The Journal of International Medical Research 1990; 18: 177 - 190

Infections in the Compromised Host L.A. Mandell McMaster University, Hamilton, Ontario, Canada

The skin and/or mechanical factors, such as coughing, ciliary action or urine flow, along with phagocytes and humoral and cell-mediated immunity, help to protect the body from infection. In compromised patients, these mechanisms are impaired or bypassed, rendering patients susceptible to infection by opportunistic organisms (bacteria, mycobacteria, fungi, viruses, parasites). Mechanical barriers may be breached in patients with burns or indwelling catheters, in diabetics or cancer patients, and in parenteral drug abusers. Humoral or cell-mediated immunity may be suppressed in non-neoplastic patients following splenectomy, in diabetics, in alcoholics and in those with certain rheumatic disorders, as well as in patients undergoing haemodialysis or receiving steroids or immunosuppressive drugs. In cancer patients infection is often a cause of death, frequently occurring as a result of granulocytopenia, obstruction of natural passages, or suppression or dysfunction of humoral or cell-mediated immunity. Diagnosis of the infection may be difficult and expert advice should be sought. Treatment should be started before a conclusive diagnosis has been made, particularly in neutropenic patients since infections may be Iifethreatening. KEY WORDS: Compromised host; infections; cell-mediated immunity; humoral immunity; non-neoplastic diseases; cancer.

INTRODUCTION

variety of defence mechanisms exist . to protect humans from infection by microbial pathogens. These mechanisms range from simple mechanical flushing to

A

Received for publication 24 January 1990; accepted 30 January 1990. Address for correspondence: Dr Lionel A. Mandell. McMaster Medical Unit. Henderson General Hospital, 711 Concession Street. Hamilton. Ontario, CanadaL8V lC3. © Copyright 1990 by Cambridge Medical Publications Ltd

sophisticated processes involving intercellular communication and complex mediators. Without these defences man would be subject to repeated, often serious and potentially life-threatening infections. The body's defences can be thought of as consisting of both first- and second-line mechanisms: the former are innate and non-specific in nature, whereas the latter are more complex, as well as being more specific (Table 1). From a functional point of view compromised hosts are patients whose normal defence mechanisms are 177

L.A. Mandell

Table 1 Selected host defence mechanisms Factors

First line - innate immunity (non-specific)

Surface and mechanical

Skin Cough reflex Ciliary motion Flushing action (e.g. urine)

Immunoglobulins (e.g. immunoglobulin A)

Humoral

Complement Lysozyme Fibronectin Interferon

Antibodies (e.g. immunoglobulins M and G)

Cellular

Phagocytes Neutrophils Monocytes Eosinophils Natural killer cells

Cell-mediated immunity

impaired or bypassed, thereby making the subjects more susceptible to infection by opportunistic organisms. Numbers of compromised patients are increasing rapidly, many being seen as a result of advances in the treatment of neoplastic diseases, as well as occurring in patients with non-neoplastic conditions, such as auto-immune disorders and following organ transplants. Cases also occur as a result of the acquired immune deficiency syndrome (AIDS). In this review not all aspects of such infections are discussed; only certain conditions or disease states that are likely to be seen by theaveragephysicianareconsidered.General immunology and congenital immunodeficiency problems, as well as AIDS and infections associated with transplantation, are not reviewed. NON-NEOPLASTIC CONDITIONS

Predisposing conditions Bypassing mechanical barriers. The skin provides an excellent barrieragainst infection, most organismsbeing unable topene178

Second line - adaptive immunity (specific)

trate the stratified epithelium, with bacteria on the skin surface being eliminated when the keratinized cells desquamate. Lipids excreted by the sebaceous glands and the acid pH of the skin surface also have an antibacterial effect. 1 The skin, therefore, provides excellent protection against invasion of the deeper tissues. Breaches of the skin barrier, which occur with the use of indwelling vascular lines, in parenteral drug abusers and in burn patients, may lead to serious systemic infections. Splenectomy. The spleen is an important site of antibody production (immunoglobulin M) directed against blood-borne antigens and splenic macrophages play a role in removing circulating opsonized organismsf thus removal of the spleen, either surgically or functionally, leads to increased susceptibility to infection. This increased susceptibility may also be due to the lack of the enzyme tuftsin endocarboxypeptidase, which is. involved in the activation of pbagocytes by the tetrapeptide tuftsin,"

Infections in the compromised host

Diabetes mellitus. The skin barrier of diabetics may be bypassed as a result of regular injections of insulin or as a result of intravascular lines inserted when hospitalization is required. Diabetic neuropathy and concomitant vascular disease may also lead to disruption of the skin surface. Specific defects in the defence mechanisms of diabetics have been investigated but, due to differences in methodology, conflicting data have been reported. It appears, however, that impaired actions of the granulocytes and the monocytes may be contributory factorsr'-' phagocytic function and microbicidal activity of granulocytes have been shown to be reduced and glucose metabolism of phagocytes is altered in diabetics.v' Alcoholism. Gross aspiration of stomach contents may occur when the level of consciousness is reduced and the cough reflex is impaired. Another factor in alcoholics is silent aspiration during sleep in individuals with increased oropharyngeal carriage of Gram-negative organisms and possible impaired microbicidal clearance by pulmonary alveolar macrophages." Defects in complement activity, granulocyte response to bacterial infection and cell-mediated immunity have also been noted in alcoholiCS. 9•1O

