Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
Bone and joint infections
- J. Wilkinson
Septic or pyogenic arthritis can be defined as the invasion of the synovial membrane by micro-organisms, usually with extension into the joint to produce an infection in a closed space. In most cases, bacteria reach the joint through the bloodstream from a distant focus of infection such as a septic skin lesion, otitis media, pneumonia, meningitis, gonorrhoea, or an infection of the urinary tract. Some infections may spread to joints while the primary focus remains undetected. Rarely, bacteria may be introduced directly into the synovial space following a penetrating wound, an operation on the joint, or an intra-articular injection. Alternatively, the joint may become infected by direct spread from an adjacent area of osteomyelitis or cellulitis. Once established, septic arthritis can give rise to secondary bacteraemia.
Staphylococcus aureus accounts for most bacteriologically proven joint infections. Other bacteria are important in specific age groups.Escherichia coli and streptococci of Lancefield group B (Streptococcus agalactiae) occur in neonates. Pneumococci, Str. pyogenes, and coliform bacilli are found in elderly people. Haemophilus influenzae of serotype b caused septicaemia and pyogenic arthritis in children under the age of 6 until childhood immunization with the H. influenzae conjugate vaccine markedly reduced the incidence of this infection.Neisseria gonorrhoeae occasionally causes septic arthritis in young adults. Patients with meningococcal infection may develop septic arthritis during the course of their illness. Other rare causes include Mycobacterium tuberculosis, opportunist mycobacteria, Brucella spp., fungi, andBorrelia burgdorferi, the spirochaete that causes Lyme disease.
Clinical and diagnostic considerations
In nine cases out of ten a single joint is involved, most commonly the knee, followed by the hip. Typically, the patient is a child with a high temperature and a red, hot, swollen joint with restricted movement. However, septic arthritis is not uncommon in elderly and debilitated people, who may have non-specific symptoms. Patients with rheumatoid arthritis have an increased incidence of septic arthritis and a poorer prognosis, which may in part be attributable to delay in making the clinical diagnosis.
A presumptive diagnosis rests on the immediate examination of the joint fluid, because of the difficulty on clinical grounds in distinguishing other conditions with similar features, such as an exacerbation of rheumatoid arthritis, gout, acute rheumatic fever, or trauma to the joint. Typically, the fluid is cloudy or purulent with a marked excess of neutrophils. The Gram-film is of immediate help not only in confirming the diagnosis but also in the choice of the most appropriate antimicrobial therapy. When patients have not had antibiotics prior to arthrocentesis and the infection is with Gram-positive organisms, the bacteria should be evident microscopically in most cases. Gram-negative bacteria are less obvious, but Gram-negative cocci are typically seen clustered in the cytoplasm of pus cells. Despite the microscopic evidence of bacterial infection, culture of synovial fluid may sometimes fail to yield the pathogen, and blood cultures should always be taken at the same time. In suspected gonococcal arthritis, cervical, urethral, rectal, and throat swabs should also be taken for culture before starting antimicrobial therapy.
Guidelines to antibiotic therapy and management
It is very important that a diagnosis is made rapidly and appropriate therapy started immediately, because permanent damage to the joint may occur and lead to long-term residual abnormalities. Most patients who are treated promptly recover completely. Infection of the hip joint is more difficult to treat since, in addition to antibiotics, open surgical drainage is needed because of the technical difficulty of needle aspiration. The key to success is a combination of antibiotics and drainage. In most cases this is achieved by needle aspiration, which should be repeated daily, if indicated, in an attempt to ‘drain the joint dry’.
The choice of initial antibiotic therapy depends on the age of the patient and the findings in the Gram-film. If organisms can be identified with reasonable confidence before culture, the appropriate antibiotic for that particular organism is the automatic choice irrespective of the age (Table 25.1). If probable staphylococci are seen and there is a risk that these may be methicillin-resistant (MRSA), then vancomycin should be considered instead of flucloxacillin. If bacteria are not seen at this stage, the initial choice is influenced by the age of the patient and/or the underlying disease. Antibiotics are chosen to cover the most likely bacterial causes of the infection (Table 25.2) and can be modified subsequently if a pathogen is isolated.
