The Problem of Resistance

What is resistance?

Bacterial isolates have been categorized as being susceptible or resistant to antibiotics ever since they became available. Where the concepts of the minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations of an antibiotic are described. Unfortunately, making an accurate judgement about microbial susceptibility or resistance is somewhat less straightforward than this traditional working definition, since there is usually no simple relationship between the MIC (or minimum bactericidal concentrations) of an antibiotic and clinical response. Therapeutic success depends not only on the concentration of the antibiotic achieved at the site of infection (i.e. its pharmacokinetic behaviour) and its activity against the infecting organisms encountered there (i.e. its pharmacodynamic behaviour), but also on the contribution that the host's own defences are able to make towards clearance of the offending microbes.

The decision as to whether a given bacterial isolate should be labelled susceptible or resistant depends ultimately on the likelihood that an infection with that organism can be expected to respond to treatment with a given drug, but microbiologists and clinicians have become accustomed to the idea that an organism is ‘resistant’ when it is inhibited in vitro by an antibiotic concentration that is greater than that achievable in vivo. Importantly the concentration of antibiotic that is achievable will vary according to the site of infection, dosage, and route of administration. For example, some antibiotics, such as trimethoprim, are excreted primarily via the kidneys and therefore achieve, in the context of urinary tract infections, advantageously high concentrations in urine. Furthermore, the intrinsic activity of an antibiotic against some bacteria (e.g. staphylococci) may be greater than for others (e.g. Escherichia coli) because of the effect of cell envelope structure on achievable intracellular antibiotic concentrations. These issues mean that several different thresholds (breakpoint concentrations) are often used to define susceptibility to an antibiotic. For example, an E. coli strain for which the MIC of ampicillin is 32 mg/l might be classed as susceptible if isolated from a urinary infection, while the same bacterium causing a bloodstream infection would be classified as ampicillin resistant. These differences in definition of susceptibility relate to the variations in achievable concentrations at the site of infection: while an ampicillin concentration of 32 mg/l can reliably be achieved in urine, this is not the case in blood.

Intrinsic resistance

If whole bacterial species are considered, rather than individual isolates, it is apparent immediately that they are not all intrinsically susceptible to all antibiotics (See Table Below); for example, a coliform infection would not be treated with erythromycin, or a streptococcal infection with an aminoglycoside, since the organisms are intrinsically resistant to these antibiotics. Similarly, Pseudomonas aeruginosa and Mycobacterium tuberculosis are intrinsically resistant to most of the agents used to treat more tractable infections. Such intrinsically resistant organisms are sometimes termed non-susceptible, with the term resistant reserved for variants of normally susceptible species that acquire mechanism(s) of resistance.

A microbe will be intrinsically resistant to an antibiotic if it either does not possess a target for the drug's action, or it is impermeable to the drug. Thus, bacteria are intrinsically resistant to polyene antibiotics, such as amphotericin B, as sterols that are present in the fungal but not bacterial cell membrane, are the target for these drugs. The lipopolysaccharide outer envelope of Gram-negative bacteria is important in determining susceptibility patterns, since many antibiotics cannot penetrate this barrier to reach their intracellular target. Fortunately, intrinsic resistance is therefore often predictable, and should not pose problems provided that informed and judicious choices of antibiotics are made for the treatment of infection. Of greater concern is the primarily unpredictable acquisition or emergence of resistance in previously susceptible microbes, sometimes during the course of therapy itself.

Acquired resistance

Introduction of clinically effective antibiotics has been followed invariably by the emergence of resistant strains of bacteria among species that would normally be considered to be susceptible. Acquisition of resistance has seriously reduced the therapeutic value of many important antibiotics, but is also a major stimulus to the constant search for new and more effective antimicrobial drugs. However, while the emergence of resistance to new antibiotics is inevitable, the rate of development and spread of resistance is not predictable.

S, usually considered susceptible; R, usually considered resistant; (S), strain variation in susceptibility; V, variation among related drugs and/or strains.

The first systematic observations of acquired drug resistance were made by Paul Ehrlich between 1902 and 1909 while using dyes and organic arsenicals to treat mice infected experimentally with trypanosomes. Within a very few years of the introduction of sulphonamides and penicillin (in 1935 and 1941 respectively), micro-organisms originally susceptible to these drugs were found to have acquired resistance. When penicillin came into use less than 1% of all strains of Staphylococcus aureus were resistant to its action. By 1946, however, under the selective pressure of this antibiotic, the proportion of penicillin-resistant strains found in hospitals had risen to 14%. A year later, 38% were resistant, and today, resistance is found in more than 90% of all strains of Staph. aureus. In contrast, over the same period, an equally important pathogen, Streptococcus pyogenes, has remained uniformly susceptible to penicillin, although there is no guarantee that resistance will not spread to S. pyogenes in future years.

There is no clear explanation for the marked differences in rate or extent of acquisition of resistance between different species. Possession of the genetic capacity for resistance does not always explain its prevalence in a particular species. Even when selection pressures are similar, the end result may not be the same. Thus, although about 90% of all strains of Staph. aureus are now resistant to penicillin, the same has not happened to ampicillin resistance in E. coli under similar selection pressure. At present, apart from localized outbreaks involving epidemic strains, about 40-50% of E. coli strains are resistant to ampicillin, and this level has remained more or less steady for a number of years. However, since an increasing incidence of resistance is at least partly a consequence of selective pressure, it is not surprising that the withdrawal of an antibiotic from clinical use may often result in a slow reduction in the number of resistant strains encountered in a particular environment. For example, fluoroquinolone resistant strains of P. aeruginosa that emerged in some hospitals as ciprofloxacin or levofloxacin were used more frequently were replaced by more susceptible strains following restriction of removal of these drugs. Conversely, sulphonamide resistant E. coli strains that became commonplace when the sulphonamide-containing combination drug co-trimoxazole was widely used are still prevalent. This is probably because the selection pressure still exists for other antibiotics, such as ampicillin, and the genes coding for sulphonamide and ampicillin resistance are often closely linked on plasmids; hence, use of one antibiotic can select or maintain resistance to another. The introduction of new antibiotics has also resulted in changes to the predominant spectrum of organisms responsible for infections. In the 1960s semi-synthetic ‘β-lactamase stable’ penicillins and cephalosporins were introduced which, temporarily, solved the problem of staphylococcal infections.