Rheumatic diseases. The rheumatic diseases most thoroughly investigated with regard to alterations in the defence mechanisms are systemic lupus erythematosus (SLE), rheumatoid arthritis and Felty's syndrome. In cases of active SLE, immunosuppressive drugs may predispose patients to infection and a number of disease-specific defects have been described. Neutropenia may occur secondary to immunoglobulin G antigranulocyte antibody formation and chemotaxis may be impaired by the defective generation of chemotactic factors, as well as by the presence of chemotactic inhibitors in serum.l'i" An inhibitor of both

phagocytosis and degranulation has been detected and impaired cell-mediated immunity, demonstrated by anergy on skin testing, has also been noted.P'!" In patients with active rheumatoid arthritis, studies have shown that a substance in the synovial fluid is capable of impairing phagocytosis by polymorphonuclear neutrophile." In addition, impaired chemotaxis and monocyte microbicidal function have been reported.lv'? Felty's syndrome comprises rheumatoid arthritis, splenomegaly and neutropenia. Not all patients, however, are susceptible to recurrent infection and the absolute granulocyte count does not identify those patients at increased risk from infection. Although defects in chemotaxis have been described, impaired bactericidal activity of the neutrophils has only been observed in patients with recurrent infections."

Uraemia. Neutrophildefectshave been found in patients with uraemia and renal failure. Quantitative defects are due to diminished granulocyte reserves in the bone marrow and qualitative defects are a result of impaired chemotaxis, probably arising from the defective generation of chemotactic factors.P-" Haemodialysis patients frequently experience transient neutropenia, probably secondary to activation of complement and sequestration of cells in the pulmonary vasculature." Defects have also been reported in cell-mediated immunity and in antibody responses to primary immunization.P:" Malnutrition. In North America and Western Europe malnutrition is generally secondary to an underlying illness. Patients with severe protein - calorie malnutrition suffer from a loss of integrity of surface defences such as the skin and mucous membranes as a result of impaired protein synthesis. This situation is made worse by reduced levels of secretory immunoglobulin A in the gut, thus allowing bacteria that normally only 179

L.A. Mandell

colonize the colon to enter the systemic circulation." Defective opsonization may result from low levels of complement and cell-mediated immunity is also impaired.25•26 A defect in neutrophil chemotaxis has been reported, although phagocytosis is usually normal.?? Phagocytic activity may, however, be impaired in cells of the fixed tissue monocyte macrophage type." Drugs and radiation. Steroids cause transient lymphopenia and monocytopenia, with more selective effects on the T-cell subpopulations.Pr" Functional defects have also been described, including altered microbicidal activity of neutrophils and monocytes, and impaired cell-mediated immunity." Cytotoxic agents, e.g. methotrexate and cyclophosphamide, exert negative effects primarily by suppressing cell proliferation. Induction of neutropenia and lymphocytopenia results in impairment of defence mechanisms associated with neutrophils, monocytes, and B- and T_cells. 32•33 Cyclosporin A, which is widely used following organ transplants, appears to have no direct effects on neutrophils or B-cells but inhibits interleukin-2 and interferon-a in T-cells. 34 Radiation affects cells with rapid renewal rates; consequently, the gastro-intestinal epithelium may be damaged, resulting in gut bacteria entering the systemic circulation. Radiation can also induce granulocytopenia because of destruction of the pool of mitotic cells and this too may lead to infection. Infection. Disease due to pathogenic organisms may be caused by: invasion of the host tissues by the pathogen; intoxication of the host cells by toxins produced by the pathogen; and/or immunological reactions initiated in response to, or as a result of, the pathogen. Many micro-organisms have evolved mechanisms whereby they can bypass or inhibit host defence mechanisms." Cell-mediated immunity may also be im180

paired following infection by certain viruses, such as the human immunodeficiency virus (HIV), cytomegalovirus, Epstein Barr virus and the non-A, non-B hepatitis virus. Infection with HIV can result in AIDS and the findings associated with this syndrome are due, at least in part, to T-cell dysfunction resulting from the HIV infection. The T-cell dysfunction results from helper/inducer T-cells being selectively destroyed by HIV and this, in turn, can lead to infection by such pathogens as Pneumocystis cariniiP-" Once the defence mechanisms have been bypassed or inhibited, a subject becomes susceptible to infection by organisms, generally referred to as opportunistic pathogens, that do not normally cause infection (Table 2). Diagnosis When treating infection in patients with impaired defences, it is essential that an accurate diagnosis is made and that treatment is initiated immediately. The physician must be careful not to take anything for granted and not to jump to conclusions. A patient, for example, who presents with sudden onset of bone pain and who has sickle cell anaemia may have experienced a bone infarct and is not necessarily suffering from osteomyelitis due to a Salmonella organism. Another relatively common mistake is to assume that a patient with rheumatoid arthritis who presents with a swollen, painful joint may be suffering from septic arthritis rather than from an exacerbation of the underlying rheumatic disease. An awareness of the status of the patient's underlying disease, of the drugs or therapeutic regimens being used and of any concurrent illnesses that might confound the clinical picture is essential. Matters may be further complicated by variations in the clinical presentation of the infection. This is particularly important in patients who are receiving high doses of anti-