Table 25.1 Initial antimicrobial therapy in septic arthritis when bacteria are seen in the Gram-film of the joint aspirate
Table 25.2 Initial antimicrobial therapy in septic arthritis when no organisms are seen in the Gram-film of the joint aspirate
Most antimicrobial agents given parenterally achieve therapeutic levels in the infected joint, so the intra-articular injection of antibiotics is not recommended, particularly as it may induce chemical synovitis. There is no consensus of opinion about the type of surgical intervention that is appropriate in septic arthritis and haematogenous osteomyelitis, nor about the choice of antibiotics, route of administration, and duration of treatment.
A sequential intravenous–oral regimen, carefully monitored at the time of oral therapy, is widely used in children. In all cases, the initial treatment must be with parenteral antibiotics until the condition of the patient has stabilized (usually 7–10 days) and the joint is reasonably dry. In selected patients high-dose oral therapy may be used in the last 2–3 weeks of treatment, provided the patient can be relied upon to comply and serum bactericidal concentrations are satisfactory.
The duration of treatment depends on the organism and the age of the patient. Neonates and young infants, in whom there may be concurrent osteomyelitis, should receive intravenous therapy for at least 3–4 weeks. For septic arthritis caused by Str. pyogenes, pneumococci, or Neisseria spp. 10–14 days of therapy may be adequate, whereas Ps. aeruginosa may require as long as 6–8 weeks. Most cases of septic arthritis caused by Staph. aureus or H. influenzae are treated for at least 3–4 weeks.
Osteomyelitis is infection of bone and is usually caused by bacteria. In the days before antibiotics, osteomyelitis was a dreaded disease not only because it was frequently fatal, but also because those who survived were often left seriously disabled with chronic discharging sinuses from the affected bone. This complication may still occur when acute osteomyelitis has not been treated promptly and adequately.
Unlike soft tissues, bone is a rigid structure and cannot swell. As infection proceeds and pus forms, there is a marked rise of pressure in the affected part of the bone which, if unchecked or unrelieved, may impair the blood supply to a wide area and result in areas of infected dead bone. Once this chronic phase of osteomyelitis is established, necrotic bone (sequestrum) must be removed surgically in addition to the use of antibiotics if the infection is to be eradicated.
Pathogenesis and aetiology
Osteomyelitis may be haematogenous (infected through the bloodstream) or non-haematogenous (infected directly through a wound).
This type of infection is most commonly caused by staphylococci that reach the site from a boil or other focus of infection through the bloodstream. The primary
focus of infection is often not apparent. Acute haematogenous osteomyelitis is principally a disease of children under 16 years, in whom more than 85 per cent of cases occur. The usual sites are the long bones (femur, tibia, humerus) near the metaphysis, where the blood supply to the bone is most dense. However, when the disease occurs in adults, the vertebrae are commonly affected.
Staph. aureus accounts for about half of all cases and for more than 90 per cent of cases in otherwise normal children. In the elderly with underlying malignancies and other diseases, and in drug addicts, Gram-negative bacilli (coliform bacilli and Ps. aeruginosa) are being reported with increasing frequency. Coliforms may also cause vertebral osteomyelitis. In neonates, the diagnosis of osteomyelitis is often difficult and many bones may be involved, as well as their adjacent joints. In addition to Staph. aureus, Esch. coli and group B haemolytic streptococci are the main bacterial causes. Group B streptococci seem to have a predilection for the humerus in neonates. As in septic arthritis, Str. pyogenes and Str. pneumoniae may occur (Table 25.2), but they are even less common in osteomyelitis. H. influenzae has become very rare since the introduction of the conjugate vaccine. Other rare causes of haematogenous osteomyelitis include M. tuberculosis,Brucella abortus and, particularly in parts of the world where sickle-cell anaemia is prevalent, salmonellae.
When bones are infected by the introduction of organisms through traumatic or post-operative wounds, Staph. aureus is still the commonest cause, but Gram-negative bacteria may also be found. Ps. aeruginosa may occasionally produce osteomyelitis of the metatarsals or calcaneum following a puncture wound of the sole of the foot and Pasteurella multocida infection may follow animal bites. Patients with infected pressure sores over a bone, or those with peripheral vascular disease or diabetes mellitus, may develop osteomyelitis with mixed aerobic and anaerobic organisms (coliforms and Bacteroides species), although Staph. aureus is an important cause of osteomyelitis by this route also.
