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Respiratory infections in the patient at risk: An overview
Respiratory Infections in the Patient at Risk: An Overview LOWELL S. YOUNG, M.D.
he last three decades have witnessed important changes in the nature, diagnostic approaches to, and treatment of lung infections. At one time, most pulmonary infections were thought to be due to either viruses or bacteria, such as the pneumococcus. Rarely, in severely debilitated patients gram-negative rods such as Klebsiella pneumoniae caused life-threatening pneumonia. We know now that many infections, indeed the majority that develop through aspiration or inhalation mechanisms, are “mixed” bacterial processes. Furthermore, new respiratory pathogens have become increasingly recognized. One need cite only the examples of Legionella pneumophila, Chlamydia species, and a host of viral agents including the cytomegalovirus as causes of lung infection in persons with impaired host defenses. Epidemiologically, the appearance of an unusual problem such as Aspergillus or Legionella infections in a hospital caring for high-risk patients is an important clue to a nosocomial infection risk. These outbreaks should be the impetus for careful investigation of sources for microorganisms in the hospital environment. In this sense, a high-risk or immunocompromised patient is much like the “sentinel guinea pig” of Riley et al [l] who studied the epidemiologic aspects of hospital dissemination of tuberculosis in a series of classic studies. Indeed, the nosocomial incidence of Legionella infections is more than 10 times greater in immunosuppressed patients than the incidence in otherwise normal patients assumed to have comparable infection exposure [ 21. Extrinsic sources of infection have received much attention from workers in the nosocomial infection field, but it is in this area that very little solid data exist. Rhame’s review concentrates on three infectious processes, Aspergillus in particular. Little question exists that nosocomial outbreaks of Aspergillus occur in construction areas or in areas where conditions lead to dispersion of spores. However, more adequately
T
controlled studies are still needed because there are institutions that have had relatively little problem with this infection as opposed to that with which Rhame has had to contend over much of the last few years. Control measures short of total filtration of air (which some investigators have resorted to) must be regarded as innovative, but Rhame and associates have realized that total sterility of the air may be an economically unrealistic goal. The interim solution represents a compromise and it has led to a quantitative reduction in dispersion of spores and a corresponding reduction in the incidence of infection. The example of nosocomial Aspergillosis stands out as one in which a clear-cut extrinsic source of infection is present. What about the many other serious respiratory infections that we must now contend with in the patient at risk? Pneumocystosis is a reactivation of a very common childhood infection, and the current epidemic of acquired immune deficiency syndrome (AIDS) suggests that not only is this a reactivation of latent infection but also, similar to studies in animal models, the host never really eradicates the pathogen. Thus, antimicrobial therapy temporarily leads to arrest of pneumocystic infection, but the rate of recurrence of pneumocystosis in patients with AIDS is very high. Most bacterial pathogens that cause pneumonia reach the lung by the aspiration route. Although much investigative work has been carried out in defining lung defense mechanisms, as outlined in Pennington’s presentation there unfortunately has been little translation of this work into practical means in the diagnosis, treatment, and prevention of serious lung infections. For instance, one might hope that antiserum or immunization against gram-negative bacilli would lead to some reduction in the incidence of gram-negative pneumonia in intensive care units or immunosuppressed patients on the basis of the encouraging work in animal models that augmentation of humoral antibodies can confer
From the Department of Medicine, U.C.L.A. School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Dr. Lowe//S. Young, Department of Medicine, U.C.L.A. School of Medicine, Los Angeles, California 90024.
78
May 15, 1984
The American Journal of Medicine
PATIENT AT RISK AND ANTIMICROBIAL
some
protection
against
dence
in human
studies
THERAPY
YOUNG
However,
evi-
treatment
of lung infections
that this is an effective
ap-
produced
by cough was the sole basis for the microbi-
pneumonia.