Infections in the compromised host

Table 2 Selected host defence mechanisms and examples of pathogen associated with their dysfunction Defect Surface and mechanical factors (e.g. intravenous lines, obstruction of ureters or bronchi)

Phagocytes Neutrophils Chemotaxis Phagocytosis Microbicidal activity Humoral immunity Complement Antibody Immunoglobulin G Immunoglobulin A Cell-mediated immunity T-cells

Mononuclear phagocytes

inflammatory drugs, such as steroids, or in patients who are neutropenic, in whom the typical fmdings associated with inflammation and infection may be absent or reduced to such an extent that it is virtually impossible to diagnose an infection. In addition, there is a problem because the clinical course may be accelerated: for example, following splenectomy. Infection, in such cases, can be fulminant, leading to severe morbidity and mortality if not managed appropriately. Table 2 lists selected host defence mechanisms and gives examples of patho-

Pathogens Staphylococcus aureus Staph. epidermidis Viridans streptococci JK diphtheroids Aerobic Gram-negative bacilli

Bacteria (Staph. aureus, Streptococcus pyogenes) Bacteria (Pseudomonas aeruginosa) Fungi (Candida albicans) Bacteria (Staph. aureus, Salmonella species)

Bacteria (Staph. aureus, Neisseria gonorrhoeae) Encapsulated bacteria (Strep. pneumoniae, Haemophilus influenzae) Giardia lamblia

Bacteria (Listeria species) Mycobacteria Herpes viruses Parasites (Toxoplasma gondii, Pneumocystis cariniii Salmonella species Mycobacteria Legionella species Nocardia species

gens associated with their dysfunction. Some of the conditions that are particularly important, either because of the frequency with which they occur or because of the morbidity and mortality associated with them, are right-sided endocarditis and AIDS in parenteral drug abusers, pneumococcal septicaemia in splenectomized patients, necrotizing fasciitis in patients with diabetes mellitus and gross aspiration pneumonia and spontaneous bacterial peritonitis in alcoholics. Specific evidence of an infectious aetiology is dependent upon seeing the organ181

L.A. Mandell

ism, growing it in culture medium, demonstrating a cytopathic effect, detecting the presence of specific microbial antigens, or demonstrating an antibody response to the organism. By using appropriate stains, cultures and serological and skin tests a diagnosis can often be made. In cases where an unusual or fastidious organism is suspected, the problem should be discussed with a specialist in infectious diseases or a microbiologist so that appropriate stains or cultures using selective media may be prepared. The physician is occasionally faced with a patient who presents with recurrent infections but who has no obvious impairment of host defences. Discussion with an immunologist or infectious disease specialist re-garding the use of appropriate tests can help in determining whether or not a defect in

host defences exists. Some of the screening tests that can be used to measure phagocytic function and humoral and cell-mediated immunity are listed in Table 3. . The use of both non-invasive and invasive procedures to help in the diagnosis is often very important. Radiological and imaging techniques, such as ultrasound and computerized axial tomography scans, may be useful in localizing a focus of infection, which can then be biopsied or drained. Radionuclide scans using such agents as gallium or technetium, or indiumlabelled leucocytes may also be helpful in pinpointing a site of infection. Treatment Infections occurring in compromised hosts may be more severe than those in noncompromised subjects; therefore, empiric

Table 3 Selected tests for investigation of possible host defence defects Possible defect Defence mechanism Phagocytes

Humoral immunity Complement

Antibody

Cell-mediated immunity T-cells

182

Investigation

Total white cell count, differential count Blood film Chemotaxis Ingestion of bacteria Killing of bacteria or nitro blue tetrazolium reduction

C3,C4 Total haemolytic complement (CHsJ Assays for other complement components C>psonizing assays Immunoglobulin (Ig) levels (IgG, IgM, IgA) Isohaemagglutinin titres Antibody responses to vaccines Quantitation of B-cells

Lymphocyte count Skin tests (e.g. mumps, Candida) Quantitation of T-cells and T-cell subsets Lymphocyte responses to mitogens