Unfortunately, Gram-negative bacteria then became the major pathogens found in hospitals and rapidly acquired resistance to multiple antibiotics in the succeeding years. In the 1970s the pendulum swung the other way with the first outbreaks of hospital infection with multiresistant staphylococci that were resistant to nearly all antistaphylococcal agents. Outbreaks of infection caused by such organisms have occurred subsequently all over the world. There are now signs that Gram-negative bacteria are once again assuming greater importance, particularly in hospitals. Resistance to newer cephalosporins—mediated by extended-spectrum β-lactamases—and fluoroquinolones in E. coli and other enterobacteria is increasing, rendering these commonly used antibiotics less effective. Multiresistant Gram-negative bacteria (such as Acinetobacter species) have emerged that are resistant to most and, occasionally, all approved antibiotics.

Types of acquired resistance

Two main types of acquired resistance may be encountered in bacterial species that would normally be considered susceptible to a particular antibacterial agent.

Mutational resistance

In any large population of bacterial cells a very few individual cells may spontaneously become resistant. Such resistant cells have no particular survival advantage in the absence of antibiotic, but after the introduction of antibiotic treatment susceptible bacterial cells will be killed, so that the (initially) very few resistant cells can proliferate until they eventually form a wholly resistant population. Many antimicrobial agents select for this type of acquired resistance in many different bacterial species, both in vitro and in vivo. The problem has been recognized as being of particular importance in the long-term treatment of tuberculosis with antituberculosis drugs.

Transmissible resistance

A more spectacular type of acquired resistance occurs when genes conferring antibiotic resistance transfer from a resistant bacterial cell to a sensitive one. The simultaneous transfer of resistance to several unrelated antimicrobial agents can be demonstrated readily, both in the laboratory and the patient. Exponential transfer and spread of existing resistance genes through a previously susceptible bacterial population is a much more efficient mechanism of acquiring resistance than the development of resistance by mutation of individual susceptible cells.

Here it is sufficient to stress that however resistance appears in a hitherto susceptible bacterial cell or population, resistance will only become widespread under the selective pressures produced by the presence of appropriate antibiotics. Also, the development of resistant cells does not have to happen often or on a large scale. A single mutation or transfer event can, if the appropriate selective pressures are operating, lead to the replacement of a susceptible population by a resistant one. Without selective pressure, antibiotic resistance may be a handicap rather than an asset to a bacterium.

Cross-resistance and multiple resistance

These terms are often confused. Cross-resistance involves resistance to a number of different members of a group of (usually) chemically related agents that are affected alike by the same resistance mechanism. For example, there is almost complete cross-resistance between the different tetracyclines, because tetracycline resistance results largely from an efflux mechanism that affects all members of the group. The situation is more complex among other antibiotic families. Thus, resistance to aminoglycosides may be mediated by any one of a number of different drug-inactivating enzymes with different substrate specificities, and the range of aminoglycosides to which the organism is resistant will depend on which enzyme it produces. Cross-resistance can also be observed occasionally between unrelated antibiotics. For example, a change in the outer membrane structure of Gram-negative bacilli may concomitantly deny access of unrelated compounds to their target sites. In contrast, multiple drug (multidrug) resistance involves a bacterium becoming resistant to several unrelated antibiotics by different resistance mechanisms. For example, if a staphylococcus is resistant to penicillin, gentamicin, and tetracycline, the resistances must have originated independently, since the strain destroys the penicillin with a β-lactamase, inactivates gentamicin with an aminoglycoside-modifying enzyme, and excludes tetracycline from the cell by an active efflux mechanism.

It is, however, not always clear whether cross-resistance or multiple resistance is being observed. Genes conferring resistance to several unrelated agents can be transferred en bloc from one bacterial cell to another on plasmids, thereby giving the appearance of cross-resistance.

In such cases, detailed biochemical and genetic analysis may be required to prove that the resistance mechanisms are distinct (multiple resistance), although the genes conferring resistance are linked and transferred together on one plasmid.

The clinical problem of drug resistance

Concerns about resistance have been raised at regular intervals since the first introduction of antimicrobial chemotherapy, but awareness of the antibiotic resistance problem has probably never been greater than it is today. It has been suggested that antibiotic resistance is becoming so commonplace that there is a danger of returning to the pre-antibiotic era. It is important not to understate or overstate the problem; the situation is presently becoming serious, but is not yet desperate since most infections are still treatable with several currently available agents. This may, however, mean that the only antibiotics that are still active are more toxic or less effective (or both) than those to which bacteria have acquired resistance. For example, it is generally accepted that glycopeptide antibiotics are less effective in the treatment of Staph. aureus infection than are antistaphylococcal penicillins (e.g. flucloxacillin); since the latter cannot be used against methicillin-resistant Staph. aureus (MRSA), this may partly explain the poorer outcome that is seen in such cases in comparison with infection caused by methicillin-susceptible strains.

There is good evidence that if the antibiotic regimen chosen is subsequently shown to be inactive against the pathogens causing infection, then patient outcome is worse (See Fig. Below). This means that clinicians are likely to opt for unnecessarily broad-spectrum therapy particularly in critically ill patients. Unfortunately, repeated use of such regimens against bacteria that harbour resistance genes intensifies the selective pressure for further resistance development, notably in hospital, where the most vulnerable patients are managed.

In many less-developed countries of the world the therapeutic options may be severely restricted for economic reasons. There is no doubt that the problem of antibiotic resistance is a global issue, and in future years there is a real possibility that physicians will be faced increasingly with infections for which effective treatment is not available. Some of the organisms in which resistance is a particular problem are summarized below.

