Drugs and aging 16: 67-80, jan 2000

Drugs & Aging 2000 Jan; 16 (1): 67-80 Adis International Limited. All rights reserved.
Bone and Joint Infections in the Elderly
Practical Treatment Guidelines

Jon T. Mader,1,2,3 Mark E. Shirtliff,1,4 Stephen Bergquist5 and Jason H. Calhoun1,3 1 The Marine Biomedical Institute, Division of Marine Medicine, University of Texas Medical 2 Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical 3 Department of Orthopaedic Surgery, University of Texas Medical Branch, Galveston, Texas, USA 4 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, 5 Department of Pharmacy, University of Texas Medical Branch, Galveston, Texas, USA Contents
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 1. Haematogenous Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 1.1 Vertebral Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 1.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681.1.2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691.1.3 Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 1.2 Haematogenous Long Bone Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 1.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691.2.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701.2.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 2. Contiguous Focus Osteomyelitis Without Generalised Vascular Insufficiency . . . . . . . . . . . . 733. Contiguous Focus Osteomyelitis With Generalised Vascular Insufficiency . . . . . . . . . . . . . . 73 3.1 Diabetic Foot Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733.2 Extension of External Otitis Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 4. Osteoporosis and Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745. Joint Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 5.1 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755.2 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 6. Antibacterial Adverse Effects in The Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767. Summary and Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Abstract
Two types of haematogenous osteomyelitis that are seen in the elderly are vertebral and long bone osteomyelitis. Osteomyelitis secondary to contiguousfoci of infection can occur in older adults without vascular insufficiency (second-ary to pressure ulcers) or with vascular insufficiency due to diabetes mellitus orperipheral vascular disease from atherosclerosis. Most cases of osteomyelitis canbe reasonably treated with adequate drainage, thorough debridement, obliterationof dead space, wound protection, and antimicrobial therapy. Patients are initiallygiven a broad spectrum antimicrobial that is changed to specific antimicrobial therapy based on meticulous bone cultures taken at debridement surgery or fromdeep bone biopsies. Surgical management is often required in the treatment ofosteomyelitis and includes adequate drainage, extensive debridement of all ne-crotic tissue, obliteration of dead spaces, stabilisation, adequate soft tissue cov-erage, and restoration of an effective blood supply.
Bone repair and bone mineral density may be significantly retarded and may be corrected by eliminating risk factors, supplementing the diet with calcium,bisphosphonates, and/or vitamin D, and treating with testosterone and/or estrogenwhen deficient. Sodium fluoride treatment and anabolic steroids may be used asalternatives.
Septic arthritis is a medical emergency, and prompt recognition and rapid and aggressive treatment are critical to ensuring a good prognosis. The treatment ofseptic arthritis includes appropriate antimicrobial therapy and joint drainage.
Adverse effects of prescribed antibacterials occur more often in the elderly patient than in young adults. The physician can help to minimise the incidenceof adverse effects and improve outcomes by being aware of the principles ofclinical pharmacology, the characteristics of specific drugs, and the special phys-ical, psychological and social needs of older patients.
The elderly are more susceptible than younger enous osteomyelitis seen in the elderly are verte- adults to a number of infections, and therefore they may be considered immunocompromised. Althoughnormal bone and joints in the elderly are resistant to infection, osteomyelitis and infectious arthritis 1.1.1 Epidemiology
can occur from a large inoculation of organisms, Vertebral osteomyelitis in the elderly population trauma leading to bone damage, or the presence of is usually haematogenous in origin but may be sec- foreign bodies. However, the risk of infection in- ondary to trauma. The lumbar vertebral bodies are creases with the presence of pre-existing medical most often involved, followed in frequency by the conditions which locally and/or systemically com- thoracic and cervical vertebrae. The infection is usu- ally monomicrobic when haematogenous in origin.
Infection of the bone may occur either second- Whereas Staphylococcus aureus remains the most ary to haematogenous spread of infection or a con- commonly isolated organism, aerobic Gram-negative tiguous focus of infection. Contiguous focus osteo- rods are isolated in 30% of cases. Common primary myelitis can be subdivided into those occurring inthe presence or absence of generalised vascular in-sufficiency. Osteomyelitis in the elderly is often Table I. Systemic and local factors that affect immune surveillance,
subtle or atypical in presentation compared with that in infants, children and young adults. Aggres- sive diagnosis, and antimicrobial and surgical ther- apy can result in successful management of this Small and medium vessel disease Renal or hepatic failure 1. Haematogenous Osteomyelitis
Haematogenous osteomyelitis accounts for 20% Tobacco abuse (∫2 packs per day) Immune disease of the total cases of osteomyelitis and is more com- mon in males of any age. Two types of haematog- Ó Adis International Limited. All rights reserved.
sources of infection in the elderly include the geni- surgical drainage (sometimes emergently) is nec- tourinary tract, skin and soft tissue, respiratory tract, essary. Surgical stabilisation in the form of fusion infected intravenous catheter sites, postoperative of vertebrae is not recommended in routine cases, wound infections, endocarditis or dental infection.
since spontaneous bony fusion often occurs after However, the primary infection focus frequently months or years with appropriate therapy. Other remains unknown in an elderly patient with verte- forms of stabilisation, such as plaster body casting, bral osteomyelitis. While uncommon in the elderly, are also not usually necessary, since neck or body intravenous drug abuse is associated with a high braces or a moulded plastic jacket can usually pro- incidence of infection by Pseudomonas aerugin- vide adequate stabilisation. In patients where the osa and Serratia marcescens.[2] Unusual pathogens infection progresses to the point of neurological such as fungi may also cause haematogenous os- defects, emergent surgical intervention and decom- pression should be performed. Also, the develop-ment or progression of bone destruction or failure 1.1.2 Treatment
of patient improvement with antibacterial treatment Elderly patients with vertebral osteomyelitis may often warrants the use of surgical debridement and be treated with antimicrobial therapy (table II) and stabilisation. The regimen of 4 weeks of intrave- bed rest alone if the infection has not progressed to nous antibacterial followed by 2 to 4 weeks of oral the point of causing extensive bone destruction.
