Part 4 - Therapeutic Use of Antimicrobial Agents
Infection in Immunocompromised Patients Including HIV/AIDS
The care of the immunocompromised patient is an increasingly important and challenging aspect of medicine that encompasses individuals suffering from a variety of underlying disease states rendering them especially vulnerable to microbial challenge. The term immunocompromised describes patients who have immunodeficiency states or those who are immunosuppressed.
Immunodeficiency may be congenital or acquired and can affect particular aspects of humoral, cell-mediated, or phagocytic cell function (Table 28.1). In general such states are relatively rare in medical practice. However, the advent of the HIV pandemic has altered this situation. It is now estimated that more than 50 million people are infected worldwide, making HIV infection the commonest cause of acquired immunodeficiency. The primary deficiency in HIV infection is one of an inexorable decline in cell-mediated immune function as a result of the human immunodeficiency virus targeting a variety of cell lines, including B cells but in particular the CD4 lymphocyte, which has a central role in orchestrating the immune system.
In contrast to immunodeficiency states, immunosuppression affects patients whose immune defences are impaired, either as a result of an underlying disease or its management by cytotoxic, immunosuppressive, or radiation therapy. The immunosuppressed patient often has an underlying malignant disease, or has undergone organ or bone marrow transplantation. In both situations, part of the therapeutic strategy involves temporary suppression or ablation of host immune functions.
In general the state of immunosuppression is finite, unlike immunodeficiency disorders, which are generally permanent or progressive; once the immunosuppressive regimen is reduced or withdrawn, the host defences can recover. The compromised defences include not only the humoral, phagocytic, and cell-mediated components of the immune system, but also skin and mucous membranes, the integrity of which may be impaired by cytotoxic drugs. The vulnerability of the patient to infection may be compounded by the use of intravascular catheters, bladder catheters, and in the case of ventilated patients, endotracheal tubes. These either interfere with pharyngeotracheal clearance mechanisms (respiratory tract) or connects a normally sterile body site (bladder, vascular compartment) with the external environment.
Table 28.1 Examples of immunodeficiency states associated with an increased frequency of severity of infection
The major features of immunosuppression associated with various malignant conditions are summarized in Table 28.2. Such patients are often cared for in high-dependency or intensive care facilities that provide opportunities for cross-infection and the acquisition of hospital-associated, and therefore more antibiotic-resistant, pathogens.
Microbial complications in the immunocompromised host
The variety of infections that may occur in the immunocompromised patient is extensive and arises from either exogenous (external source) or endogenous (host derived) micro-organisms. The distinction between exogenous and endogenous infections is not always clear-cut, since in hospital the bacterial flora of the skin and mucous membranes often alters.
In the case of virus infections, the herpes group predominates and may represent primary infection or reactivation of latent virus; these infections are often more severe than those in the immunocompetent host and carry the risk of dissemination. Adenovirus and para-influenza virus infections of the lung are also observed in profoundly neutropenic patients.
Fungal infections can be particularly severe. Candidosis of the mouth and upper gastrointestinal tract is particularly common and from time to time may be complicated by candidaemia, with spread to other organs. Cryptococcus neoformans, a yeast that was an uncommon cause of meningitis until the AIDS pandemic, occasionally complicates organ transplantation and malignant lymphoma.
Table 28.2 Examples of immunosuppressive states associated with an increased frequency or severity of infection according to altered host defences
Among the filamentous fungi, Aspergillus spp. are the most common pathogens. Their ubiquitous spores are normally harmless to the immunocompetent, but in the immunocompromised patient they can cause serious lung infection that may disseminate throughout the body. This risk is greatest in patients with profound neutropenia. Aspergillosis is not only difficult to treat but is also difficult to diagnose, especially in the early stages of infection.
Pneumocystis carinii (jiroveci) has emerged as the leading opportunistic infection complicating HIV infection. It primarily affects the lung where it produces a severe progressive pneumonia, which may be fatal unless treated early. Pneumocystosis may also occur in patients undergoing organ transplantation and in those with lymphoblastic leukaemia or malignant lymphoma; profound impairment of cell-mediated immunity characterizes all these conditions. P. carinii, although a fungus, has a pattern of susceptibility to chemotherapeutic agents that is more in keeping with a protozoon. Other parasitic infections in the immunocompromised host include toxoplasmosis and in endemic regions, leishmaniasis. There are also a variety of gut infections such as giardiasis, cryptosporidiosis, microsporidiosis, and strongyloidiasis. The latter can progress to a state of hyperinfection with extensive larval invasion of the body.