Enteric Gram-negative bacteria

The prevalence of resistance in hospital strains of enteric Gram-negative bacteria has been rising steadily for the past 40 years, particularly in large units. Although cephalosporins, quinolones, and aminoglycosides have been developed to cope with the problem, resistance to these newer compounds continues to increase in most countries. Outbreaks of infection caused by multiresistant Klebsiella strains and extended-spectrum β-lactamase-producing enterobacteria in general are being reported with worrying frequency, especially in high dependency areas of hospitals.

Mortality recorded in three separate studies for patients who received antibiotic treatment that was subsequently shown to be inactive (dark grey) or active (light grey) against pathogens isolated. VAP, ventilator associated pneumonia. Data from: Kollef MH, Ward S. The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest 1998; 113: 412-420; Kollef MH Sherman G, Ward S, Fraser VJ Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115: 462-474; Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118: 146-155.

Widespread resistance in enteric bacteria is a particular problem in less-developed areas of the world where heavy and indiscriminate use of antibiotics may combine with a high prevalence of drug-resistant bacteria in the faecal flora, poor standards of sanitation, and a high incidence of diarrhoeal disease to encourage the rapid emergence and spread of multiresistant strains of enteric bacteria. Epidemics of diarrhoeal disease caused by multiresistant strains of intestinal pathogens, including Vibrio cholerae, shigellae, salmonellae, and toxin-producing strains of E. coli, have occurred around the world.


Acinetobacter

These organisms cause hospital-acquired infections especially in patients in intensive care units, e.g. ventilator-associated pneumonia. Such infections are usually extremely difficult to treat because of the multiple classes of antibiotic resistance found in these bacteria. Very few antibiotics are now reliably effective for treatment of acinetobacter infections. Even with carbapenems such as imipenem, resistance has started to emerge. Colistin, a relatively toxic old antibiotic that has largely been abandoned for systemic administration, has been used to treat some strains that were resistant to all other licensed antibiotics. Many multiresistant Acinetobacter spp. strains are currently susceptible to the new antibiotic tigecycline, and this may be helpful in such infections.

Staphylococci and enterococci

MRSA is endemic in many hospitals and nursing homes. The proportion of Staph. aureus isolates causing serious sepsis, such as bloodstream infection, that are resistant to methicillin has reached 40-50% in the UK and some countries in southern Europe. The prevalence is even higher in countries in the Far East and USA. MRSA infections have often been treated with glycopeptides, and isolates with low-level resistance to these antibiotics can be found. Very occasional MRSA strains with high-level resistance to glycopeptides have also been reported. Several newer antibiotics, including linezolid, daptomycin, and tigecycline, are active against these strains, but occasional reports of resistance have already occurred.

Coagulase-negative staphylococci and enterococci are often multiresistant and cause infections typically in patients with indwelling prosthetic material, such as catheters, vascular grafts, joints and heart valves. A combination of antibiotics may be required to treat serious enterococcal infections, but the emergence of high-level aminoglycoside resistance may seriously limit this option. Enterococci carrying genes conferring high-level resistance to glycopeptides have emerged.

Linezolid has been used successfully to treat infection caused by such strains, but resistance has some occurred in patients receiving long courses of therapy, particularly if the focus of infection has not been removed.

Streptococcus pneumoniae

Another major problem concerns the emergence of resistance in Streptococcus pneumoniae, the most common cause of community-acquired pneumonia and other respiratory infections. This organism used to be combated easily by treatment with penicillin and its derivatives. Unfortunately, isolates with resistance to most antibiotics can now be found in most countries of the world. Such infections are often treated with broad-spectrum cephalosporins, which can attain sufficient tissue concentrations to exceed the raised MIC for these strains. The prevalence of macrolide-resistant pneumococci tends to correlate with how often these antibiotics are used, especially in the community where most respiratory tract infections are treated. Newer fluoroquinolones such as moxifloxacin have increased activity against pneumococci. Some resistance emergence has developed in units where these agents have been used commonly.

Neisseria meningitidis

Decreased levels of susceptibility to penicillin have been seen in many countries, but high-level resistance is exceptionally rare. The emergence of resistance to penicillin in N. meningitidis has important strategic implications because of the need for immediate treatment of the life-threatening infections caused by these organisms. Currently penicillin is still used empirically in some cases of suspected meningococcal infection. The cephalosporins cefotaxime or ceftriaxone are often favoured for the empirical treatment of meningitis because the antibiotic concentration achieved in the cerebrospinal fluid more reliably exceeds the MIC for the pathogen in both meningococcal and pneumococcal infection.

Tuberculosis

Strains of M. tuberculosis that are resistant to two or more of the first line drugs—isoniazid, ethambutol, rifampicin, and streptomycin—are increasing common, particularly in HIV-infected patients. The prevalence of resistant strains varies markedly between countries: in 0-14% of new cases of tuberculosis (median: 1.4%) and 0-54% of previously treated cases (median: 13%) in recent World Health Organization surveys. The resistant bacteria can be transmitted, for example in hospitals, prisons and in the community, and represent a major public health issue. The emergence of resistance is associated with poor compliance with antituberculosis medication. Directly observed therapy is increasingly advocated therefore for patients in whom compliance may be unreliable.

Read More

Sexually Transmitted Diseases

Under Construction

Read More

Blood infections (Bacteremia)

Under Construction

Read More

CNS infections

Under Construction

Read More

Bone and Joint infections

common pathogenic bacteria in bone and joint infection

Bone and Joint Infections

Septic arthritis

Bacteria can infect joints via the bloodstream (haematogenous septic arthritis) from a distant focus of infection such as a septic skin lesion, otitis media, pneumonia, meningitis, gonorrhoea, or an infection of the urinary tract. However, in adults prosthetic joint infection is now by far the most common presentation. Rarely bacteria may be introduced directly into the synovial space following a penetrating wound or an intra-articular injection. Also, 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.