therapy should also be used after the last major de- We suggest an antimicrobial regimen of 4 weeks’ bridement. Although there is a need for a prospec- intravenous antibacterials. As with all forms of tive study analysing the efficacy of oral antibacte- osteomyelitis, the choice of antimicrobial therapy rials following an intravenous regimen, we have had should be based on meticulous bone or blood cul- good success with this regimen in the treatment for tures and sensitivity results. Erythrocyte sedimen- long bone and vertebral osteomyelitis (data not dis- tation rates should be monitored to gauge the suc- cess of treatment. Using scanning techniques mayalso provide an indication of patient response to 1.1.3 Outcome
Treatment results vary and recurrence of osteo-
therapy. While radiographic tests can be useful, fa- myelitis has been reported to occur in 3 to 40% of vourable response to therapy may often progress patients.[5] However, the rate of chronic cases of ver- for several weeks before being detected on plain tebral osteomyelitis (patients demonstrating symp- films. Magnetic resonance imaging (MRI) is clearly toms after 2 years) has been reduced and has ranged superior to radiography in the early detection and between 0 and 10% in recent studies.[6] The mor- evaluation of vertebral osteomyelitis.[4] Computed tality from this disease in the antibacterial era has tomography (CT) is very useful in detecting se- been less than 5%.[5] Residual neurological deficits questra, and guiding bone biopsy for cultures and may be expected to occur in less than 7% of survi- histology. Radionuclide scans demonstrate excellent vors but rates of up to 20% have been reported.[5,7] sensitivity, usually detecting the infectious process Generally, the best way to reduce the morbidity and within a few days of infection. However, these scans mortality associated with vertebral osteomyelitis is are not specific and often give false positives for to limit the time between onset of symptoms and noninfectious reactive bone formation such as that which occurs following trauma or surgery.[4] Forpatients with vertebral osteomyelitis, the most ben- eficial scan is MRI, followed by CT and gallium67 Surgical debridement is usually not necessary 1.2.1 Epidemiology
when the infection is diagnosed early. However, Instances of long bone haematogenous osteo- when epidural and paravertebral abscesses develop, myelitis in elderly patients without implants are Ó Adis International Limited. All rights reserved.
Table II. Choice of antibacterial and regimen for treatment of osteomyelitis in elderly patients
Methicillin-sensitive Staphylococcus aureus Nafcillin 2g q6h or clindamycin 900mg q8hb Cotrimoxazole(trimethoprim-sulfamethoxazole) orminocycline Η rifampicin (rifampin) Benzylpenicillin (penicillin G), cefazolin P. vulgaris, P. rettgeri, Morganella morganii Ticarcillin-clavulanic acid, levofloxacin Ticarcillin-clavulanic acid, levofloxacin Ciprofloxacin, amikacin,ticarcillin-clavulanic acid Amphotericin B 2g followed by fluconazole forindefinite course Same 12-month antibacterial course as used forpulmonary tuberculosis Because of age-related decline in renal function, estimation of creatinine clearance should be performed and ideal bodyweight should be used to calculate appropriate dosage for the elderly (i.e. via the standard Cockcroft/Gault equation).[3] Dose should be individualised with serum concentration monitoring.
qxh = every x hours.
rare. In the elderly the most common scenario is 1.2.2 Diagnosis
reactivation of a site of quiescent haematogenous Both the diagnosis and antimicrobial therapy of osteomyelitis acquired during childhood. Reacti- long bone osteomyelitis are based on the isolation vation of osteomyelitis may occur secondary to lo- of the pathogen(s) from the bone lesion, blood orjoint cultures.[10] In haematogenous osteomyelitis, cal bone or adjacent soft tissue trauma. However, positive blood or joint cultures can often obviate any reduction in host defences may allow quiescent the need for a bone biopsy when there is radio- walled-off organisms to be released, leading to the graphic or radionuclide scan evidence of osteomy- reactivation of the site of haematogenous osteomy- elitis. If possible, cultures should be obtained either elitis. When such reactivation occurs, a single patho- before antibacterials are initiated or after the pa- genic organism is almost always recovered from tient has been off antibacterial therapy for at least the bone.[8,9] The most common bone isolates are 24 to 48 hours. Sinus tract cultures are not reliable coagulase-negative Staphylococcus, methicillin- for isolating causative organisms other than S. au- sensitive S. aureus and methicillin-resistant S. epi- reus.[11] Cultures should always be taken to appro- dermidis; the most common Gram-negative organ- priately select the correct antibacterial management.
ism is P. aeruginosa and the most common anaerobe Aerobic, anaerobic and fungal cultures should be is Peptostreptococcus. However, in the immuno- obtained at the time of debridement surgery. Bone compromised patient, other organisms must also be biopsies are not suggested, since there are ‘skip areas’ considered, including fungi and mycobacteria.
in the involved bone where no organisms are present.
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Scanning techniques are often useful during treat- uniform Haversian or cancellous bleeding, termed ment of haematogenous osteomyelitis. However, radiographic improvement may lag behind clinicalrecovery when the patient is undergoing appropri- ate antimicrobial therapy.[12] Additional changes may Adequate debridement may leave a large bony be seen with more severe infections. Radionuclide defect termed dead space, and appropriate manage- scans,[13,14] CT[15,16] or MRI[17,18] scans may be ob- ment of dead space is mandatory to arrest the disease tained to help gauge the extent of bone and soft and to maintain the integrity of the skeletal part.
tissue involvement. However, it is not usually nec- The goal of dead space management is to replace essary to obtain these scans for long bone osteo- dead bone and scar tissue with durable vascular- myelitis. In patients with suspected osteomyelitis, ised tissue. Local tissue flaps or free flaps may be the order in which the scans should be performed used to fill dead space.[20-22] An alternative technique after the radiograph are the CT, MRI, technetium is to place cancellous bone grafts beneath local or (3-phase) followed by indium-labelled white blood transferred tissues where structural augmentation cell (WBC) scan, and finally a gallium67 citrate scan.