Infections in the compromised host

therapy may occasionally have to be employed before a definitive diagnosis can be made. Changes can be introduced, if necessary, once the organism has been identified and sensitivity results are available. If Gram-positive coccal infection is suspected, vancomycin is an excellent initial choice as it is usually effective against staphylococci, including methicillin-resistant Staphylococcus aureus, and streptococci, including the enterococcus.:" If, however, a methicillin-sensitive strain of Staph. aureus is the pathogen, a penicillinase-resistant semi-synthetic penicillin, such as cloxacillin or oxacillin, may be used. Streptococcus species are usually treated with penicillin, with or without an aminoglycoside. In cases of infecction with aerobic Gram-negative bacilli,. an aminoglycoside is usually employed but thirdgeneration cephalosporins can be used in patients with impaired renal function or eighth nerve damage. In the case of Pseudomonas aeruginosa infections, ceftazidime is the only third-generation cephalosporin withconsistently reliable activity.39 All thirdgeneration cephalosporins, with the exception of cefsulodin, generally have excellent activity against the Enterobacteriaceae and Haemophilus injluenzae. For the management of anaerobic organisms, which may occur in intra-abdominal or pelvic infections, metronidazole or clindamycin are excellent. A drug such as imipenem has a broad spectrum of activity including aerobic Gram-negative bacilli and many of the Gram-positive cocci as well as anaerobes. It may be used as monotherapy for the management of intra-abdominal infection in patients where renal failure or eighth nerve toxicity is a problem and when dealing with organisms that are resisitant to aminoglycosides." Prevention Infection is best prevented by controlling the underlying condition that predisposes to infection. In some cases, however, more

specific preventive measures may have to be employed: for example, the use of pneumococcal and meningococcal vaccines in patients who are asplenic or hypocomplementaemic, respectively. The dangers of infection must be pointed out to patients with underlying diseases and they must be alerted to the possible symptoms that could be experienced with the onset of infection. If any such symptoms are noted, patients should be urged to contact their doctor immediately. NEOPLASTIC CONDITIONS

Infection is the main cause of death in patients with leukaemia or lymphoma, as well as in those with most solid tumours. In addition to being a complication of both the neoplastic disease and its treatment, infection may also complicate staging procedures in such malignancies as Hodgkin's disease. The most common causes of infection are the aerobic Gram-negative bacilli, such as Escherichia coli, Klebsiella species and Ps. aeruginosa (Table 4). These infections tend to originate in the oropharynx, oesophagus, anorectal area, sinuses, lungs and skin. More recently, Gram-positive organisms, such as coagulase-negative staphylococci, as well as the JK diphtheroids, have been reported." Fungal infections are those typically associated with neutrophil defects, such as candidiasis, aspergillosis and mucormycosis, as well as those associated with aT-cell mononuclear phagocyte defect, such as cryptococcosis (Table 4). Predisposing conditions Bypassing mechanical barriers. The use of indwelling catheters for drug administration and blood sampling in patients with haematological malignancies has been associated with an increased incidence of infections due to Staph. epidermidis and the JK diphtheroids. Catheters can also predispose patients to local infection, throm183

L.A. Mandell

Table 4 Selected microbial pathogens causing infection in cancer patients Bacteria Klebsiella pneumoniae Escherichia coli Pseudomonas aeruginosa Serratia marcescens Salmonella species Staphylococcus aureus Staph. epidermidis JK diphtheroids Clostridium perjringens Listeria monocytogenes Nocardia asteroides Fungi Candida species Aspergillus species Cryptococcus neoformans Mucor species Parasites Toxoplasma gondii Pneumocystis carinii Strongyloides stercoralis Viruses Herpes simplex Varicella zoster Cytomegalovirus Hepatitis B

bophlebitis and, occasionally, sepsis due to skin-related organisms.f

Granulocytopenia. This is the most common factor predisposing to infection in cancer patients, as well as being the most important. The risk of infection is related not only to the degree of neutropenia but also to its duration; a marked increase in the incidence of infection is seen in patients with levels of less than 500 cells/rum'." The problem with neutrophils may be quantitative as well as qualitative: for example, in patients with acute myelogenous leukaemia, cells that appear to be morphologically mature may actually 184

have impaired bactericidal and fungicidal activity."

Cell-mediated and humoral immunosuppression. Problems with cell-mediated and humoral immunity may be seen in disease states in which T - and B-cell functions, respectively, are impaired, such as in haematological malignancies, Hodgkin's disease and multiple myeloma. In order that T-cells can function normally, there must be a balance between the helper and the cytotoxic/suppressor T-cells. In HIV infection, for example, the virus appears to destroy selectively the helper T -cells, whereas in Hodgkin's disease there seems to be an excess of suppressor Tvcells." Humoral immunity may be disturbed when either insufficient or abnormal immunoglobulin is produced. In chronic lymphocytic leukaemia, a progressive decrease in normal immunoglobulin and antibody response occurs and in plasma cell dyscrasias there may be an excessive amount of homogeneous immunoglobulin molecules or fragments produced, with a progressive decrease in antibody response." Obstruction of natural passages. Partial or complete obstruction may lead to infection due to the stasis of body fluids and excessive growth of micro-organisms. One of the most frequent sites of obstruction is the urinary tract due to prostatic, ovarian, cervical or renal carcinoma. Another is obstruction of the bronchial tree, which can occur in carcinoma of the lung, resulting in post-obstructive pneumonia. Obstruction of the biliary tree secondary to neoplastic disease can result in acute cholangitis. Chemotherapy. Some drugs used to treat neoplastic diseases are themselves irnmunoand myelosuppressive and can lead to profound granulocytopenia. They may also affect the mucous membranes, resulting in mucositis and subsequent local infection.