proach has only been suggested by some less than satisfactory clinical studies [3]. Epidemiologic data have provided extremely interesting insights into the pathogenesis of pneumonia in debilitated subjects, but how this new knowledge can be translated into practical preventive measures remains to be seen. Johanson and his colleagues have demonstrated the importance of pharyngeal colonization by gram-negative bacilli as the antecedent event in gram-negative pneumonia. Simply put, sick patients in hospitals become colonized by gram-negative bacilli, whereas well patients do not. Whether early intervention can really make a difference in the subsequent incidence of gram-negative pneumonia is unclear. The studies presented in Johanson’s review reopen the issue of antimicrobial prophylaxis with drugs such as polymyxin B applied as an aerosol. Nonetheless, the painful lessons of the past suggest that topically applied antibiotics (an aerosol antibiotic should be considered in this light) have limited usefulness and may predispose towards emergence of resistance. In a very specific patient population, antimicrobial prophylaxis has definitely prevented some respiratory infections. No doubt the landmark study in this area is that of Hughes and collaborators [4] who reported a two-year study in which trimethoprim-sulfamethoxazole was effective in preventing Pneumocystis carinii pneumonia in children with leukemia. In this double-blinded study, the overall incidence of a variety of other respiratory infections was also significantly reduced. Nonetheless, most subjects in that study were children with leukemia in remission, and the clinical circumstances are different in many adults who are at risk of respiratory infection in an intensive care unit setting or subsequent to immunosuppressive therapy for an unremitting neoplastic process. A most frustrating aspect of pulmonary disease is that it is so easy for the physician to examine the lungs at the bedside with the hands and stethoscope and to order a chest x-ray as well. Yet, studies of the last decade have shown us how misleading “pattern reading” of lung infiltrates can be and how bacteriologic studies of expectorated sputum can yield erroneous etiologic evidence. Pneumocystis pneumonia can assume a number of radiologic configurations. Gram-negative rods that colonize the upper respiratory tract may not reflect the origin of the pneumonia that is so readily detected by x-ray and confirmed by physical examination. Unfortunately, more invasive techniques are required to fully delineate the microbiologic spectrum of respiratory infections in the patient at risk. One has to question a number of reports in the literature of the
in which culture of sputum
ologic diagnosis of infection. Since our knowledge of the epidemiologic and etiologic aspects of respiratory infection is imprecise, much of the treatment data, particularly the empiric therapy data of respiratory infections, must be regarded with caution. Despite these caveats, progress in the therapy of gram-positive and gram-negative respiratory infections is fairly encouraging. Among the bacteria three notable exceptions remain; Pseudomonas, Serratia, and Enterobacter infections are still associated with a high rate of failure even with the important new antimicrobial agents. In the area of opportunistic fungal disease we have very little effective therapy, particularly in those patients whose underlying disease is unremitting. The latter circumstance does not seem to be a totally limiting factor for those with bacterial infection. Most patients who have significant neutropenia and in whom gram-negative septicemias develop seem to respond whether or not their hematologic picture improves [ 5,6], suggesting that the potency of new antimicrobial agents against bacteria is sufficient to hold many of these processes at bay despite failure of the underlying disease to improve. With regard to the selection of antibiotics for lung infection, the total duration of therapy, and the method of administration, empiricism still rules. We have no data correlating the relation between sputum or bronchial secretion levels of antimicrobial agents and eventual clinical outcome. Optimal modes of drug administration and dosages remain to be identified. Even for pneumococcal pneumonia, probably all of the doses used for conventional, penicillin-susceptible organisms represent therapeutic excess, if not “overkill.” However, there are serious doubts as to whether we can give enough drug or drugs for Pseudomonas lung infections occurring in a patient with cancer or cystic fibrosis. Even if blood levels seem adequate by conventional criteria, the concentrations of antipseudomonal agents achieved in thick purulent secretions have been poorly studied, and whether these drugs are functioning optimally under in vivo conditions remains in doubt. Looking ahead to the future, it seems that new pathogens, new diagnostic techniques, new therapeutic approaches, new antimicrobial agents, and hopefully new prophylactic approaches involving both augmentation of host defenses and innovative use of new antimicrobials will be further explored during the coming decade. We can only hope that studies to delineate the role of these modalities will be well controlled and evidence for their clinical usefulness convincingly based on the study of large numbers of patients.
May 15, 1994
The American Journal of Medicine
79
PATIENT AT RISK AND ANTIMICROBIAL
THERAPY-YOUNG
REFERENCES 1. 2.
3.
80
Riley RL: Airborne infection. Am J Med 1974; 57: 466475. Meyer RD: Legionnaire’s disease in the compromised host. In: Rubin RH. Youna LS. eds. Clinical aporoach to infection in the compromised host. New York: Plenum Publishing, 1981; 335-388. Young LS, Pollack M: Immunologic approaches to the prophylaxis and treatment of Pseudomonas aeruginosa infection. In: Sabath LD, ed. Pseudomonas aeruginosa. Bern: Hans Huber, 1980; 119-132.
May 15, 1984
The American Journal of Medicine
4.
5.
6.