is necessary. Careful preoperative planning is crit-ical to conservation of the patient’s limited cancel- 1.2.3 Therapy
lous bone reserves. Open cancellous grafts without Appropriate therapy of osteomyelitis includes soft tissue coverage are useful when a free tissue adequate drainage, thorough debridement, obliter- transfer is not a treatment option and local tissue ation of dead space, wound protection and antimi-crobial therapy.[10,19] Surgical management of os- flaps are inadequate.[23] Complete wound closure teomyelitis can be very challenging. The principles should be attained whenever possible. Suction ir- of treating any infection are equally applicable to rigation systems are not recommended because of the treatment of infection in bone.[10] These include the high incidence of associated nosocomial infec- adequate drainage, extensive debridement of all ne- tions and the unreliability of these setups.[24,25] Sec- crotic tissue, obliteration of dead spaces, stabilisa- ondary intention healing is also discouraged, since tion, adequate soft tissue coverage and restoration the scar tissue that fills the defect may later become of an effective blood supply.[10] The number of sur- gical procedures performed to achieve these goals Antibacterial-impregnated acrylic beads can be increases with the severity of the infection, and used to sterilise and temporarily maintain dead procedures can be divided into 4 categories.
space.[26-29] The beads are usually removed within2 to 4 weeks and replaced with a cancellous bone graft. The most commonly used antibacterials in Removal of necrotic tissue by extensive debride- beads are vancomycin, tobramycin and gentami- ment surgery is the foundation of osteomyelitis treat- cin. Local delivery of antibacterials, such as ami- ment. It is the most commonly performed procedure kacin or clindamycin, into dead space can also be and patients may require multiple debridements.
achieved with an implantable pump.[30] Adequate The goal of debridement is to leave healthy, viable soft tissue coverage of the bone is necessary to ar- tissue. However, even when all necrotic tissue hasbeen adequately debrided, the remaining bed of tis- rest osteomyelitis. Most soft tissue defects are closed sue must be considered contaminated with the re- by primary closure. Small soft tissue defects may sponsible organism. Debridement should be direct, be covered with a split thickness skin graft. In the atraumatic and executed with reconstruction in mind.
presence of a large soft tissue defect or an inade- All dead or ischaemic hard and soft tissue is ex- quate soft tissue envelope, local muscle flaps and cised unless a noncurative procedure has been cho- free vascularised muscle flaps may be placed in a sen. Surgical excision of bone is carried down to Ó Adis International Limited. All rights reserved.
infection. When the nidus of infection is entirely Soft tissue coverage may be achieved by split within the medullary canal of the bone, surgical treat- thickness skin grafts or local or vascularised mus- ment is usually more straightforward than in other cle flaps. Local muscle flaps and free vascularised types of bone involvement. Patients are surgically muscle transfers improve the local biological envi- treated with a thorough intramedullary reaming, and ronment by bringing in a blood supply important unroofing is usually performed with or without bone in host defence mechanisms, antibacterial delivery grafting. Soft tissues are reapproximated and the limb and osseous and soft tissue healing. In combination is protected by external means (brace or cast) until with antibacterials and surgical debridement of all the structural integrity of the bone is re-established nonviable osseous and soft tissue for chronic osteo- by normal remodelling. When osteomyelitis is char- myelitis, local and free muscle flaps have a success acterised by a full thickness, cortical sequestration, patients can usually be treated with removal of the dead infected bone (bone saucerisation). Bone graft- If movement is present at the site of infection, ing may be necessary to augment structural sup- measures must be taken to achieve permanent sta- port. These patients may require external fixation bility of the skeletal unit. Stabilisation may be for structural support while the bone graft incorpo- achieved by external/open reduction or by internal rates. Complex reconstruction of both bone and soft fixation, using an external fixator and/or plates, screws and rods. One type of external fixation al- In some cases, osteomyelitis progresses to an in- lows reconstruction of segmental bone defects and fection involving a segmental section of the bone.
difficult infected nonunions.[33] The Ilizarov exter- These patients often require an intercalary resection nal fixation method uses the theory of distraction of the bone to arrest the disease process. Since this histogenesis, whereby bone is fractured in the me- advanced stage of osteomyelitis involves an entire taphyseal region. Growth of new bone in the me- through-and-through section of bone, there is a loss taphyseal region pushes a segment of healthy bone of bone stability either before or after debridement into the defect left by surgery. The Ilizarov tech- surgery. As a result, treatment often must be di- nique is used for difficult cases of osteomyelitis rected toward establishing structural stability and when stabilisation and bone lengthening are neces- obliterating debridement gaps by means of cancel- sary.[34] It can also be used to compress nonunions lous bone grafts or the Ilizarov technique (see above and correct malunions, and in a small group of pa- in this section). Free flaps and vascularised bone tients for reconstruction of difficult deformities that grafts are other possible treatment modalities. All result from osteomyelitis. However, this technique of the modalities previously discussed may have a is labour intensive and requires an extended periodof treatment averaging 9 months in the device. Fur- place in the treatment of this type of osteomyelitis.
thermore, the Ilizarov pins commonly become in- After surgery, patients are initially given a broad spectrum antibacterial that is changed to specific an- Infected pseudoarthrosis with segmental osseous timicrobial therapy based on meticulous bone cul- defects can be treated by debridement and micro- tures taken at debridement surgery or from deep vascular bone transfers.[35] Vascularised bone transfer bone biopsies.[10,19,36] Antimicrobial regimens for is also useful for the treatment of infected segmen- specific pathogens usually associated with osteo- tal osseous defects of long bones that are >3cm in myelitis are listed in table II. We recommend 2 weeks length. Vascularised bone transfers can be placed of intravenous antibacterial therapy followed by 4 weeks of oral therapy except in cases of candidia- Surgical procedures for long bone osteomyelitis sis, blastomycosis, tuberculosis, actinomycosis and can be tailored to the specific anatomy of the bone Ó Adis International Limited. All rights reserved.
