When selecting an antibiotic for the treatment of pneumonia, the prescriber should consider the issues that will be of particular importance in the next century. The most important issue is the emerging resistances that threaten the effectiveness of all available antibiotics. These resistances involve not only respiratory tract pathogens, but also organisms infecting other parts of the body. The recognition of new respiratory tract pathogens is another issue to be considered. Chlamydia pneumoniae is increasingly being identified as playing a significant role in pneumonia.
Community-acquired pneumonia is a significant cause of morbidity and mortality today, just as it was in any of the preceding decades of the antibiotic era. Many of the questions on the management of patients with community-acquired pneumonia have remained unchanged over time. However, there are some specific issues of particular relevance in the 1990s. These are the increasing problem of antimicrobial resistance and the recognition of new pathogens. These factors are the main reasons for the latest recommendations for the empirical treatment of community-acquired pneumonia.1
Emerging antimicrobial resistance
The emergence of bacterial resistance is of global concern. When making recommendations for therapy, the current level of resistance for all pathogens must be known. This includes not only respiratory pathogens, but also `bystander' organisms as the antibiotics used in the respiratory tract will exert selective pressure on bacteria in other parts of the body. This has consequences for the treatment of other infections not only in the same patient, but also within the whole community. The organisms with significant emerging resistances are Streptococcus pneumoniae and Haemophilus influenzae in the respiratory tract and as bystanders, aerobic Gram negative rods (e.g. Klebsiella) and enterococci.
During the last decade we have seen the emergence of penicillin resistance in pneumococci. Penicillin was used for almost 4 decades before resistance was detected. What caused this to occur after such a long exposure? The widespread use of cephalosporins is thought to have provided the selective pressure, initially in normal oral flora, with transmission of the genetic material coding for this resistance to the pneumococcus. The resistance seen in pneumococci is due to a structural change in the binding site for penicillin and cephalosporins. It is not due to enzymatic breakdown by a beta lactamase.
There are two levels of resistance possible in these organisms: intermediate resistance (minimum inhibitory concentration (MIC) between 0.1 mg and 1.0 mg/L) and full resistance (MIC >=2.0 mg/L). The combined resistance rates are rising in all areas of the world with rates in excess of 50% in many parts of Europe and the U.S.A. In Australia, 1997 surveillance data collected by the Australian Group on Antimicrobial Resistance (AGAR) show intermediate resistance at 16.8% and resistance at 3.7%. It is current opinion that those isolates with the lower level of resistance can still be successfully treated with penicillin if antibiotic concentrations in excess of the MICs are reached in the lung. However, the higher level of resistance may be associated with treatment failure. With time these MICs are expected to rise such that, at some stage, penicillin will no longer be the treatment of choice for pneumococcal infections in the respiratory tract.
Resistance in this organism is mediated by the production of a beta lactamase. Resistance figures for 1996 from the National Antibiotic Resistance Surveillance Programme (NARSP) show that almost 28% of H. influenzae are resistant to penicillin/amoxycillin. This is an increase from 19% in 1992.
Resistance mediated by extended spectrum beta lactamases (ESBLs) has emerged in aerobic Gram negative bacilli, in particular Klebsiella and E. coli. As a result, the third generation cephalosporins are not effective therapy. The selection of ESBL producing organisms is of particular concern within hospitals. Enterococci with resistance to amoxycillin and vancomycin, the so-called vancomycin resistant enterococci (VRE), have emerged primarily in the 1990s. These organisms can not only cause hospital-acquired infection, but also community infections such as infective endocarditis and urinary tract infections. These organisms are virtually untreatable and for serious infections have a very high mortality.
It is not sufficient in the 1990s to establish the susceptibility profiles for respiratory pathogens and prescribe for that disease in isolation. What we must also take into consideration is the impact that prescribing will have on other organisms. We must be aware as we approach the new millennium that every antimicrobial that is prescribed has the potential for global impact. There is a very real possibility that the outcomes of infectious diseases will resemble those of the pre-antibiotic era. These population concerns may conflict with the prescriber's duty of care to the individual patient.
Recognition of new pathogens
Less than half the sputum cultured from patients with pneumonia will be positive for one of the recognised respiratory pathogens. This is in part due to difficulties with obtaining a specimen from a representative area of infection, lack of diagnostic capabilities for some pathogens and lack of sensitivity for some techniques. When legionellosis first occurred in 1976, it took some time to identify the previously unrecognised pathogen. We must therefore be aware that it is quite possible that there are other such organisms waiting to be `discovered'. Chlamydia pneumoniae is an organism that was only recognised in the 1980s and is now known to play a very significant role as a respiratory pathogen. Typically it causes a primary infection in the young adult with a mild respiratory illness. Reinfection in the elderly is associated with more severe disease and is often accompanied by infection with other organisms, particularly S. pneumoniae.
Choice of antimicrobial therapy
The choice of empirical therapy must take into account the range of pathogens potentially causing the infection, the severity of the infection, the known susceptibility patterns for the respiratory pathogens and the effect of any antibiotics on the bystander organisms. The current Australian antibiotic guidelines1 consider these factors (Table 1).
Pneumonia of mild to moderate severity
The requirement for hospitalisation of a patient will depend not only on the severity of illness, but also on a number of factors that are associated with higher morbidity and mortality. The suggested criteria for hospitalisation are shown in Table 2.
