normal after 72 hours. Both sets of blood cultures and a catheter tip culture (more than 15 colonies) eventually grew MRSA sensitive to vancomycin with MIC of 1 [micro]g/mL. West Nile viral serologies were ordered and eventually returned positive (IgG and IgM). A spinal cord MRI scan without IV contrast was performed on day 7 of vancomycin and was negative. On day 8 of vancomycin therapy the patient was discharged to the physical rehabilitation facility to complete 14 days of vancomycin. Vancomycin trough level was 19.2 [micro]g/mL. No follow-up blood cultures were done after the completion of vancomycin. Three weeks after the last dose of vancomycin the patient began complaining of mid-thoracic back pain. She had no fever, chills, or leukocytosis. MRI study of the thoracic spine showed T9-T10 diskitis with vertebral osteomyelitis and paraspinous and epidural phlegmon, but no spinal cord compression. A culture of the needle biopsy specimen of the involved area grew MRSA with the same susceptibility pattern. Blood cultures were negative. The patient received 56 days of therapy with vancomycin intravenously 1,250 mg daily and rifampin 600 mg orally daily. A repeat MRI after 10 days of therapy showed no change. Pain gradually diminished and patient demonstrated increasing muscle strength in both legs. At the end of antibiotic therapy she was able to walk with a walker.

Patient 5:

A 53-year-old, morbidly obese female patient underwent a gastric bypass surgery, Postoperatively, she developed fever and MRSA susceptible to vancomycin was isolated from two sets of blood cultures. Central venous line was removed at the onset of fever, and the catheter tip also grew MRSA (greater than fifteen colonies). IV vancomycin was started and the patient defervesced in 24 hours. Adequate vancomycin serum levels (peak, 23 [micro]g/mL; trough, 6 [micro]g/mL) were documented. Vancomycin was continued for fourteen days after the removal of the central venous line. Three weeks after the completion of vancomycin therapy, the patient presented with back pain and a low-grade fever. She rapidly developed paraplegia and the MRI showed T8-T9 diskitis and osteomyelitis of both vertebrae, and an epidural abscess with spinal cord compression. A T7-T9 laminectomy was performed and MRSA susceptible to vancomycin was isolated on culture. Two sets of blood cultures also grew MRSA. A transthoracic echocardiography showed no evidence of endocarditis. The patient was treated with vancomycin and rifampin and transferred to a rehabilitation facility. She has remained paraplegic.

Discussion

A remarkable feature of our patients' clinical course is the failure of IV vancomycin to prevent the development and progression of vertebral osteomyelitis due to MRSA, despite the in vitro susceptibility of the isolates and apparent clinical response of bacteremia with defervescence and resolution of leukocytosis. No alternative source of vertebral seeding (eg, endocarditis) was apparent in any of our patients. While transesophageal echocardiography was not performed, none of the patients had any clinical evidence of endocarditis and transthoracic echocardiogram was normal.

Vancomycin monotherapy of MRSA osteomyelitis is recommended in a recent review of osteomyelitis by Lew and Waldvogel, (2) and in a standard infectious diseases textbook. (3) Few data are available, however, on the success rate of vancomycin therapy in MRSA vertebral osteomyelitis.

Aspinall et al (4) have reported a patient with MRSA vertebral osteomyelitis who was treated with six weeks of IV vancomycin with resolution of fever, back pain, and elevated ESR. The patient relapsed two days after the completion of vancomycin therapy with back pain, MRSA bacteremia, and a worsening radiographic appearance of the vertebrae. He was successfully retreated with eight weeks of vancomycin, rifampin and low-dose gentamicin. Serum inhibitory and bactericidal titers were used to confirm effective therapy.

Khatib et al (5) have reported two patients with protracted and recurrent MRSA bacteremia despite defervescence with vancomycin therapy. Both MRSA isolates demonstrated reduced vancomycin killing rates in time-kill studies compared with a control isolate. One of the patients developed vertebral osteomyelitis and a spinal epidural abscess after 38 days of vancomycin therapy. Bacteremia cleared in both patients after the addition of gentamicin.

Torda et al (1) have reported a series of twenty patients with pyogenic vertebral osteomyelitis, including six patients with MRSA infection. All six infections were nosocomially acquired, and four out of the six were intravascular catheter infection-related. Two out of the six patients with MRSA relapsed and were successfully retreated. Among them was a patient with MRSA bacteremic line infection who was treated with 2 weeks of IV vancomycin. Back pain developed on day five of therapy, but technetium bone scan was negative. The patient later relapsed with a T10-T11 vertebral osteomyelitis. Prolonged courses of therapy with vancomycin and oral fusidic acid and rifampin resulted in the recovery of this patient. All of the patients with MRSA infection in their report were treated with IV vancomycin, followed by prolonged courses of oral antibiotics (rifampin and fusidic acid or ciprofloxacin).