Infections in the compromised host

Treatment with broad-spectrum antibiotics. Although broad-spectrum antibiotics are frequently used, particularly in febrile neutropenic patients, they may occasionally increase the possibility ofsuperinfection with resistant organisms.

Diagnosis The status of the underlying neoplastic disease, the use of recent chemotherapy, radiotherapy or surgery, and a knowledge of other underlying illnesses that the patient might have are critical in assessing whether or not a problem is due to infection and, if so, what the pathogen might be. The importance of a careful physical examination cannot be overemphasized and, when dealing with neutropenic patients, certain sites must be thoroughly examined. Oropharyngeal thrush may suggest that a fungal infection is the cause of a fever that has not responded to antibacterial therapy. Stomatitis as a result of mucositis and/or gingivitis may also be the source of serious infection. The skin should be examined daily for the presence of any new lesions; the appearance of discrete nodular erythematous lesions with a central dark area may indicate ecthyma gangrenosum, which is typically caused by Ps. aeruginosa. It is recommended that tissue from any new skin lesions be submitted for histological and microbiological examination, as such biopsies may reveal fungal infections that were not otherwise suspected. Herpes simplex or Varicella zoster infections may also be found and, if suspected, electron microscopy may provide a rapid diagnosis. Close attention should be paid to the perirectal area, particularly in patients with acute leukaemia, as this may be a site of serious infection. If a perirectal "focus is noted in patients failing to respond to standard antibacterial therapy, clindamycin or metronidazole should be administered. Other sites that should be assessed regularly are the eye grounds because fungal

infections, particularly systemic candidiasis, may be associated with choroidal infiltrates. The lungs are the most common site of fatal bacteraemia in cancer patients. In patients with neoplastic diseases, a variety of non-infectious and infectious processes may involve the lungs and an organized approach to the patient with a pulmonary infiltrate and neoplastic disease cannot be overemphasized (Table 5). It is important to determine the status of the neoplastic process and whether or not the underlying disease involves the lung. It is also important to know if the patient has been receiving any chemotherapeutic agents, such as methotrexate or bleomycin, that might cause a pneumonitis and whether or not the patient has recently received any radiation to the lung fields. The possibility of haemorrhage into the lungs, particularly in thrombocytopenic patients, must also be considered. A chest X-ray should be obtained and, if there is any suggestion of cavitation or other unusual fmdings, tomograms or a computerized axial tomography scan should be performed. The rate of onset of the infiltrate may help to narrow the possibilities but it is important not to rely too much on such information and not to look for •typical' radiographical features as they are not always reliable. A rapid onset generally suggests bacterial infection, whereas a subacute onset implies a viral or fungal infection, as well as less common pathogens such as P. carinii. A more chronic course may suggest a nocardial or tuberculous infection; although any of these infections may present in a rapid or fulminating manner. Sputum samples should be obtained, although these are often difficult to assess in neutropenic patients where standard criteria such as the presence of neutrophils on microscopic examination are no longer applicable. Many patients, however, are unable to produce sputum, in particular those with post-obstructive pneumonia in 185

L.A. Mandell

Table 5 Pulmonary inflitrates in patients with neoplastic disease Infectious Bacterial Staphylococcus aureus Aerobic Gram-negative bacilli Legionella species Nocardia species

Non-infectious Underlying neoplasm Haemorrhage Radiation pneumonitis Drug-induced pneumonitis Congestive heart failure

Aetiology unknown Non-specific interstitial pneumonitis

Mycobacterial Typical and atypical tuberculosis Fungal Candida species Aspergillus species Cryptococcus species Viral Cytomegalovirus Herpes simplex Varicella zoster Parasites Pneumocystis carinii Toxoplasma gondii Strongyloides stercoralis

whom there may be no link between the site of infection and the proximal respiratory tract. The decision to use invasive techniques to obtain a diagnosis of. a lung infiltrate must be carefully made. The risk of the procedure has to be balanced against the information it may yield. In general, bronchoscopy with broncho-alveolar lavage or open lung biopsy should be employed if the chances of fmding a treatable pathogen that is not easily covered by empiric therapy outweigh the risks associated with the procedure. Treatment In cancer patients who are not neutropenic it may be possible to avoid the use of 186

empinc antimicrobial therapy unless the patient is very ill, but in febrile neutropenic patients at least 60% of febrile episodes are due to either microbiologically or clinically documented infection and empiric therapy should be implemented." The reason for such aggressive management is the potential severity of the infections.w" The standard treatment for febrile neutropenic patients has been a combined antibacterial regimen in order to provide broad coverage against both Gram-positive and Gram-negative pathogens, to have an additive or synergistic effect against some of the organisms and to prevent the emergence of resistant bacteria." Coverage has generally been aimed at the aerobic Gramnegative bacilli, such as E. coli, Klebsiella