If the patient is a compromised host, an effort is An important factor in restoring immune function also made to correct or improve the host defect(s).
and promoting healing is the correction of nutri- These include improving the nutritional, medical and vascular status of the patient and treating any Loss of bone stability, bone necrosis and soft underlying diseases. Host factors are primarily in- tissue damage occur frequently, making this form volved with containment of the infection once it is of osteomyelitis difficult to treat. Surgical debride- introduced adjacent to or into bone.[1] A systemi- ment of infected bone and soft tissue provide spec- cally and/or locally compromised host does not con- imens for culture and hasten eradication of the in- tain the infection as well as a normal host, and the fection. Other steps in the surgical management of infection may permeate the bone. Host deficiencies contiguous focus osteomyelitis should be tailored that lead to bacteraemia favour the development of to the specific anatomy of the bone infection as is haematogenous osteomyelitis. While surgical man- done in cases of haematogenous long bone osteo- agement is usually initiated prior to antimicrobial myelitis (section 1.1.2). Antimicrobial therapy therapy, there are instances when antibacterials are should begin with a broad spectrum antibacterial given first. Examples of these situations include that is changed to specific antimicrobial therapy delaying surgical treatment when the treatment is based on meticulous bone cultures taken at debride- worse than the disease or when the patient’s con- ment surgery or from deep bone biopsies (see table dition is serious. Under these conditions, patients II).[10,19,36] If the patient is a compromised host (ta- are treated with antimicrobial therapy until they ble I), an effort is made with adjunctive therapy to have stabilised. Antibacterials are then halted for 2 correct or improve the host deficit(s) [table III].
to 3 days and surgical management is performed.
This includes improving the nutritional, medicaland vascular status of the patient and treating any 2. Contiguous Focus Osteomyelitis
Without Generalised
Vascular Insufficiency

3. Contiguous Focus Osteomyelitis With
Generalised Vascular Insufficiency

Osteomyelitis secondary to contiguous foci of The majority of patients with osteomyelitis in infection accounts for at least half of all cases. Two this category have diabetes mellitus or peripheral recent studies have documented a decline in haem- vascular disease from atherosclerosis. In these pa- atogenous osteomyelitis accompanied by a rise in tients, two main types of contiguous focus osteo- contiguous disease.[37] The infection occurs in youn- myelitis infections occur: osteomyelitis involving ger individuals secondary to trauma and related sur- the small bones of the feet and malignant external gery, and in older adults secondary to pressure ul- In contrast to haematogenous osteomyelitis, mul- tiple organisms are usually isolated from the bonein contiguous focus osteomyelitis. S. aureus and The small bones of the feet, and the talus, calca- coagulase-negative staphylococci account for 75% neus, distal fibula and tibia are commonly involved of bacterial isolates.[8] However, Gram-negative ba- in this category of infection. The infection is usu- cilli and anaerobic organisms are frequently iso- ally initiated in soft tissue by minor trauma of the lated. While blood cultures are only occasionally feet, such as infected nail beds, cellulitis or a tro- positive, if positive they are invaluable for select- phic skin ulceration. The diminished arterial blood ing culture-directed antibacterials. In the elderly supply has traditionally been considered to be the patient, it may be useful to analyse serum albumin major predisposing factor. Recent observation sug- levels and determine ideal bodyweight versus ac- gests that neuropathy is an equally important factor tual bodyweight to determine the state of nutrition.
in patients with diabetes mellitus. Identifiable neu- Ó Adis International Limited. All rights reserved.
Table III. Adjunctive therapy in patients with bone or joint infections
ness skin graft or local or free tissue transfer may provide tissue coverage. Some investigators recom- mend the use of hyperbaric oxygen therapy to aug- ment wound healing and promote angiogenesis. Also, amputation may be a viable treatment alternative when there is no acceptable antimicrobial agent (i.e.
one to which the organism is susceptible and the patient is not allergic), no response to medical ther- apy, or no chance at restoring the normal architec- ture of the foot. The level of amputation depends on the location of the infection and the vascular status of the patient at the involved site. Although arrest of the infection is desirable, a more attainable treatment goal is to suppress the infection and main- tain the functional integrity of the involved limb.
Recurrent or new bone infections occur in the ma- jority of patients even after appropriate treatment.
Patients demonstrating localised or diffuse osteomyelitis and are locally compromised with respect to immune surveil- lance, metabolism and/or local vascularity.
Bl = locally compromised B host (according the Cierny Mader
Malignant external otitis, also known as necro- tising external otitis, is an unusual but potentiallyfatal infection that may occur in elderly patientswith diabetes mellitus. The treatment consists of local ropathy as a complication of diabetes mellitus is debridement of the external auditory canal granu- present in approximately 80% of patients with foot lation tissue and an aggressive course of intrave- disease.[38] Multiple organisms are found in patients nous antibacterials, administered for at least 4 to 6 with osteomyelitis involving the small bones of the weeks. Since most of these infections are mediated feet including S. aureus, coagulase-negative staph- through Pseudomonas spp., the initial broad spec- ylococci, Streptococcus spp., Enterococcus spp., trum antibacterial regimen should cover this ge- Gram-negative bacilli and anaerobes. Aerobic Gram- nus.[40] If necessary, the antibacterial regimen can negative bacilli are usually a part of mixed infec- be adjusted following culture results from samples tion.[39] Cultures obtained by deep bone biopsy or obtained during debridement of the external audi- during debridement procedures are indispensable in tory canal granulation tissue and subsequent anti- the diagnosis and selection of appropriate antimicro- bacterial sensitivity results. With aggressive ther- bial therapy. Culture results not only accurately iden- apy, the cure rate has been found to be between 74 tify responsible pathogens but also identify patients and 91%.[41] Oral antibacterial therapy with the with bone lesions that resemble, but are not, osteo- quinolone class of antibacterials has been associ- ated with an improved cure rate. Surgical interven- Treatment of this type of osteomyelitis is like tion is currently used only as a last resort. Monitor- that of contiguous focus osteomyelitis without vas- ing the response to therapy is best done with serial cular insufficiency. Resection of the infected bone is almost always necessary. However, in patients 4. Osteoporosis and Osteomyelitis
with compromised vascularity it is extremely im-portant to provide soft tissue coverage after an ad- The surviving bone in the osteomyelitis field equate debridement to bleeding cortex. A split thick- usually becomes osteoporotic during the active pe- Ó Adis International Limited. All rights reserved.