Priest and Peacock, (6) in a preliminary report, demonstrated that factors associated with failure of therapy of hematogenous vertebral osteomyelitis due to S aureus included MRSA etiology, duration of parenteral therapy less than eight weeks, and failure to administer oral continuation therapy.

Vancomycin concentrations achievable in the bone may not be adequate, as shown by Graziani et al. (7) Adherent growth of MRSA on bone may prevent vancomycin bactericidal effect. (8) The MRSA isolates in our series were not available for tolerance or heteroresistance testing, but all had MICs to vancomycin of less than or equal to 1 [micro]g/mL. Although the value of routine vancomycin serum levels has been questioned, all of our patients had adequate serum levels. (9)

A new back pain was the only manifestation of developing vertebral osteomyelitis in four of our five patients. The significance of this symptom was underestimated by the treating physicians because of the resolution of fever and leukocytosis. We want to emphasize that the onset of back pain in any patient under treatment for staphylococcal bacteremia should be interpreted with concern and thoroughly evaluated. Secondary septic foci are common in S aureus bacteremia. (3) Ringberg et al (10) have performed an extensive investigation for secondary septic foci in patients with S aureus bacteremia. They were able to document secondary septic foci in 36 (53%) of 68 consecutive patients with S aureus septicemia, including 18 patients (26%) with involvement of bones.

Our experience and review of the literature suggest that vancomycin monotherapy may not be the best option in managing MRSA hematogenous vertebral osteomyelitis. Tice et al (11) have recently reported that vancomycin therapy is associated with high failure rate in the treatment of methicillin-sensitive S aureus osteomyelitis, as compared with [beta]-lactam antibiotics. This may be related to a limited bactericidal activity of vancomycin, limited bone penetration, or other unknown factors. Similar limited therapeutic efficacy of vancomycin has previously been reported in cases of endocarditis and pneumonia, both MRSA and methicillin-sensitive S aureus (MSSA). (12-14) The best combination of antibiotics for MRSA osteomyelitis is unknown. Vancomycin and rifampin with or without low-dose gentamicin is one possible option. (4) Rifampin was used in combination with vancomycin for retreatment in three of the patients in our series with good results. However, Khatib et al (5) reported a patient who continued to be bacteremic and developed a spinal epidural abscess while receiving vancomycin and rifampin.

Optimal duration of therapy for staphylococcal vertebral osteomyelitis is also unknown. A minimum of eight weeks of therapy may be necessary. (15) A long-term (12 weeks or longer) oral regimen to follow the completion of IV vancomycin should also be considered. Minocycline or trimethoprim/sulfamethoxazole, each in combination with rifampin, are possible options. Fusidic acid is not marketed in the United States, but is an option where available. (1) Linezolid is a more recent oral alternative, but is bacteriostatic against MRSA, and published experience with use in cases of osteomyelitis is limited. (16)

Conclusion

Patients with MRSA bacteremia should be carefully monitored for the symptoms of spine infection during and after therapy. Monotherapy of MRSA bacteremia with vancomycin, while apparently successful by conventional clinical and laboratory criteria, may not prevent the development of vertebral osteomyelitis. The onset of back pain may represent a secondary focus of infection and deserves careful clinical, laboratory, and radiographic investigation.

Accepted February 5, 2004.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0593

References

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RELATED ARTICLE: Key Points

* Vancomycin therapy of methicillin-resistant Staphylococcus aureus bacteremia may not prevent the development of hematogenous vertebral osteomyelitis.

* Resolution of fever and leukocytosis during vancomycin therapy of MRSA bacteremia may not be a reliable indication of the absence of hematogenous seeding of the spine.

* Back pain may be the earliest and only sign of the development of MRSA hematogenous vertebral osteomyelitis during vancomycin therapy for MRSA bacteremia.

* Vancomycin monotherapy may not prevent the progression of MRSA vertebral osteomyelitis.

Michael S. Gelfand, MD, and Kerry O. Cleveland, MD

From the Methodist University Hospital of Memphis, Memphis TN.

Reprint requests to Michael S. Gelfand, MD, 6369 Massey Manor Cove, Memphis, TN 38120. Email: [e-mail]