Hughes WT, Kuhn S, Chaudhary S, et al: Successful chemoprophylaxis of Pneumocystis carinii pneumonitis. N Engl J Med 1977; 297: 1419-1426. Young LS, Meyer-Dudnik D, Hindler J, Martin WJ: Aminoglycosides in the treatment of bacteremia infections in the immunocompromised host. J Antimicrob Chemother 1981; 8 (suppl A): 121-132. Love LJ, Schimpff SC, Schiffer CA, Wiernik PH: Improved prognosis for granulocytopenic patients with gram-negative rod bacteremia. Am J Med 1980; 68: 643-648.
he last three decades have witnessed important changes in the nature, diagnostic approaches to, and treatment of lung infections. At one time, most pulmonary infections were thought to be due to either viruses or bacteria, such as the pneumococcus. Rarely, in severely debilitated patients gram-negative rods such as Klebsiella pneumoniae caused life-threatening pneumonia. We know now that many infections, indeed the majority that develop through aspiration or inhalation mechanisms, are “mixed” bacterial processes. Furthermore, new respiratory pathogens have become increasingly recognized. One need cite only the examples of Legionella pneumophila, Chlamydia species, and a host of viral agents including the cytomegalovirus as causes of lung infection in persons with impaired host defenses. Epidemiologically, the appearance of an unusual problem such as Aspergillus or Legionella infections in a hospital caring for high-risk patients is an important clue to a nosocomial infection risk. These outbreaks should be the impetus for careful investigation of sources for microorganisms in the hospital environment. In this sense, a high-risk or immunocompromised patient is much like the “sentinel guinea pig” of Riley et al [l] who studied the epidemiologic aspects of hospital dissemination of tuberculosis in a series of classic studies. Indeed, the nosocomial incidence of Legionella infections is more than 10 times greater in immunosuppressed patients than the incidence in otherwise normal patients assumed to have comparable infection exposure [ 21. Extrinsic sources of infection have received much attention from workers in the nosocomial infection field, but it is in this area that very little solid data exist. Rhame’s review concentrates on three infectious processes, Aspergillus in particular. Little question exists that nosocomial outbreaks of Aspergillus occur in construction areas or in areas where conditions lead to dispersion of spores. However, more adequately
T
controlled studies are still needed because there are institutions that have had relatively little problem with this infection as opposed to that with which Rhame has had to contend over much of the last few years. Control measures short of total filtration of air (which some investigators have resorted to) must be regarded as innovative, but Rhame and associates have realized that total sterility of the air may be an economically unrealistic goal. The interim solution represents a compromise and it has led to a quantitative reduction in dispersion of spores and a corresponding reduction in the incidence of infection. The example of nosocomial Aspergillosis stands out as one in which a clear-cut extrinsic source of infection is present. What about the many other serious respiratory infections that we must now contend with in the patient at risk? Pneumocystosis is a reactivation of a very common childhood infection, and the current epidemic of acquired immune deficiency syndrome (AIDS) suggests that not only is this a reactivation of latent infection but also, similar to studies in animal models, the host never really eradicates the pathogen. Thus, antimicrobial therapy temporarily leads to arrest of pneumocystic infection, but the rate of recurrence of pneumocystosis in patients with AIDS is very high. Most bacterial pathogens that cause pneumonia reach the lung by the aspiration route. Although much investigative work has been carried out in defining lung defense mechanisms, as outlined in Pennington’s presentation there unfortunately has been little translation of this work into practical means in the diagnosis, treatment, and prevention of serious lung infections. For instance, one might hope that antiserum or immunization against gram-negative bacilli would lead to some reduction in the incidence of gram-negative pneumonia in intensive care units or immunosuppressed patients on the basis of the encouraging work in animal models that augmentation of humoral antibodies can confer
From the Department of Medicine, U.C.L.A. School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Dr. Lowe//S. Young, Department of Medicine, U.C.L.A. School of Medicine, Los Angeles, California 90024.
78
May 15, 1984
The American Journal of Medicine
PATIENT AT RISK AND ANTIMICROBIAL
some
protection
against
dence
in human
studies
THERAPY
YOUNG
However,
evi-
treatment
of lung infections
that this is an effective
ap-
produced
by cough was the sole basis for the microbi-
pneumonia.