riod of infection. Osteoporosis associated with os- elderly population. Therefore, we will limit our dis- teomyelitis is the result of the inflammatory reac- cussion to non-gonococcal arthritis.
tion and disuse atrophy. This lack of bone mineraldensity may be exacerbated by age-associated os- teoporosis seen in elderly patients. After the infec-tion subsides and function of the part is increased, Septic arthritis is a medical emergency that can bone density returns and it may undergo extensive lead to significant morbidity and mortality. There- transformation to meet the lines of stress and strain.
fore, prompt recognition and rapid and aggressive In time, it may be difficult to distinguish between treatment are critical to ensuring a good prognosis.
the old living bone and the newly formed bone.
The treatment of septic arthritis includes both ap- However, bone repair and bone mineral density may propriate antimicrobial therapy and joint drainage.
be significantly retarded in elderly men and women Initial antimicrobial therapy is based on the clini- because of a number of factors (table IV). The re- cal presentation, initial Gram stain and joint fluid duction in bone mineral density may be corrected analysis. An effective broad spectrum antibacterial by correcting risk factors, supplementing the diet should be initiated as soon as possible.
with calcium, bisphosphonates and/or vitamin D, There is a variety of methods to drain the puru- and treating with testosterone and/or estrogen when lent fluid from the infected joint. Presented in as- deficient.[49-55] Sodium fluoride treatment and an- cending order of invasiveness, cost and effective- abolic steroids may be used as alternatives.[56] ness in the thoroughness of drainage, they includeneedle aspiration, tidal irrigation, arthroscopy andarthrotomy. There are no universally accepted cri- 5. Joint Infections
teria for choosing the drainage method. The spe-cific method of drainage used should be tailored Non-gonococcal bacterial arthritis is an infec- according to the clinical situation of the patient.
tious process with serious sequelae. Mortality rates However, some general guidelines can be made.
as high as 12% have been reported, and up to 75% Patients should initially be treated with needle of survivors develop a significant functional dis- aspiration if a joint infection is easily accessible, if ability of the involved joint.[57] The classical pre- almost all the purulent fluid can be removed, and sentation includes fever, pain, warmth, swelling and if the patient does not have negative prognostic decreased range of motion in the involved joint.[58,59] indicators (see next paragraph). Tidal irrigation is Aspiration and culture of the joint effusion is crit- reportedly as effective as arthroscopy and can be ical in determining the causative agent. Whereas performed at the bedside. This closed system irri- Neisseria gonorrhoeae is the most common cause gation method may be useful when needle aspira- of septic arthritis in young healthy North American tion results in incomplete evacuation or when mul- adults,[58,60,61] it is very rarely encountered in the tiple synovial fluid samples demonstrate differentcharacteristics indicating the presence of loculat- Table IV. Causes of and risk factors associated with decreased
ing pockets of infection. Arthroscopic lavage has bone mineral density in elderly men and women been increasingly used in the treatment of septic Vitamin D deficiency and the related hyperparathyroidism[42,43] arthritis of the knee. A recent study demonstrated Reduced bioavailable testosterone (usually due to that this method may also be effective for deep joints, such as the hip. Arthroscopy is advantageous in that extensive debridement can be performed with Reduced bioavailable estrogen and adrenal androgens[44,45] a small incision, thereby allowing for a more rapid Growth hormone and insulin-like growth factor I deficiency[47] and effective rehabilitation period. The compara- tive efficacy of tidal irrigation versus that of arthr- Ó Adis International Limited. All rights reserved.
Arthrotomy should be used when an infected joint disease states. Septic arthritis following cases of must be decompressed urgently because of neurop- infectious diarrhoea may be caused by Shigella spp., athy or compromised blood supply, when the in- Salmonella spp., Campylobacter spp. or Yersinia fected joint is inaccessible by less invasive methods spp.[42,44] A rare form of migrating polyarthritis may (such as the hip and sometimes shoulder), when the be caused by Streptobacillus moniliformis. The ini- joint has been damaged by pre-existing disease, when tial antibacterial therapy is adjusted, if necessary, bacterial arthritis is complicated by osteomyelitis, on the basis of appropriate culture and sensitivity and when the less invasive methods of treatment fail. Also, when the isolated pathogen (e.g. P. aeru- During the acute phase of bacterial arthritis, bed ginosa) can only be treated with aminoglycosides, rest and optimal joint position are absolutely required arthrotomy is often required to overcome the low to prevent the occurrence of joint deformation and oxygen tensions and pH of the infected joint. There deleterious contractures. Splints may be used to are also a number of patient factors in septic arthri- maintain proper joint position (hip in neutral rota- tis that may increase the need for invasive surgical tion in some abduction, knee in full extension, el- intervention. These negative prognostic indicators bow in flexion at 90° and forearm in neutral rota- include a long period between symptom onset and tion). Isotonic exercise is often helpful in preventing treatment, complicated joint site, extremes of age, muscular atrophy. After the acute phase, early physi- underlying illness, immunosuppressive drugs, un- cal therapy and aggressive mobilisation are vitalfor optimal recovery.[45,61] derlying joint diseases, presence of juxta-articularosteomyelitis, and repeated failure of less invasive methods to clear the infection as demonstrated bypositive blood or synovial fluid cultures, continued The results of treatment vary greatly with the back pain and restriction of motion.