Principles of chemotherapeutic control
The vulnerability of the immunocompromised patient to infection has been emphasized. Not only is the range of possible infections broad, but, because of the state of immunosuppression, the presentation may be atypical and the course fulminant. A specific clinical and microbiological diagnosis can be difficult to establish; the therapeutic management of such patients is consequently based on a set of principles that has evolved to meet their particular needs.
It is essential that the patient is thoroughly examined at the earliest suspicion of infection. Particular attention should be paid to the skin, perineum, entry sites for catheters, the mouth, lungs, and abdomen. Appropriate microbiological samples should be collected and necessary radiographic investigations obtained. Timely biopsy of lymph nodes, bone marrow, cutaneous or intrapulmonary lesions is appropriate in selective cases. The approach to the chemotherapeutic management of the immunocompromised patient is particularly well demonstrated in:
- patients with haematological malignancies undergoing cytotoxic chemotherapy or bone marrow transplantation, especially during episodes of profound neutropenia;
- patients with AIDS;
- those with specific immunological defects such as hyposplenism.
In the neutropenic patient infection can develop rapidly over a matter of hours, and if untreated can prove fatal. If fever above 38°C persists for 2 h or more, broad-spectrum antibiotic therapy should be administered promptly by the intravenous route. However, documentation of infection can be difficult: about 15% of infections will be documented by blood culture, a further 20% by other microbiological investigations, and a further 20% by clinical criteria. In the remainder, infection may only be strongly suspected without supporting clinical or laboratory evidence; non-microbial causes such as drug reactions, blood or platelet transfusions, or the underlying disease state may be responsible for the febrile episode.
The variety and relative frequency of bloodstream pathogens in the neutropenic patient are summarized in Table 28.3. There has been a striking increase in Gram-positive infections in recent years, which in part relates to the widespread use of vascular catheters for drug administration, as well as the selective pressure arising from the use of broad-spectrum antibiotics, notably β-lactam and quinolone agents.
In general the antibiotic regimens have been based on a combination of a β-lactam antibiotic and an aminoglycoside, which together are active against most of the likely pathogens. Among the β-lactam agents, a broad-spectrum cephalosporin such as ceftazidime has been most widely used, although the ureidopenicillin piperacillin, in combination with tazobactam, is also popular. An aminoglycoside such as gentamicin or amikacin is administered simultaneously since both are active against Gram-negative bacilli, including Pseudomonas aeruginosa. Some centres have adopted the use of a single agent such as ceftazidime or imipenem, but the combined regimen offers synergistic activity that may be useful, especially when dealing with serious Ps. aeruginosa bacteraemia. The increase in Gram-positive infections caused by staphylococci, enterococci, and viridans streptococci reflects a relative weakness in these regimens; as a result a glycopeptide, such as vancomycin or teicoplanin, may be needed, especially in patients who have recently undergone bone marrow transplantation in whom a neutropenic febrile episode can be particularly serious. However, increased use of glycopeptides is being accompanied by infections caused by glycopeptide-resistant enterococci.
Table 28.3 Distribution of bloodstream isolates complicating neutropenic states
Candida infection is best treated with intravenous amphotericin B or caspofungin with the azole fluconazole as a reserve agent. Amphotericin B is a toxic drug and careful dosaging and monitoring of renal function is essential to avoid serious nephrotoxicity. Lipid formulations of amphotericin B are less nephrotoxic but much more expensive.
Cryptococcal yeast infections are managed with a combination of amphotericin with or without the addition of flucytosine (see Chapter 26, p. 372). Filamentous fungal infections, notably Aspergillus infection, are best treated with intravenous amphotericin B or voriconazole. An alternative agent for unresponsive disease is caspofungin.
The seriousness of infections in the severely immunosuppressed neutropenic patient has led to the use of chemoprophylactic drug regimens, particularly in patients undergoing cytotoxic chemotherapy for haematological malignancies and in bone marrow transplant recipients. Regimens are directed at those micro-organisms likely to result in bacteraemic disease.