As for the treatment of any infection, oral antibiotic therapy is preferred unless parenteral therapy is specifically indicated (Table 3). The choice of oral therapy includes the macrolides, roxithromycin and erythromycin. These drugs will provide cover for S. pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae. The choice between these two drugs will depend on two factors: the likelihood of haemophilus infection (patients with pre-existing pulmonary disease or with a history of smoking) and any previous gastric intolerance to erythromycin. Roxithromycin is the preferred drug in both these situations. It has somewhat better activity against H. influenzae and, as it is not a motilin receptor agonist, there are fewer problems with gastric pain, nausea and vomiting.3
|Mild to moderate infection|
|cefotaxime or ceftriaxone|
|Alternative parenteral therapy||erythromycin|
|* Not suitable for young children (8 years of age or younger) as teeth may be permanently stained.|
One or more of the following not attributable to another cause:
In the absence of any of these, a high risk is also associated with two or more of the following:
Amoxycillin is effective against pneumococcal infections and 70% of the haemophili, however it does not provide any cover for infections with mycoplasma or chlamydia. Any failure to respond to amoxycillin should prompt the substitution of a drug active against these `atypical' organisms.
Doxycycline is active against most pneumococci, haemophilus, mycoplasma and chlamydia. It cannot be used in children (8 years of age or younger) as it may cause permanent discolouration of the teeth.
For empirical parenteral therapy, benzylpenicillin remains the treatment of choice. In the elderly patient, however, I would add a macrolide as Chlamydia pneumoniae can be of significance and, as already mentioned, may be part of a mixed infection. The use of a third generation cephalosporin in patients with mild to moderate pneumonia should be avoided because it encourages the emergence of resistance.
Choice of oral or parenteral therapy*
Compared with oral administration, parenteral use of antimicrobials has several disadvantages, including a greater risk of serious adverse events, additional time and expertise to administer, a much higher drug product cost and additional cost of equipment, e.g. syringes, needles, tubing.
Oral administration should be used in preference to parenteral therapy unless:
Once parenteral administration is commenced, the need for the parenteral route should be reassessed daily, with the aim of converting to oral administration as soon as possible.
|* Adapted with permission from the 10th edition of `Therapeutic Guidelines: Antibiotic'.|
For patients with severe pneumonia, there are two recommended treatment regimens. One regimen includes a third generation cephalosporin; the other does not (Table 1). Overseas authorities (American Thoracic Society4, Infectious Diseases Society of America5 and United Kingdom - expert committee6) recommend a combination of a third generation cephalosporin and erythromycin. The new Australian guidelines include an alternative regimen in which there is no third generation cephalosporin. This is in recognition of the influence of antibiotics prescribed for pneumonia on bystander organisms. This particular regimen is recommended for institutions where there is a particular concern about resistant enterococci or Gram negative organisms.
For all patients, if a pathogen is cultured and susceptibilities are available, treatment should be altered to the antibiotic with the narrowest spectrum possible. Also, for patients receiving parenteral therapy, oral therapy should be substituted when the patient's clinical condition is improving, they are haemodynamically stable and they can tolerate oral medication, often within 2-4 days.
Prescribing in the 1990s and into the new millennium brings with it an enormous responsibility. Treatment of infections in the respiratory tract is one of the main indications for antibiotic use in Australia. There is an immense potential for these drugs to select for resistant organisms. Resistance is increasing at an alarming rate and, although the release of drugs such as the newer fluoroquinolones will offer temporary respite, all prescribers must be held accountable for our rapid progression towards an era of untreatable infections. Adherence to antibiotic prescribing guidelines offers the possibility of slowing this progression.
I would like to thank the Australian Group on Antimicrobial Resistance (AGAR) for providing the Australian data on pneumococcal resistance, and Jan Bell and John Turnidge for providing data from the National Antibiotic Resistance Surveillance Programme (NARSP).
O'Brien TF. The global epidemic nature of antimicrobial resistance and the need to monitor and manage it locally. Clin Infect Dis 1997;24(1 Suppl): 2S-8S.
Acar JF. Consequences of bacterial resistance to antibiotics in medical practice. Clin Infect Dis 1997;24(1 Suppl):17S-18S.
Niederman MS. Community-acquired pneumonia: a North American perspective. Chest 1998;113(3 Suppl):179S-182S.
The following statements are either true or false.
1. A cephalosporin is the preferred oral treatment for mild or moderate pneumonia.
2. Benzylpenicillin is the drug of choice for the empirical parenteral treatment of mild-moderately severe pneumonia.
Answers to self-test questions
- Writing Group for Therapeutic Guidelines: Antibiotic. Therapeutic guidelines: antibiotic. 10th ed. Melbourne: Therapeutic Guidelines Limited, 1998.
- Fine MJ, Smith DN, Singer DE. Hospitalization decision in patients with community-acquired pneumonia: a prospective cohort study. Am J Med 1990;89:713-21.
- Sarna SK, Soergel KH, Koch TR, Stone JE, Wood CM, Ryan RP, et al. Gastrointestinal motor effects of erythromycin in humans. Gastroenterology 1991;101:1488-96.
- Niederman MS, Bass JB, Campbell GD, Fein AM, Grossman RF, Mandell LA, et al. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity and the initial antimicrobial therapy. American Thoracic Society. Medical Section of the American Lung Association. Am Rev Respir Dis 1993;148:1418-26.
- Bartlett JG, Breiman RF, Mandell LA, File TM. Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis 1998;26:811-38.
- Woodhead M. Community-acquired pneumonia guidelines - an international comparison: a view from Europe. Chest 1998; 113(3 Suppl):183S-187S.