virulence of the invading organism, adequacy of host Once the pathogenic organism is obtained from defences, integrity of the joint and duration of symp- joint or blood cultures, optimal antibacterial(s) can be toms prior to treatment. Patients who start treatment continued. In most patients, septic arthritis is treated after 7 days of onset of symptoms have a very poor with 3 weeks of parenteral antibacterial therapy di- outcome. The outcome in patients with septic ar- rected against the isolated micro-organism. The thritis due to some of the more virulent organisms micro-organisms responsible for bacterial arthritis such as superantigen-producing S. aureus and cer- are largely dependent on host factors, including age tain Gram-negative bacilli is poor in spite of optimal and risk factors such as intravenous drug abuse, therapy.[58,66] Even with rapid and correct antibac- asplenia or joint infection following a domestic dog terial treatment, the prognosis for good or excellent or cat bite. Whereas S. aureus is the most common function of the joint ranges from 27 to 90%, while causative agent of non-gonococcal bacterial arthri- the mortality rate is reported to be between 7 and tis in adults, Gram-negative bacilli account for ap- proximately 20% of cases[61-65] and Streptococcus 6. Antibacterial Adverse Effects
spp. are responsible for 10 to 15% of cases.[65,66] in The Elderly
Approximately 10% of patients with non-gonococcalseptic arthritis have polymicrobial infections. Al- Individuals older than 65 years constitute 12% though not common in elderly patients, intravenous of the population of the US, but this segment of the drug abuse often produces significant rates of in- population accounts for about 25 to 30% of the total fection with Gram-negative organisms. The most drug expenditure in developed countries.[46-48,67] The common Gram-negative organisms causing septic elderly population is predicted to reach 23% in the arthritis are P. aeruginosa and Escherichia coli. Mi- US by the year 2030.[68] The incidence of adverse crobiological associations exist with concomitant drug effects is much higher in older patients and Ó Adis International Limited. All rights reserved.
leads to repeated hospitalisations.[48] This high rate ototoxicity and nephrotoxicity in the elderly pa- of adverse effects is caused by the complicating tient. Monitoring of plasma drug concentrations is factors associated with drug therapy in the elderly important for drugs that have appreciable renal clear- including decreased organ reserve capacity, altered ance such as vancomycin and aminoglycosides.[46] pharmacokinetics and pharmacodynamics of drugs, In Australia, cases of cholestatic hepatitis were re- and polypharmacy with associated drug-drug and ported in elderly patients (predominantly women) drug-disease interactions. Also, compliance factors after 3 weeks of flucloxacillin treatment.[69] The associated with prolonged oral regimens may re- use of amoxicillin-clavulanic acid has also been sult in poor treatment outcomes. The patient is of- associated with cholestatic hepatitis. However, this ten more likely to complete the drug regimen when adverse effect was noted primarily in elderly men treatment is accomplished with a simple, once or who had received treatment for >2 weeks.[70] Be- twice daily oral regimen. The physician can help cause of reports of seizures, the intravenous dose to minimise the incidence of adverse effects and of imipenem 0.5g every 6 hours should be reduced improve outcomes by being aware of the principles in elderly patients with decreased renal function, of clinical pharmacology, the characteristics of spe- cerebrovascular disease or seizure disorders.[71] cific drugs and the special physical, psychological Cefamandole may increase creatinine levels in the elderly. Seizures due to hypo- or hyperglycaemia The most important and best-studied pharmaco- were noted in 4 elderly patients being treated with kinetic alteration that occurs in the elderly is the ofloxacin.[72] Fluoroquinolones and tetracycline age-associated decline in renal function. Creatinine may have decreased oral absorption when coadmin- clearance is a very useful measure of renal function istered with aluminium- or magnesium-containing in elderly patients and can be estimated by the antacids or sucralfate. Quinapril, an ACE inhibitor, Cockroft/Gault equation,[3] in which the creatinine contains a high concentration of magnesium which clearance (in ml/min) is assumed to equal the per- may also decrease oral absorption of fluoroquin- olones and tetracycline. Rifampicin (rifampin) in-teraction with a large number of therapeutic agents requires close patient monitoring and follow-up.[73] It is important to note that potent loop diuretics decrease extracellular fluid volume, thereby elevat- ing serum concentrations of antibacterials and ne- Antibacterial loading and maintenance doses cessitating further reductions in dose levels.
should be estimated and confirmed by measuringpeak and trough serum concentrations after the fourth 7. Summary and Future Research
dose. Loading dose may be calculated by using theideal bodyweight to estimate lean mass.[46] Normal bone is highly resistant to infection.
Pathogenic organisms reach the bones by direct ex- Ideal bodyweight Ζ [Εheight in inches ϑ 60Φ ⌠ 2.3] Η tension from neighbouring infected soft tissues,through penetrating wounds and open fractures, or by the blood stream. While osteomyelitis in the The dose may be adjusted upward or downward elderly is often subtle or atypical in presentation to compensate for increased or decreased extracel- when compared with infants, children and young lular fluid volume. Maintenance dose should be adults, successful management of this infection can estimated using ideal bodyweight and percentage result when diagnosis, and antimicrobial and surgi- cal therapy are aggressive. Joint infections should Prolonged use of aminoglycosides should be be treated as medical emergencies; prompt recog- avoided if possible because of increased risk for nition, and rapid and aggressive treatment are crit- Ó Adis International Limited. All rights reserved.
ical to ensuring a good prognosis. The treatment of Acknowledgements
septic arthritis includes appropriate antimicrobial The authors wish to thank Michael Cripps and Donna Milner Mader for manuscript review, reference research and The treatment of bone and joint infections in the elderly patient represents a special set of circum-stances for surgical and infectious disease specialists.