Infections in the compromised host

species and Ps. aeruginosa. Regimens employing both an antipseudomonal penicillin, e.g. piperacillin, and an aminoglycoside, e.g. tobramycin or amikacin, are regularly used. An alternative to the aminoglycoside-containing regimens is the use of l3-lactam combinations, such as an antipseudomonal penicillin plus a thirdgeneration cephalosporin." The most important factor to consider is the presence of a synergistic effect against the documented pathogens.t-" Data suggest that, in certain patients with severe neutropenia and proven infection with Gram-negative bacilli, combination treatment is required for the duration of the antibacterial course. 54 Until the development of third-generation cephalosporins or carbapenems, monotherapy was not a viable option. With the appearance of such drugs, however, the prospect of monotherapy has become more feasible. In a study by Pizzo et al. 55 patients were randomized to received either ceftazidime or the combination of cephalothin, carbenicillin and gentamicin. In this study, it was claimed that ceftazidime alone was equivalent to the combination regimen. The study has, however, been criticized because the number of cases of documented infections was small and the mean duration of granulocytopenia was short (8.5 days). The major criticism was that the defmition of success: the investigators allowed the addition of antimicrobial agents to the initial monotherapy without counting such cases as failures. A international multicentre study has been undertaken compared ceftazidime with piperacillin plus amikacin in patients who were likely to remain neutropenic for a prolonged period of time; the results are currently being analysed. Another trial designed to compare the role of irnipenem with piperacillin plus amikacin supported the used of irnipenem 56 Despite the increased numbers of Grampositive infections observed in recent years, theyhave beenassociated with.only moderate morbidity and minimal mortality. It

has been suggested that because of the low virulence of such organisms as coagulasenegative staphylococci, initial therapy with vancomycin may not be necessary. 57 This is important because the drug is not only expensive but is also potentially toxic. Patients with documented fungal infections or those who fail to respond to initial antibacterial therapy usually require the addition of an antifungal agent such as photericin B. For patients failing to respond to antibacterial therapy but without proven fungal infection, amphotericin B may be given after 7 days. With the exception of cryptococcal meningitis, in which the use of amphotericin B and 5-fluorocytosine is more efficacious than amphotericin alone, there are no conclusive data concerning the efficacy of combined antifungal therapy.

am-

Prevention The patient at risk must be protected from a variety of organisms, including various bacteria, fungi, viruses and parasites.P-" consequently, no single approach is possible. Trimethoprim - sulphamethoxazole has been shown to be effective against pneumocystis infection'? and acyclovir can prevent Herpes simplex infection in seropositive patients." Among the strategies that have been used to protect against bacterial infections, the most recent involves the use of 6-fluoroquinolones, which are employed for selective gut decontamination, since they preserve the gastro-intestinal anaerobic flora.These drugs,particularlyciprofloxacin, are well absorbed and, in effect, provide systemic prophylaxis, Studies suggest that the quinolones, e.g. ciprofloxacin and norfloxacin, may be effective in preventing Gram-negative, but not Gram-positive bacterial infections.s-" REFERENCES 1. Reichert U, Saint Leger D, Schaeffer H: Skin surface chemistry and microbial infection. Semin ~atoI19&2;1:91~' 100.