Aetiology

Haematogenous septic arthritis

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 coli form bacilli are found in elderly people. Haemophilus influenzae of serotype b cause septicaemia and pyogenic arthritis in children under the age of 6 but childhood immunization with the H. influenzae conjugate vaccine has 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, and Borrelia burgdorferi, the spirochaete that causes Lyme disease.

Prosthetic joint infection

Acute infections (within 1 year of the primary operation) are often caused by Staph. aureus or Str. pyogenes. Infections occurring more than a year after surgery are caused by a much wider range of bacteria, including coagulase negative staphylococci, enterococci, aerobic Gram-negative bacilli and anaerobic bacteria.

Management

Haematogenous septic arthritis

In nine cases out of 10 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 (Table 1). 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.

In young adults who present with acute mono-arthritis but do not have purulent joint fluid a diagnosis of reactive arthritis secondary to sexually transmitted disease should be suspected.

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 multidisciplinary management, including input from orthopaedic surgeons, medical microbiologists, and physicians. Surgeons in particular should determine whether drainage of pus should be by repeated needle aspiration or wash-out of the joint in an operating theater.

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 1). If bacteria are not seen at this stage, the initial choice is influenced by the age of the patient or the underlying disease. Antibiotics are chosen to cover the most likely bacterial causes of the infection (Table 2) and can be modified subsequently if a pathogen is isolated.

Table 1 Initial antimicrobial therapy in septic arthritis when bacteria are seen in the Gram-film of the joint aspirate

Description of the Gram-film Probable organism Initial choice of antibiotic Comments Gram-positive cocci in clusters Staphylococci Flucloxacillin Clindamycin if penicillin-allergic Gram-positive cocci in chains or pairs Streptococci Benzylpenicillin Clindamycin if penicillin-allergic Gram-negative coccobacilli H. influenzae Fluoroquinolone May change to ampicillin if sensitive Gram-negative large rods Coliform bacilli or Pseudomonas Fluoroquinolone Modify according to culture results Gram-negative diplococci Neisseria spp. Benzylpenicillin Ciprofloxacin if penicillin allergic or resistant

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.

A sequential intravenous-oral regimen, carefully monitored at the time of oral therapy, is widely used. 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. Switch to oral therapy is appropriate once the condition has stabilized as all of the first choice drugs are well absorbed after oral administration. The total duration of treatment is usually between 4 and 8 weeks and should be determined by clinicians who are experienced in management of these infections.

Prosthetic joint infection

Most patients with prosthetic joint infection are not systemically unwell. Infection should be suspected in any patient who develops pain or signs of local inflammation in the joint, although it is impossible to distinguish between mechanical loosening of the joint and infection unless there are obvious signs of infection such as purulent discharge from a sinus.

Because there is rarely systemic illness it is not necessary to start empirical treatment and the chances of establishing a definitive microbiological diagnosis are greatly enhanced if antibiotics are not given. Serious systemic illness is the only reason for giving empirical antibiotics, as it is extremely unlikely that prosthetic joint infection will resolve with antibiotic therapy alone.

Table 2 Initial antimicrobial therapy in septic arthritis when no organisms are seen in the Gram-film of the joint aspirate

Type of patient Most common organisms Less common organisms Initial choice of antibiotic Neonate (0-2 months) Staph. aureus Group B streptococci Gram-negative bacilli Flucloxacillin + gentamicin Infant (2 months-6 years) Staph. aureus Str. pyogenes Str. pneumoniae H. influenzae Flucloxacillin + cefotaxime Child (7-14 years) Staph. aureus MRSA Flucloxacillin Adult (>15 years) Staph. aureus N. gonorrhoeae, MRSA Flucloxacillin Elderly or debilitated Staph. aureus Str. pyogenes Str. pneumoniae MRSA Gram-negative bacilli Flucloxacillin + gentamicin MRSA, methicillin-resistant Staph. aureus.

Patients with suspected prosthetic joint infection should be referred urgently to an orthopaedic surgeon who specializes in revision surgery for prosthetic joints and who is likely to work closely with medical microbiologists and infectious diseases physicians.

Osteomyelitis

Osteomyelitis is infection of bone and is usually caused by bacteria. 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, including a fracture or an overlying chronic ulcer).

Haematogenous osteomyelitis

This type of infection is most commonly caused by staphylococci that reach the site through the bloodstream, usually with no obvious primary focus of infection. Acute haematogenous osteomyelitis is principally a disease of children under 16 years, in whom more than 85% 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% 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 reported with increasing frequency. Coliforms are particularly likely to cause vertebral osteomyelitis, as it is associated with recurrent urinary tract infection. 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.

Non-haematogenous osteomyelitis

When bones are infected by the introduction of organisms through traumatic or postoperative 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 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 biopsy. A bone scan may help to localize the site and extent of the infection. However, bone scan is simply a demonstration of increased blood supply to the affected area and cannot distinguish between infection and other causes of inflammation. A positive bone scan should be a stimulus to further investigation, whereas a negative bone scan makes the diagnosis of osteomyelitis unlikely. Magnetic resonance imaging provides additional information about the presence and location of a sequestrum. Blood cultures should be taken in addition to 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 that are secondarily colonizing the sinus. For precise bacteriological diagnosis, material must be obtained during the surgical removal of dead bone and tissue.

Guidelines for antibiotic therapy and management

It is generally agreed that acute haematogenous osteomyelitis can be cured without surgical intervention, provided 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 biopsy 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. aureus is the prime suspect in any age group, and an antistaphylococcal agent should be used (flucloxacillin or clindamycin). If Gram-negative bacteria are isolated a fluoroquinolone is the drug of choice.

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 details of treatment, including duration of intravenous therapy and total duration of treatment should be determined by specialists with experience in the management of these complex conditions.