Clinical and diagnostic considerations
The typical manifestations of acute, haematogenous osteomyelitis include the abrupt onset of high fever and systemic toxicity, with marked redness, pain, and swelling over the bone involved. In adults, the presentation may not be so dramatic as in children. The most important physical sign is bony tenderness at the metaphysis; this is particularly helpful in older children and adults, in whom the features of infection are not so pronounced. In vertebral osteomyelitis, there may be general malaise, with or without low-grade fever and low back pain. If the infection is not controlled, it may spread to produce a spinal epidural abscess, with consequent neurological symptoms.
The diagnosis of osteomyelitis is confirmed by bone aspiration, which will also reveal any abscess that requires surgical drainage, and the isolation of the
causative organism from material from the lesion. A bone scan may help to localize the site and extent of the infection. At least two sets of blood cultures must be taken; this will confirm the diagnosis in about half the cases and remove the need for bone biopsy. In patients with chronic osteomyelitis, it may be misleading to base antibiotic treatment on the results of cultures of pus obtained from a draining sinus, which will often yield organisms from the exterior that are secondarily colonizing the sinus. For precise bacteriological diagnosis, material must be obtained during the surgical removal of dead bone and tissue, or by deep needle aspiration of exudate.
Guidelines for antibiotic therapy and management
It is generally agreed that acute haematogenous osteomyelitis can be cured without surgical intervention, provided that antibiotics are given while the bone retains its blood supply and before extensive necrosis has occurred. In practice, this is within the first 72 h of the development of symptoms. Antibiotic therapy must, therefore, start immediately after a bone aspirate and blood cultures have been obtained. Results from a Gram-film of aspirated material may help in the initial choice of antibiotic. If no organisms are seen, Staph. aureusis the prime suspect in any age group, and an antistaphylococcal agent that penetrates well into bone and pus should be used. Penicillins and fusidic acid fulfil this criterion; however, since Staph. aureus is usually resistant to benzylpenicillin and resistance to fusidic acid arises easily when that drug is used alone, a combination of flucloxacillin and fusidic acid is recommended. In the neonate, where group B streptococci occur, benzylpenicillin may be used. Alternative antistaphylococcal agents include clindamycin, vancomycin, teicoplanin, and rifampicin. Vanco-mycin is the preferred first choice if MRSA is suspected.
To ensure adequate concentration at the site of infection, high doses of antibiotics should be given parenterally. If an abscess has already formed when the patient is first seen, or there is no significant clinical improvement within 24 h of starting parenteral therapy, then surgical drainage of the abscess is essential.
The duration of antimicrobial therapy of acute staphylococcal osteomyelitis should be not less than 4 weeks and may need to be much longer. This is a long period for a patient, particularly a young child, to receive intravenous therapy. If the initial clinical response is good, the patient can be relied upon to comply, and the serum antibiotic activity can be monitored, parenteral therapy may be changed to high-dose oral therapy for the remaining 3–4 weeks. Flucloxacillin and fusidic acid are both suitable for oral therapy, as is clindamycin. The recommended duration of treatment of osteomyelitis caused by Str. pneumoniae or Str. pyogenes is 10–14 days, but this may need to be prolonged in individual cases.
The management of osteomyelitis caused by enteric Gram-negative bacilli is difficult. Prolonged intravenous therapy with an aminoglycoside such as gentam-icin, in combination with an extended-spectrum cephalosporin such as cefotaxime
(enterobacteria) or ceftazidime (Ps. aeruginosa) should accompany appropriate surgical intervention. Fluoroquinolones like ofloxacin and ciprofloxacin are also active against this group of bacteria and achieve good penetration into bone. They may be given both orally and parenterally, and are particularly useful in osteomyelitis caused by Brucella spp., Ps. aeruginosa, Esch. coli, Proteus spp., and Salmonella enterica. The development of resistance has been reported when fluoroquinolones have been used as single agents, however, and combination with another effective antimicrobial agent is recommended.
In chronic osteomyelitis, where surgical drainage and excision of dead bone and tissue is essential, high-dose oral antibiotics have to be continued post-operatively for several months if the infection is to be eradicated. Improvements in techniques for venous access now make long-term intravenous therapy possible for outpatients who can visit a clinic daily or on alternate days. This approach is particularly useful where there is no suitable oral agent for the causative organism, and also offers the opportunity for regular monitoring of aminogly-coside concentrations and serum antimicrobial activity without the need for expensive, inconvenient, hospital inpatient care.