2. Schumacher MJ: Serum Immunoglobulin and

187

L.A. Mandell

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

188

transferrin levels after childhood splenectomy. Arch Dis Child 1970; 45: 114 - 117. Naijar VA, Fridkin M: Antineoplastic, imrnunogenic and other effects of tetrapeptide tuftsin: a natural macrophage activator. Ann NY Acad Sci 1983; 419: 1 - 273. Miller ME, Baker L: Leukocyte function in juvenile diabetes mellitus: humoral and cellular aspects, J Pediatr 1972; 81: 979 - 982. Hill HR, Augustine NH, Rallison ML, et al: Defective monocyte chemotactic responses in diabetes mellitus. J Clin Immunoll983; 3: 7077. Bagdade Jl), Root RK, Bulger RJ: Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes 1974; 23: 9 - 15. Tan JS, Anderson JL, Watanakunakorn C, et al: Neutrophil dysfunction in diabetes mellitus. J Lab Clin Med 1975; 85: 26 - 33. Laurenzi GA, Guarneri JJ: Efects of bacteria and viruses on ciliated epithelium. A study of the mechanisms of pulmonary resistance to infection: the relationship of bacterial clearance to ciliary and alveolar macrophage function. Am Rev Respir Dis 1966; 93: 134 - 141. Brayton RG, Stokes PE, Schwartz MS, et al: Effect of alcohol and various diseases on leukocyte mobilization phagocytosis and intracellular bacterial killing. N Engl J Med 1970; 282: 123128. Berenyi MR, Straus B, CruzD: In vitro and in vivo studies of cellular immunity in alcholic cirrhosis. Am J Dig Dis 1974; 19: 199 - 205 Clark RA, Kimball HR, Decker JL: Neutrophil chemotaxis in systemic lupus erythematosus. Ann Rheum Dis 1974; 33: 167 - 172. Perez HD, Lipton M, Goldstein 1M: A specific inhibitor of complement- (C5) derived chemotactic activity in serum from patients with systemic lupus erythematosus. Clin Res 1978; 26: 519A. Zurier RB: Reduction of phagocytosis and lysosomal enzyme release from human leucocytes by serum from patients with lupus erythematosus. Arthritis Rheum 1976; 19: 73 -78. Hahn BH, Bagby MK, Osterland CK: Abnormalities of delayed hypersensitivity in systemic lupus erythematosus. Am J Med 1973; 55: 25 - 31. Turner RA, Schumacher HR, Myers AR: Neutrophil chemotaxis in rheumatic diseases. J Clin Invest 1974; 52: 1632 - 1635. Mowat AG, Baum J: Chemotaxis of polymorphonuclear leukocytes from patients with rheumatoid arthritis. J Clin Invest 1971; 59: 2541- 2549. BarEli M, Ehrenfeld M, Litvin Y, et al: Monocyte function in rheumatoid arthritis. Scand J Rheu-

matol 1980; 9: 17 - 23. 18. Gupta RC, Laforce FM, Mills DM: Polymorphonuclear leukocyte inclusions and impaired bacterial killing in patients with Felty's syndrome.J Lab Clin Med 1976; 88: 183 - 193. 19. Pereschenschi G, Zakouth V, Spirer Z, et al: Leukocyte mobilization by epinephrine and hydrocortisone in patients with chronic renal failure. Experientia 1977; 33: 1529 - 1530. 20. Salant DF, Glover AM, Anderson R, et al: Depressed neutrophil chemotaxis in patients with chronic renal failure and after renal transplantation. J Lab Clin Med 1976; 88: 536 - 545. 21. Craddock PR, Fehr J, Dalmasso AP, et al: Hemodialysis leukopenia. J Clin Invest 1977; 59: 879 - 888. 22. McIntosh J, Hansen P, Ziegler J, et al: Defective immune and phagocytic function in uremia and renal transplanation. Int Arch Allergy Appl Immunol1976; 51: 544 - 559. 23. Boulton-Jones JM, Vick R, Cameron JS, et al: Immune responses in uremia. ClinNephroll973; 1: 351 - 360. 24. Phillips I, Wharton B: Acute bacterial infection in kwashiorkor and marasums. Br Med J 1968; i: 407 - 409. 25. SirisinhaS, SuskindR,EdelmanR, etal: Complement and C3-proactivator levels in children with protein - calorie malnutrition and effect of dietary treatment. Lancet 1973; i: 1016 - 1020. 26. Edelman R, Suskind RM, Olsen RE, et al: Mechanisms of defective delayed cutaneous hypersensitivity in children with protein - calorie malnutrition, Lancet 1973; i: 506 - 508. 27. Schopfer K, Douglas SD: Neutrophil function in children with kwashiorkor. J Lab Clin Med 1976; 88: 450 - 461. 28. Deo MG, Bhan I, Ramalingaswami V: Influence of dietary protein on phagocytic activity of the reticuloendothelial cells. J Patholl973; 109: 215 -224. 29. Fauci AS, Dale DC: The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest 1974; 53: 240 - 246. 30. Yu DTY, Clements PJ, Paulus HE, et al: Human lymphocyte subpopulations: effect of corticosteroids. J Clin Invest-1974; 53: 565 - 571. 31. Fauci AS: Mechanism ofthe immunosuppressive and anti-inflammatory effects of glucocorticosteroids. J Immunopharmacoll978; 1: 1 - 25. 32. Fauci AS, WolffSM, Johnson JS: Effect of cyclophosphamide upon the immune response in Wegener's granulomatosis. N Engl J Med 1971; 285: 1493 - 1496. 33. Hyams JS, Donaldson MH, Metcalf JA, et al: Inhibition of human granulocyte function by methotrexate. Cancer Res 1978; 38: 650 - 655.