Read More

Skin and Soft tissue infections

Under Construction

Read More

Gastrointestinal tract infections

Under Construction

Read More

Urinary tract infections

Under Construction

Read More

Respiratory tract infections

Respiratory Tract Infections

Respiratory Tract Infections

Respiratory infections are caused by viruses, or bacteria, or both. If the illness is entirely viral in origin, an antibiotic will not help. If there is a bacterial component, antibiotic treatment will sometimes help, and may be vital. It is often difficult to recognize when bacteria may be involved in respiratory infection as secondary bacterial infection may complicate viral respiratory infections. However, the key question in the decision about treatment with antimicrobials is: do the benefits to the patient outweigh the risks? It is not necessary to prescribe antimicrobials for all bacterial respiratory infections.

When considering the role of antimicrobial chemotherapy it is important to reflect on the epidemiology of infection in the twentieth century (Fig. 1). There are two striking features: the doubling of mortality in 1918, caused by the influenza pandemic; and the steep decline in mortality through the first half of the century, before the arrival of antimicrobial chemotherapy or vaccines. The introduction of antimicrobial chemotherapy did accelerate the decline in mortality from some respiratory infections (e.g. otitis media, pneumonia, and tuberculosis) but had no impact on others (e.g. bronchitis). Two conclusions can be drawn from Fig. 19.1 first, it is clear why there is so much concern about the possibility of an influenza pandemic given the massive impact on mortality of the 1918 pandemic. Second, antimicrobial chemotherapy has not had the dramatic effect on mortality from infections that is popularly attributed to it. The major impact in the first half of the twentieth century came from improvements in public health, which is why death from all infections still increases with increasing socio-economic deprivation in the twenty-first century. Antimicrobial chemotherapy is just one component of an overall strategy to prevent and treat infections.

Fig. 1 Infectious diseases mortality in the USA during the twentieth century. Reproduced from Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. Journal of the American Medical Association 1999; 28: 61-66 with permission from American Medical Association.

Upper respiratory tract infection

Sore throat

This is one of the commonest acute problems seen in general medical practice, with an incidence of 100 cases per 1000 inhabitants per year, although only a minority of these will present to a doctor. It is commoner in females than men. Symptoms include: sore throat with anorexia, lethargy, and systemic illness. On examination there may be inflamed tonsils or pharynx, a purulent exudate on tonsils, fever, and anterior cervical lymphadenopathy.

Sore throat may be part of the early symptom complex of many upper respiratory viral infections, in which case cough is a common additional feature. Occasionally, it may be a presenting symptom of acute epiglottitis or other serious upper airway disease.

There is no evidence that bacterial sore throats are more severe or long-lasting than viral ones. The most commonly identified organism is Streptococcus pyogenes, the group A β-haemolytic streptococcus. Most other cases are caused by adenoviruses. There is no reliable way to distinguish between bacterial and viral causes based on symptoms and signs.

The gold standard for diagnosis of streptococcal infection in the throat includes a positive anti-streptolysin O (ASO) titre in addition to culture of Str. pyogenes from the throat. There is a high asymptomatic carrier rate for the organism (up to 40%) and it is common to culture it from sore throats when there is no serological evidence of infection. Moreover a negative culture does not rule out Str. pyogenes as a cause of sore throat. Neither culture of throat swabs nor rapid tests based on detection of streptococcal antigen are helpful in most cases.

Most people with sore throat manage the condition successfully without seeing a doctor. Paracetamol is an effective analgesic, with less risk of adverse effects than non-steroidal anti-inflammatory drugs. Aspirin should be avoided in children because of the risk of Reye's syndrome. The immediate benefits from antimicrobial chemotherapy are actually very meagre. Symptoms usually persist for 5-7 days with or without antibiotics, which only shorten illness by 24 h. The same control of symptoms can probably be achieved with paracetamol.

Streptococcal sore throat is important because it may lead to serious complications, particularly rheumatic fever, which is still prevalent in many countries. Evidence about the effectiveness of antibiotics for preventing nonsuppurative and suppurative complications comes from studies on military personnel living in overcrowded barracks in the late 1940s and early 1950s. This evidence has little relevance to management of sore throat in modern communities, at least in the developed world, where rheumatic fever is now very uncommon. Similarly experience with the use of antibiotics to prevent cross-infection in sore throat comes mainly from army barracks and other closed institutions. It is very unlikely (and unproven) that trying to eradicate Str. pyogenes with routine antibiotic therapy for sore throat will produce any measurable health gain in the general public in Western countries, whereas it is likely that this would increase the prevalence of antimicrobial resistance.

A patient information leaflet may be of value in the management of acute sore throat and may assist in managing future episodes at home without general practitioner involvement. Patients who are skeptical about withholding antibiotics can be given a prescription with the suggestion that they do not use it unless their symptoms persist for more than 3 days. Only about 30% of patients who are given delayed prescriptions go to the pharmacy to get their antibiotics.

If antibiotics are to be prescribed the drugs of choice are penicillin V or a macrolide, and these should be given for at least 10 days to eradicate the organism and prevent recurrence. Glandular fever commonly causes symptoms and signs that are indistinguishable from streptococcal throat infection (including a very impressive purulent exudate on the tonsils). Ampicillin, amoxicillin, and co-amoxiclav should not be used, as they will cause a rash if the sore throat is the herald of glandular fever. Tetracyclines are also inappropriate because of the high incidence of resistance among streptococci.

Other infections that may present with sore throat

Croup

Noisy difficult breathing, hoarseness, and stridor are common signs of croup, a distressing condition that is usually viral in origin. Treatment is supportive; the condition is usually self-limiting and resolves in 2-4 days if uncomplicated, but severe cases may require endotracheal intubation or tracheostomy. Acute epiglottitis is a much less common, but much more dangerous, cause of croup caused by infection with Haemophilus influenzae type b; it can occur in adults as well as in children. There is systemic illness as well as local respiratory difficulty, and the swollen oedematous epiglottis can cause complete airways obstruction with dramatic suddenness. It is this complication that makes acute epiglottitis such a life-threatening condition. Treatment is as much concerned with maintaining the airways as with controlling the infection.

If breathing difficulty is present in a patient with croup, urgent referral to hospital is mandatory and attempts to examine the throat should be avoided.