proach has only been suggested by some less than satisfactory clinical studies [3]. Epidemiologic data have provided extremely interesting insights into the pathogenesis of pneumonia in debilitated subjects, but how this new knowledge can be translated into practical preventive measures remains to be seen. Johanson and his colleagues have demonstrated the importance of pharyngeal colonization by gram-negative bacilli as the antecedent event in gram-negative pneumonia. Simply put, sick patients in hospitals become colonized by gram-negative bacilli, whereas well patients do not. Whether early intervention can really make a difference in the subsequent incidence of gram-negative pneumonia is unclear. The studies presented in Johanson’s review reopen the issue of antimicrobial prophylaxis with drugs such as polymyxin B applied as an aerosol. Nonetheless, the painful lessons of the past suggest that topically applied antibiotics (an aerosol antibiotic should be considered in this light) have limited usefulness and may predispose towards emergence of resistance. In a very specific patient population, antimicrobial prophylaxis has definitely prevented some respiratory infections. No doubt the landmark study in this area is that of Hughes and collaborators [4] who reported a two-year study in which trimethoprim-sulfamethoxazole was effective in preventing Pneumocystis carinii pneumonia in children with leukemia. In this double-blinded study, the overall incidence of a variety of other respiratory infections was also significantly reduced. Nonetheless, most subjects in that study were children with leukemia in remission, and the clinical circumstances are different in many adults who are at risk of respiratory infection in an intensive care unit setting or subsequent to immunosuppressive therapy for an unremitting neoplastic process. A most frustrating aspect of pulmonary disease is that it is so easy for the physician to examine the lungs at the bedside with the hands and stethoscope and to order a chest x-ray as well. Yet, studies of the last decade have shown us how misleading “pattern reading” of lung infiltrates can be and how bacteriologic studies of expectorated sputum can yield erroneous etiologic evidence. Pneumocystis pneumonia can assume a number of radiologic configurations. Gram-negative rods that colonize the upper respiratory tract may not reflect the origin of the pneumonia that is so readily detected by x-ray and confirmed by physical examination. Unfortunately, more invasive techniques are required to fully delineate the microbiologic spectrum of respiratory infections in the patient at risk. One has to question a number of reports in the literature of the
in which culture of sputum
ologic diagnosis of infection. Since our knowledge of the epidemiologic and etiologic aspects of respiratory infection is imprecise, much of the treatment data, particularly the empiric therapy data of respiratory infections, must be regarded with caution. Despite these caveats, progress in the therapy of gram-positive and gram-negative respiratory infections is fairly encouraging. Among the bacteria three notable exceptions remain; Pseudomonas, Serratia, and Enterobacter infections are still associated with a high rate of failure even with the important new antimicrobial agents. In the area of opportunistic fungal disease we have very little effective therapy, particularly in those patients whose underlying disease is unremitting. The latter circumstance does not seem to be a totally limiting factor for those with bacterial infection. Most patients who have significant neutropenia and in whom gram-negative septicemias develop seem to respond whether or not their hematologic picture improves [ 5,6], suggesting that the potency of new antimicrobial agents against bacteria is sufficient to hold many of these processes at bay despite failure of the underlying disease to improve. With regard to the selection of antibiotics for lung infection, the total duration of therapy, and the method of administration, empiricism still rules. We have no data correlating the relation between sputum or bronchial secretion levels of antimicrobial agents and eventual clinical outcome. Optimal modes of drug administration and dosages remain to be identified. Even for pneumococcal pneumonia, probably all of the doses used for conventional, penicillin-susceptible organisms represent therapeutic excess, if not “overkill.” However, there are serious doubts as to whether we can give enough drug or drugs for Pseudomonas lung infections occurring in a patient with cancer or cystic fibrosis. Even if blood levels seem adequate by conventional criteria, the concentrations of antipseudomonal agents achieved in thick purulent secretions have been poorly studied, and whether these drugs are functioning optimally under in vivo conditions remains in doubt. Looking ahead to the future, it seems that new pathogens, new diagnostic techniques, new therapeutic approaches, new antimicrobial agents, and hopefully new prophylactic approaches involving both augmentation of host defenses and innovative use of new antimicrobials will be further explored during the coming decade. We can only hope that studies to delineate the role of these modalities will be well controlled and evidence for their clinical usefulness convincingly based on the study of large numbers of patients.
May 15, 1994
The American Journal of Medicine
79
PATIENT AT RISK AND ANTIMICROBIAL
THERAPY-YOUNG
REFERENCES 1. 2.
3.
80
Riley RL: Airborne infection. Am J Med 1974; 57: 466475. Meyer RD: Legionnaire’s disease in the compromised host. In: Rubin RH. Youna LS. eds. Clinical aporoach to infection in the compromised host. New York: Plenum Publishing, 1981; 335-388. Young LS, Pollack M: Immunologic approaches to the prophylaxis and treatment of Pseudomonas aeruginosa infection. In: Sabath LD, ed. Pseudomonas aeruginosa. Bern: Hans Huber, 1980; 119-132.
May 15, 1984
The American Journal of Medicine
4.
5.
6.
Hughes WT, Kuhn S, Chaudhary S, et al: Successful chemoprophylaxis of Pneumocystis carinii pneumonitis. N Engl J Med 1977; 297: 1419-1426. Young LS, Meyer-Dudnik D, Hindler J, Martin WJ: Aminoglycosides in the treatment of bacteremia infections in the immunocompromised host. J Antimicrob Chemother 1981; 8 (suppl A): 121-132. Love LJ, Schimpff SC, Schiffer CA, Wiernik PH: Improved prognosis for granulocytopenic patients with gram-negative rod bacteremia. Am J Med 1980; 68: 643-648.