1. Cierny G, Mader JT, Pennick H. A clinical staging system of In reference to osteomyelitis, the speed of bone re- adult osteomyelitis. Contemp Orthop 1985; 10: 17-37 pair following treatment may be significantly re- 2. Holzman RS, Bishko F. Osteomyelitis in heroin addicts. Ann tarded in the elderly population. Therefore, elimi- 3. Cockroft DW, Gault MH. Prediction of creatinine clearance nating the risk factors associated with deficiencies from serum creatinine. Nephron 1976; 16: 31-41 in bone mineral density may be considered. Whether 4. Gold RH, Hawkins RA, Katz RD. Bacterial osteomyelitis: find- ings on plain radiography, CT, MR, and scintigraphy. Am J the infection is associated with the bone or joint, the immunocompromised nature of the elderly pa- 5. Sapico FL, Montgomerie JZ. Vertebral osteomyelitis. Infect Dis tient must be taken into consideration. The general 6. Jensen AG, Espersen F, Skinhoj P, et al. Bacteremic Staphylo- compromised nature of the immune system that oc- coccus aureus spondylitis. Arch Intern Med 1998; 158: 509-17 7. Sapico FL, Montgomerie JZ. Pyogenic vertebral osteomyelitis: curs in this patient subset, possibly due to age- report of nine cases and review of the literature. Rev Infect dependent declines in interleukin-2 and its associ- 8. Mader JT, Ortiz M, Calhoun JH. Update on the diagnosis and ated receptor, can make treatment problematic. Also, management of osteomyelitis. Clin Pod Med Surg 1996; 13 the elderly have a higher risk of other diseases that often interfere with pathogen clearance and the nat- 9. Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations, and unusual ural healing process. Therefore, we feel that diagnos- aspect. N Engl J Med 1970; 282: 198-202, 260-6, 316-22 tic procedures and therapeutic regimens should be 10. Mader JT, Calhoun JH. Osteomyelitis. In: Mandell GL, Douglas RG, Bennett Jr JE, editors. Principles and practice of infec- appropriate, rapid and aggressive. However, before tious diseases. New York: Churchill Livingstone, 1995: 1039 prescribing any medication or surgical procedure, 11. Mackowiak PA, Jones SR, Smith JW. Diagnostic value of sinus tract cultures in chronic osteomyelitis. JAMA 1978; 239: 2772 it must be understood that there is a very real risk of 12. Butt WP. The radiology of infection. Clin Orthop 1973; 96: 20 adverse effects and drug toxicity/cross reactivity in 13. Lisbona R, Rosenthall L. Observations of the sequential use of the elderly patient. The physician can minimise ad- 99mTc phosphate complex and 67 Ga imaging in osteomyeli-tis, cellulitis, and septic arthritis. Radiology 1977; 123: 123 verse drug reactions and improve outcomes by being 14. Propst-Proctor SL, Dillingham MF, McDougall IR, et al. The aware of the principles of clinical pharmacology, the white blood cell scan in orthopedics. Clin Orthop 1982; 168: 157 15. Kuhn JP, Berger PE. Computed tomographic diagnosis of os- characteristics of specific drugs, and the special physical, psychological and social needs of older pa- 16. Seltzer SE. Value of computed tomography in planning medical and surgical treatment of chronic osteomyelitis. J Comput In order to effectively treat bone and joint infec- 17. Erdman WA, Tamburro F, Jayson HT, et al. Osteomyelitis: char- acteristics and pitfalls of diagnosis with MR imaging. Radi- tions in the elderly, further research in this area must continue. The search for safe, easy and inexpen- 18. Tehranzadeh J, Wang F, Mesgarzadeh M. Magnetic resonance sive means of rapid diagnosis and treatment should imaging of osteomyelitis. Crit Rev Diagn Imaging 1992; 33: 495 19. Cierny G, Mader JT. Adult chronic osteomyelitis. Orthopedics be a worthwhile target. Also, new antimicrobial re- gimens, antimicrobial agents or medications should 20. Anthony JP, Mathes SJ, Alpert BS. The muscle flap in the treat- ment of chronic lower extremity osteomyelitis: results in pa- be studies for their ability to promote healing, re- tients over 5 years after treatment. Plast Reconstr Surg 1991; store normal immune function, and safely eliminate 21. May Jr JW, Jupiter JB, Gallico GG 3d, et al. Treatment of infection without surgical intervention in older pa- chronic traumatic bone wounds. Microvascular free tissue tients. Lastly, prevention of the disease through vac- transfer: a 13-year experience in 96 patients. Ann Surg 1991; cines against the major responsible pathogens would 22. Ruttle PE, Kelley PJ, Arnold PG, et al. Chronic osteomyelitis also be a valuable goal of future research.
treated with a muscle flap. Orthop Clin North Am 1984; 15: 451 Ó Adis International Limited. All rights reserved.
23. Papineau LJ, Alfageme A, Dalcourt JP, et al. Osteomyelite chro- 43. Andersen K, Bennedbaek FN, Hansen BL. Septic arthritis.
nique: Excision et greffe de spongieux a l’air libre apres mises a plat extensives. Int Orthop 1979; 3: 165 44. Keat A. Sexually transmitted arthritis syndromes. Med Clin 24. Clawson DK, Davis FJ, Hansen ST. Treatment of chronic os- teomyelitis with emphasis on closed suction-irrigation tech- 45. Smith JW. Infectious arthritis. Infect Dis Clin North Am 1990; 25. Letts RM, Wong E. Treatment of acute osteomyelitis in children 46. Chutka DS, Evans JM, Fleming KC, et al. Drug prescribing for by closed-tube irrigation: a reassessment. Can J Surg 1975; elderly patients. Mayo Clin Proc 1995; 70: 685-93 47. Sloan RW. Principles of drug therapy in geriatric patients. Clin 26. Adams K, Couch MSL, Cierny G, et al. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated 48. Salom IL, Davis K. Prescribing for older patients: how to avoid polymethylmethacrylate (PMMA) beads. Clin Orthop 1992; toxic drug reactions. Geriatrics 1995; 50 (10): 37-43 49. Diamond T, Smerdely P, Kormas N, et al. Hip fracture in elderly 27. Calhoun JH, Mader JT. Antibiotic beads in the management of men: the importance of subclinical vitamin D deficiency and surgical infection. Am J Surg 1989; 157: 443 hypogonadism. Med J Aust 1998; 169 (3): 138-41 28. Henry SL, Seligson D, Mangino P, et al. Antibiotic-impregnated 50. Riggs BL, Khosla S, Melton LJ. A unitary model for involutio- beads. Pt I. Bead implantation versus systemic therapy. Or- nal osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contrib- 29. Wilson KJ, Cierny G, Adams KR, et al. Comparative evaluation utes to bone loss in aging men. J Bone Miner Res 1998; 13 of the diffusion of tobramycin and cefotaxime out of antibi- otic-impregnated polymethylmethacrylate beads. J Orthop 51. Tan RS, Bransgrove L. Testosterone replacement therapy. What is its potential in elderly men? Postgrad Med 1998; 103 (5):247-8, 251-6 30. Perry CR, Davenport K, Vossen MK. Local delivery of antibi- otics via an implantable pump in the treatment of osteomyeli- 52. Seeman E. Osteoporosis in men. Baillieres Clin Rheumatol 53. Shane E, Rivas M, McMahon DJ, et al. Bone loss and turnover 31. Beris AE, Soucacos PN, Xenakis TA, et al. Latissimus dorsi free after cardiac transplantation. J Clin Endocrinol Metab 1997; transfer for coverage of extensive soft tissue defects. Acta 54. Seeman E. The dilemma of osteoporosis in men. Am J Med 32. Gayle LB, Lineaweaver WC, Oliva A, et al. Treatment of chronic osteomyelitis of the lower extremities with debride- 55. Legrand E, Le Levier F, Chappard D, et al. Male osteoporosis.