Diphtheria

Although rare in countries with effective vaccination policies, diphtheria is still prevalent in many parts of the world. Diagnosis is made on clinical grounds, notably the presence of a characteristic membranous exudate on the tonsils and pharynx. Treatment with antitoxin should be given immediately without waiting for laboratory confirmation. Antibiotics have no part to play in treating the infection, but penicillin or erythromycin is effective in eradicating the infection to prevent spread.

Thrush

Oral thrush, infection of the mucous membrane with the yeast Candida albicans, is predominantly a neonatal infection. Candida is a common vaginal commensal, especially in pregnancy, and the infant acquires infection during passage through the birth canal. It presents in the first few days of life as white curdy patches on cheeks, lips, palate, and tongue. Treatment is with local nystatin.

In adults, oral thrush may follow treatment with antibacterials or corticosteroids. However, it may be indicative of serious underlying disease, such as diabetes or immunodeficiency. In all these conditions one of the oral polyene or azole derivatives may be used to control the candida.

Acute otitis media

Three-quarters of cases of acute otitis media occur in children; one in four children will have an episode during their first 10 years of life. Acute otitis media should be distinguished from otitis media with effusion, commonly referred to as glue ear; as many as 80% of children suffer this infection at least once before the age of 4.

Acute otitis media is an inflammation of the middle ear of rapid onset presenting with local symptoms (earache, rubbing or tugging of the affected ear) and systemic signs (fever, irritability, disturbed sleeping). It is often preceded by other upper respiratory symptoms such as cough or rhinorrhoea. On examination a middle ear effusion may be present but in addition the drum looks opaque and may be bulging.

The condition is caused predominantly by H. influenzae and Streptococcus pneumoniae. Staphylococci, Str. pyogenes, and α-haemolytic streptococci are less often involved. However, acute otitis media should not be treated routinely with antibiotics. As with sore throat, antibiotics only have a small impact on the duration of acute symptoms, which can be controlled equally effective with paracetamol. If an antibiotic is to be prescribed a 5-day course is sufficient; the antibiotic of choice is amoxicillin; erythromycin and coamoxiclav are logical alternatives and may be necessary if β-lactamase-producing H. influenzae is involved. Decongestants, antihistamines, and mucolytics are not effective. As with sore throat, patient information leaflets and delayed antibiotic prescriptions are effective strategies for reducing the unnecessary use of antibiotics.

Glue ear is an inflammation of the middle ear with accumulation of fluid in the middle ear but without symptoms or signs of acute inflammation. It is often asymptomatic and earache is uncommon. On examination a middle ear effusion is present but with a normal looking ear drum. Antibiotics should not be given.

Acute sinusitis

Acute sinusitis presents with pain originating in the maxillary, frontal, ethmoid, or sphenoid sinuses, with the maxillary sinus being by far the commonest. Onset of facial pain is often preceded by non-specific symptoms of upper respiratory inflammation and there may be systemic signs of inflammation. The bacterial causes of acute sinusitis are the same as acute otitis media. If X-ray or culture confirms the clinical diagnosis then antibiotics can substantially reduce the duration of symptoms. However, neither of these investigations is routinely available in primary care.

Culture of the sinuses requires percutaneous sinus puncture and aspiration, which is not a procedure that most general practitioners are trained to do (or that many patients would consent to). Unfortunately antibiotic treatment of patients with symptoms suggestive of sinusitis but without confirmation by X-ray or culture is no more effective than symptomatic relief.

As with acute otitis media antibiotics for acute sinusitis should be reserved for the more severe cases. Penicillin V or amoxicillin are as effective as newer antibiotics. The recommended duration of treatment is 10 days in the absence of evidence that shorter courses are as effective.

Lower respiratory tract infections

Acute cough is the most common symptom of lower respiratory infection, whether as a new symptom or as an exacerbation of chronic symptoms. Cough is not a universal feature: some patients with pneumonia present with pleuritic chest pain or with symptoms of systemic inflammatory response (fever, malaise, headache, or myalgia) without cough. The most important diagnosis to make is pneumonia because it can be life threatening and its outcome can be improved with antimicrobial chemotherapy. However, it is not possible to distinguish reliably between pneumonia and other causes of lower respiratory tract infection from clinical history and signs. Consequently, in primary care management must be based on an assessment of severity of illness and need for referral to hospital.

Epidemiology

The incidence of lower respiratory tract infection in the UK is between 40 and 90 cases per 1000 population per year, being commoner in the very young and old and in the winter months. In the UK there is about a four-fold higher incidence in the most deprived communities in comparison with the most affluent communities.

Mortality is highest in the elderly. The 30-day mortality associated with lower respiratory tract infection in people over 65 years old is 10%. However, many of these elderly people die ‘with’ rather than ‘of’ the infection. Bronchopneumonia is often recorded as the immediate cause of death in people with chronic, life-threatening diseases. Mortality from ‘pneumonia’ has actually increased in developed countries since the introduction of antibiotics, but more people are living longer and most of this mortality is from bronchopneumonia.

Most people with lower respiratory infections manage their own symptoms without seeking medical attention. Of 1 million people with lower respiratory tract infection only 300 000 will see a primary care physician. Of these 1 in 4 (70 000) will be treated with antibiotics, although only about 1 in 10 (7000 people) will have a diagnosis of pneumonia. From the original 300 000 people who presented to a primary care physician only about 200 (0.7%) will be admitted to hospital with pneumonia.

Management in primary care

The key to management of lower respiratory tract infection in primary care is to distinguish between patients who have severe infection that should be referred to hospital and the majority (99%) who can be managed safely at home. There are four questions to address:

• Has the patient been previously well or is there underlying chronic respiratory or other disease?
• Has there been the development or deterioration in either dyspnoea or sputum purulence?
• Are there any new localizing physical signs in the chest to suggest pneumonia?
• Are any features of severity present (Box 19.1).