Infections in the compromised host 34. Granelli-Piperno A, Inaba K, Steinman RM: Stimulation of Iymphokine release from T Iymphoblasts, requirements for mRNA synthesis and inhibition by cyclosporin A. J Exp Med 1984; 160: 1792 - 1802. 35. Densen P, Mandell GL: Phagocytic strategy vs. microbial tactics. Rev Infect Dis 1980; 2: 817838. 36. Piel l: What science knows about AIDS. Sci Am 1988; 259: 40 - 134. 37. Seligmann M, Pinching N, Rosen FS, et at: Immunology of human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Ann Intern Med 1987; 107: 234 -242. 38. Kucers A, Bennett NMcK: Vancomycin. In: The Use ofAntibiotics, 3rd edn. London: Heinemann, 1979; pp 646 - 653. 39. Thornsberry C. Review of in vitro activity of third generation cephalosporins and other newer beta1actam antibiotics against clinically important bacteria. Am J Med 1985; 79: 14A - 20A. 40. Mandell LA, Bergeron M, Marrie T, et at: Imipenem: a new carbapenem. Can Med Assoc J 1988; 139: 505 - 506. 41. Wade Je. Antibiotic therapy for the febrile granulocytopenic cancer patient: combination therapy vs. monotherapy. Rev Infect Dis 1989; 11 (suppl 7): S1572 - S1578. 42. Karp JE, Dick JD, Angelopulos C, et at: Empiric use of vancomycin during prolonged treatmentinduced granulocytopenia. Am J Med 1986; 81: 237 - 242. 43. Miller SP, Shanbrom E: Infectious syndromes of leukemia and lymphomas. Am J Med Sci 1963; 246: 420 - 428. 44. Cline Ml: A test of individual phagocyte function in a mixed population of leukocytes. Identifications of a neutrophil abnormality in acute myelocytic leukemia. J Lab C/in Med 1973; 81: 311 315. 45. Engleman El, Benike Cl, Hoppe RT, et at: Autologous mixed lymphocyte reaction in patients with Hodgkin's disease.J Clin Invest 1980; 66: 149 - 158. 46. Owens AH: The malignant lymphomas. In: The Principles and Practice of Medicine, 22nd eOO (Harvey AMc, Johns RJ, McKusick VA, et at. eds). East Norwalk: Appleton and Lange, 1988; pp419 -429. 47. EORTC International Antimicrobial Therapy Project Group: Three antibiotic regimens in the treatment of infection in granulocytopenic patients with cancer. J Infect Dis 1978; 137: 1429. 48. Levine AS, Schimpff SC, Graw RG Jr, et at: Hematologic malignancies and other marrow

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

failure states: progress in the management of complicating infections. Semin Hemato/ 1974; 11: 141 - 202. Armstrong D, Brown AE: Controversies in the management of infectious complications of neoplastic diseases. Rev Infect Dis 1989; 11 (suppI7): SI527 - S171O. Wade JC, Schimpff SC: Approaches to therapy for bacterial infections in the granulocytopenic patients. In: Infections in Cancer Patients (Klastersky J, ed). New York: Raven Press, 1982; pp 105 - 129. Feld R, Louie TJ, Mandell LA, et at: A multicenter comparative trial of tobramycin and ticarcillin vs. moxalactam and ticarcillin in febrile neutropenic patients. Arch Intern Med 1985; 145: 1083 - 1088. Klastersky J, Cappel R, Daneau D: Clinical significanceof in vitro synergism between antibiotics in gram-negative infections. Antimicrob Agents Chemother 1972; 2: 470 - 475. Love LJ, Schimpff SC, Schiffer CA, et at: Improved prognosis of granulocytopenic patients with gram-negative bacteremia. Am J Med 1980; 68: 643 - 648. EORTC International Antimicrobial Therapy Cooperative Group: Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. N Eng/ J Med 1987; 317: 1692 - 1698. Pizzo PA, Hathorn JW, Hiemenz JW, et at: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N EnglJ Med 1986; 315: 552 - 558. Wade lC, Bustamante CI, Delin A, et at: Imipenem vs. piperacillin plus amikacin, empiric therapy for febrile neutropenic patients: a doubleblind trial (Abstract). In: Program and Abstracts of the 27th Interscience Conference on Antimicrobia/ Agents and Chemotherapy. Washington: American Society for Microbiology, 1987; p. 315. Rubin M, Hathorn lW, Marshall D, et at: Grampositive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Ann Intern Med 1988; 108: 30 - 35. Wade lC, Schimpff SC: Epidemiology and prevention of infection in the compromised host. In: Clinical Approach to Infection in the Compromised Host (Rubin RH, Young LS, eds). New York: Plenum, 1988; pp 5 - 40. Pizzo PA: Considerations for the prevention of infectious complications in patients with cancer. Rev Infect Dis 1989; 11 (suppI7): SI551-S1563. Hughes WT, Kuhn S, Chaudhary S, et al: Sue-

189

L.A. Mandell cessful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977; 297: 1419 -1426. 61. Wade JC, Newton B, Flournoy N, et al: Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med 1984; 100: 823 - 828. 62. Dekker AW, Rozenberg-Arska M, Verhoef J: Infection prophylaxis in acute leukemia: a com-

190

parison of ciprofloxacin with trimethoprim - sulfamethoxazole and colistin. Ann Intern Med 1987; 106: 7 - 12. 63. Karp IE, Men WG, Hendricksen C, et al: Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. Ann Intern Med 1987; 106: 1 - 7.