ment and microvascular muscle transfer. Clin Plast Surg 56. Eastell R, Boyle IT, Compston J, et al. Management of osteo- 33. Green SA. Osteomyelitis. The Ilizarov perspective. Orthop Clin porosis: report of the UK Consensus Group. Q J Med 1998; 34. Calhoun JH, Anger DM, Mader JT. The Ilizarov technique in 57. Rosenthal J, Giles GB, Robinson WD, et al. Acute nongonococ- the treatment of osteomyelitis. Texas Med 1991; 87: 56 cal infectious arthritis. Evaluation of risk factors, therapy, and 35. Minami A, Kaneda K, Itoga H. Treatment of infected segmental outcome. Arthritis Rheum 1980; 23: 889-97 defect of long bone with vascularized bone transfer. J Recon- 58. Knights EM. Infectious arthritis. J Foot Surg 1982; 21: 229-33 59. Nelson JD, Koontz WC. Septic arthritis in infants and children: 36. Perry CR, Pearson RL, Miller GA. Accuracy of cultures of a review of 117 cases. Pediatrics 1966; 38: 966-71 material from swabbing of the superficial aspect of the wound 60. al-Eissa YA, Kambal AM, al-Nasser et al. Childhood brucello- and needle biopsy in the preoperative assessment of osteomy- sis: a study of 102 cases. Pediatr Infect Dis J 1990; 9: 74-9 elitis. J Bone Joint Surg 1991; 73 (A): 745 61. Sharp JT, Lindsky MD, Duffey J, et al. Infectious arthritis. Arch 37. Espersen F, Frimodt-Moller N, Thandrup Rosdahl V, et al.
Changing pattern of bone and joint infections due to Staphy- 62. Barton LL, Dunkle LM, Habib FH. Septic arthritis in child- lococcus aureus: study of cases of bacteremia in Denmark: hood: a 13 year review. Am J Dis Child 1987; 141: 898-900 1959-1988. Rev Infect Dis 1991; 13: 347-85 63. Deesomchok U, Tumrasvin T. Clinical study of culture proven 38. Caputo GM, Cavanagh PR, Ulbrcht JS, et al. Assessment and cases of non-gonococcal arthritis. J Med Assoc Thai 1990; management of foot disease in patients with diabetes. N Engl 64. Dickie AS. Current concepts in the management of infection in 39. Calhoun JH, Cantrell JS, Cobos J, et al. Treatment of diabetic foot infections: Wagner classification, therapy and outcome.
65. Vyskocil JJ, Mcllroy MA, Brennan TA, et al. Pyogenic infection of sacroiliac joint. Case reports and review of literature. Med- 40. Englender M, Harell M, Guttman R, et al. Typing of Pseudom- onas aeruginosa ear infections related to outcome of treat- 66. Goldenberg DH, Cohen AS. Acute infectious arthritis: a review of patients with nongonococcal joint infection (with emphasis 41. Johnson MP, Ramphal R. Malignant external otitis: report on on therapy and prognosis). Am J Med 1976; 60: 369-72 therapy with ceftazidime and review of therapy and progno- 67. Jones-Grizzle AJ, Draugalis JR. Demographics. In: Bressler R, Katz MD, editors. Geriatric pharmacology. New York: 42. Fryden A, Bengtsson A, Foberg U, et al. Early antibiotic treat- ment of reactive arthritis associated with enteric infection: 68. Cessna CB, Landes A, Foster CD. Growing old in America: the clinical and serological study. BMJ 1990; 301: 1299-302 information series on current topics. In: Cessna CB, Landes Ó Adis International Limited. All rights reserved.
A, Foster CD, editors. Information plus. New York (NY): 73. Gleckman RA. Antibiotic concerns in the elderly. Infect Dis 69. Fairley CK, Boyd I, Purcell P, et al. Flucloxacillin jaundice.
70. Larrey D, Vial T, Micaleff A, et al. Hepatitis associated with amoxycillin-clavulanic acid combination report of 15 cases.
Correspondence and reprints: Professor Jon T. Mader, Sec- tion Surgical Infectious Diseases, Division of Infectious Dis- 71. Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity eases, Department of Internal Medicine, Marine Biomedical with penicillin in humans. J Allergy Clin Immunol 1988; 82 Institute, New Trauma Building, Hyperbaric Facility, Uni- versity of Texas Medical Branch, Galveston, Texas 77555- 72. Traeger SM, Bonfiglio MF, Wilson JA, et al. Seizures associated with ofloxacin therapy. Clin Infect Dis 1995; 21 (6): 1504-6 Ó Adis International Limited. All rights reserved.

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