The answers to these questions distinguish between four broad populations of people with lower respiratory tract infection. These will be discussed starting with the most severe (but least common).

Box 19.1 Features of severity of lower respiratory tract infection that can be easily assessed in primary care (items in bold are most important)

• Raised respiratory rate (>30/min)
• Low blood pressure (<90mmHg systolic and or <60mmHg diastolic)
• Confusion of recent onset
• Age>50 years
• Coexisting disease present (e.g. severe chronic obstructive pulmonary disease, cardiac failure, cerebrovascular, neoplastic, renal or liver disease)
• Very high or very low temperature (<35°C or >40°C)
• Tachycardia (>125/min)

Patients with features indicating severe infection

Referral to hospital should be considered in patients who exhibit one or more of the features of severity , especially if they are over the age of 50. This applies whether or not the patient has additional physical signs indicating pneumonia because the absence of these signs is not a reliable method for excluding pneumonia. The final decision should be based on clinical judgement that includes social factors. Even a relatively well patient who lives in poor social circumstances or in an isolated rural area with no home support may require referral to hospital. Conversely patients who are 65 years old and have signs of pneumonia can be managed safely at home if they have sufficient social support.

Suspected community-acquired pneumonia without features of severity

These patients have new focal signs in the chest (crackles or altered breath sounds), but are not severely ill. In the absence of chest X-ray (not available in many primary care settings) pneumonia can be diagnosed from symptoms of an acute lower respiratory infection (cough or dyspnoea or pleuritic chest pain) with at least one systemic symptom of infection (fever or tachycardia) and new focal signs on chest examination. However, only 50% of those with all of these features will actually have an abnormal chest X-ray.

Below the age of 45 very few patients with pneumonia also have chronic obstructive pulmonary disease. Between the ages of 45 and 64 the proportion is up to 10% and rises to 20% between the ages of 75 and 84. Pneumonia in these patients is more likely to be associated with severity criteria.

A wide variety of organisms can cause pneumonia, including viruses. The commonest bacterial cause is Str. pneumoniae, which accounts for about 70-80% of cases in which a bacterial pathogen is identified. Atypical bacteria (Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae, Chlamydophila psittaci, Legionella pneumophila, and Coxiella burnetii) collectively account for 10-20% of cases and the remainder are caused by H. influenzae or Staphylococcus aureus. The latter is particularly associated with secondary bacterial infection following influenza.

With current technology neither sputum culture nor blood tests such as C-reactive protein or white cell count provide sufficient added value to the diagnosis to justify routine use. Sputum culture may be recommended in areas with a high prevalence of penicillin-resistant pneumococci.

Pneumonia is a life-threatening illness. None the less, patients with no features of severity can be managed safely at home with oral amoxicillin, a macrolide, or a tetracycline. There is no need to give combination therapy. A macrolide or tetracycline may be preferred if there are clinical features suggesting infection with one of the atypical bacteria (e.g. prominent upper respiratory symptoms, headache, or symptom duration for >1 week) particularly in younger patients or during an epidemic year for M. pneumoniae.

Patients with underlying chronic respiratory disease

These patients often have no new signs in the chest other than dyspnoea and sputum purulence. In the absence of signs of severity or of pneumonia the diagnosis is an acute exacerbation of the underlying condition. The likely bacterial pathogens are H. influenzae, Str. pneumoniae, and Moraxella catarrhalis. The development of green (purulent) sputum is a good indicator of a high bacterial load in the sputum. However, even in these patients antibacterial treatment has only a slight impact on the course of an acute exacerbation, shortening an illness of 5-7 days by no more than 1 day. Antibacterial treatment does not benefit patients with acute exacerbations of chronic obstructive pulmonary disease who do not have purulent sputum. The prevalence of resistance to aminopenicillins in H. influenzae is 10-30% and is much higher in Mor. catarrhalis. Despite this the clinical effectiveness of amoxicillin is just as good as co-amoxiclav or fluoroquinolones, probably because of the modest benefit from any antibacterial treatment. For the same reason routine sputum culture is not recommended and should be reserved for patients with symptoms that persist despite treatment with amoxicillin. A macrolide or tetracycline is appropriate for patients who are allergic to penicillin, or who have not responded to amoxicillin treatment. Fluoroquinolones should not be used empirically in the management of exacerbations of respiratory disease in primary care.

Non-pneumonic lower respiratory infection (acute bronchitis)

Most patients with no signs in the chest, who have been previously well and do not have other features of severity, have non-pneumonic infection, most of which are caused by viruses. A few cases are caused by M. pneumoniae, Bordetella pertussis, C. pneumoniae, Str. pneumoniae, or H. influenzae. Patients will have an illness lasting several days with or without antibiotics, which should not be prescribed unless patients have signs in the chest or features of severity (Box 19.1). Sputum purulence alone is not an indication for antibiotics in a previously well patient with no chest signs. As with sore throat and acute otitis media, patient information leaflets and delayed prescriptions are effective strategies for reducing unnecessary antibiotic treatment.

Pertussis (whooping cough)

Antibiotics are notoriously ineffective in controlling the distressing cough of pertussis; nevertheless, erythromycin has been shown to eradicate the organism from the respiratory tract and can also be used for the protection of susceptible close contacts. Vaccination is the only reliable way of preventing and controlling this early childhood infectious disease.

Cystic fibrosis

The susceptibility of patients with cystic fibrosis to pulmonary infection is well recognized and is often the cause of early death. Most lung infections in patients with cystic fibrosis are managed in the community, usually by outreach teams from secondary care. One of the striking features of chest infections in cystic fibrosis is that relatively few pathogens are involved. Early in the disease the organisms implicated are frequently Staph. aureus or H. influenzae, or both. As patients progress through adolescence to adulthood, these pathogens are replaced by Pseudomonas aeruginosa. Major problems arise when Ps. aeruginosa is replaced by Stenotrophomonas maltophilia or Burkholderia cepacia; these organisms are often resistant to many antibiotics and treatment should be guided by laboratory findings. The selection of antibiotics in patients with cystic fibrosis should be determined by the specialist services that manage the patient.

Management in hospital

Community-acquired pneumonia

In hospital the clinical diagnosis can be confirmed with a chest X-ray, although it should be recognized that its sensitivity is not 100%. The gold standard for diagnosis of bacterial pneumonia is culture of bacteria from lung tissues or a needle aspirate from the lung but these tests are too dangerous to use in routine clinical practice. The point is that some patients with pneumonia can have a normal chest X-ray at presentation, so if the clinical features strongly suggest pneumonia it is reasonable to treat and repeat the chest X-ray after 24-48 h.

The severity criteria for community-acquired pneumonia are based on assessments of confusion, urea concentration, respiratory rate, and blood pressure for those 65 years of age and older (CURB-65 score; Table .1). It is similar to but importantly different from the classification of severity of sepsis. The CURB-65 score is specifically designed to be used in patients who present to hospital in order to identify low-risk patients who do not need to be admitted to hospital, whereas the classification of sepsis is intended to be used for any patient with infection (community or hospital acquired) to identify patients who are deteriorating and require more intensive therapy. The CURB-65 score identifies low-risk patients more accurately than the sepsis severity score. There are more complex pneumonia-specific scores (for example the pneumonia severity index used in North America) but these are no more accurate than CURB-65.

Table .1 The CURB-65 severity score for patients presenting to hospital with community acquired pneumonia and the mortality range measured in two prospective cohort studies. CURB-65: score one point for each of: Confusion; urea >7mmol/l; respiratory rate ≥30/min; low systolic (<90mm Hg) or diastolic (≤60mm Hg) blood pressure); age ≥65 years
Risk CURB-65 score 30-day mortality Low risk 0-1 0-1% Intermediate 2 8-9% High risk >2 22-23% All patients Not applicable 9-10% Data from Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377-382.

Between 30 and 50% of patients who present to hospital with community-acquired pneumonia are found to be in the CURB-65 low-risk group. However, about half of these patients have other reasons for admission. Some will have co-morbidities that require inpatient management. In particular, patients with chronic obstructive pulmonary disease and pneumonia could be in respiratory failure and yet have a CURB-65 score of 0 (if they have a respiratory rate <30/min, which is likely if they have Type 2 respiratory failure). In addition to medical reasons for admission some patients will have poor social circumstances or insufficient support to be managed at home.

The management of patients admitted to hospital should be determined by their CURB-65 score. Low-risk patients who are admitted for other reasons can be managed in the same way as low-risk patients in the community, with either amoxicillin, a macrolide, or a tetracycline. Some guidelines do recommend that all patients admitted to hospital with pneumonia should receive antibiotics for pneumonia caused by atypical bacteria but several clinical trials shows that treatment with an aminopenicillin alone is just as effective for patients with low or intermediate risk pneumonia.

At the other end of the scale, patients at high risk should be treated with intravenous antibiotics that are effective against the full range of pathogens that may cause community-acquired pneumonia. Possible regimens include co-amoxiclav or cefuroxime plus a macrolide, or a fluoroquinolone with good activity against Str. pneumoniae (e.g. levofloxacin). The patient must receive the antibiotic(s) immediately and certainly within 4h of admission as later administration is associated with increased mortality. If patients are admitted through an Accident and Emergency Department they must receive their first dose of antibiotics there before transfer to the ward. If they are admitted direct to a ward the first dose must be clearly written for immediate administration, not left until the next drug round. In addition to intravenous antibiotics patients with severe pneumonia must have their oxygen requirements assessed by pulse oximetry or blood gas measurement within 4h of admission and receive high flow oxygen (5 litres per minute) if they are hypoxic. Adequate fluid replacement is also essential. Patients should be referred to a high dependency or intensive care unit if their vital signs do not improve rapidly. When young patients die from community-acquired pneumonia it is usually because of failure to recognize the need for intensive care.

The management of patients at intermediate risk falls between these two extremes and is a matter for clinical judgement. If in doubt it would be wise to treat as severe pneumonia while waiting for senior review.

Hospital-acquired pneumonia

Pneumonia is the leading cause of mortality resulting from infection acquired in hospital. The incidence of hospital-acquired pneumonia in intensive care units ranges from 10 to 65%, with case fatalities of 13-55%. It is often associated with mechanical ventilation. The risk of hospital-acquired pneumonia can be substantially reduced by using non-invasive methods for respiratory support instead of ventilation and by having clear care protocols for protecting host defences against respiratory infection during mechanical ventilation. Chemoprophylaxis plays a role through the use of selective decontamination of the digestive tract, which reduces the numbers of Gram-negative bacilli and hence the risk of infection.

The micro-organisms causing pneumonia within 5 days of admission are quite different from those seen in disease with a later onset. The bacteria responsible for early onset pneumonia are Str. pneumoniae, H. influenzae, Staph. aureus, and only rarely enteric Gram-negative bacilli. In contrast late onset infection is almost always caused by Gram-negative bacteria, mainly enterobacteria but also Ps. aeruginosa and Acinetobacter spp.

Methicillin-resistant Staph. aureus (MRSA) is becoming increasingly common in some units. Since tracheal aspirates are poor indicators of the cause of ventilator-associated pneumonia, bronchoalveolar lavage is recommended to confirm the diagnosis.

Empirical treatment for early onset pneumonia in patients who have not received antibiotics should be with co-amoxiclav or cefuroxime. Treatment of patients who have already received antibiotics or have late onset disease should be with a broad-spectrum cephalosporin such as cefotaxime, a fluoroquinolone or piperacillin plus tazobactam. Combination therapy is no more effective than monotherapy. Subsequent treatment should be directed by the results of broncho-alveolar lavage.

Other respiratory tract infections

Pneumonia developing in association with neutropenia following treatment with cytotoxic drugs, or in patients with immunosuppression, including those suffering from AIDS, may be due to Pneumocystis carinii, other fungi, or viruses

Read More