The varied choice of prophylactic regimen reflects different views on the pathogenesis of infection in these patients. One view is that oral, nonabsorbable antibiotics are desirable in that their effect is confined to the gastrointestinal tract, which is the major source of invasive micro-organisms. These regimens are less widely used than in the past, but have included agents active against Candida spp., because of the frequency and severity of upper gastrointestinal candidosis, together with framycetin and colistin, which are non-absorbed agents. Other variations have included neomycin, colistin, and nystatin; or gentamicin, vancomycin, and nystatin. One important problem with these regimens is that their bitter taste leads to poor patient compliance. Moreover, evidence that they reduce the frequency and severity of bacteraemic infections has been difficult to obtain.
As an alternative to these regimens, other agents have been adopted which have systemic antibiotic effects. Co-trimoxazole has been widely used for its activity against many Gram-negative enteric bacilli and Gram-positive pathogens. It is also active against P. carinii. However, the emergence of drug-resistant strains, poor activity against Ps. aeruginosa, and the danger of bone marrow suppression in bone marrow recipients make this antifolate compound less than ideal.
Fluoroquinolones provide broad-spectrum activity, high potency, and a systemic antibiotic effect, with substantial drug concentrations within the gut. There is strong evidence to indicate that these drugs achieve a reduction in serious Gram-negative bacteraemia, although the relative weakness of the quinolones against Gram-positive pathogens has also been clearly demonstrated. Ciprofloxacin has been the most widely used agent. When given by mouth it provides a cost-effective approach in high-risk patients, especially those undergoing bone marrow transplantation.
Selective decontamination of the digestive tract
As well as patients rendered neutropenic by chemotherapy or disease, the ventilated patient on the intensive care unit is at considerable risk of infection, in particular from pneumonia from aspiration of oropharyngeal flora. One approach has been to use a topical antibiotic regimen, applied to the mouth in the form of paste and given in liquid form via a nasogastric tube into the stomach and hence the gastrointestinal tract. The aim is to suppress the flora of the gastrointestinal tract, which is largely made up of aerobic and anaerobic micro-organisms. One widely studied regimen is a combination of polymyxin, gentamicin, and amphotericin B, often supplemented for the first few days with intravenous cefotaxime. The pathogens targeted by this regimen include Staphylococcus aureus, Escherichia coli, Proteus spp.,Klebsiella spp., and Candida spp., which are among the more common causes of infection in such patients. Studies have shown a reduction in bacterial counts in the mouth, stomach, and colon. There is also evidence that nosocomial pneumonia can be reduced. This is more readily achievable, in young, relatively fit patients who have sustained major trauma than in the elderly or those with chronic lung disease. Among other populations of ventilated patients the cost-benefit of this procedure in terms of reduced mortality and length of stay in hospital has proved difficult to establish.
The clinical impact of HIV infection lies in its persistent nature and the accompanying progressive immunodeficiency which gives rise to a range of complicating infections and malignancies. These target many organs as well as producing systemic illness. Table 28.4 summarizes the more important complicating infections.
In contrast to their effects in the immunocompetent host, these infections often present atypically and with heightened severity. Furthermore, many of the infections recur after treatment in those with advanced HIV disease. Thus, in the HIV-infected patient the initial course of treatment must be more intensive than in the immunocompetent host, and for many conditions long-term suppressive therapy is needed to prevent relapse. In addition, by controlling the underlying HIV infection, the frequency and severity of opportunistic infections can be reduced, as well as the risk of recurrent opportunistic infection.
The introduction of ‘highly active antiretroviral therapy’ (HAART), in which three-drug regimens of two nucleoside analogues with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor are used, has permitted cessation of primary prophylaxis against P. carinii in selected patients. These regimens are discussed in Chapter 27. They are generally well tolerated and, provided the patient is compliant with the medication, have a major impact on the quality of life. Although they all act in a suppressive manner to delay disease progression, none is curative.
The chemotherapeutic approach to selected opportunistic infections is discussed in order to emphasize the principles and associated problems that arise.
Pneumocystis carinii (P. jiroveci)
Among the many opportunistic infections that complicate HIV infection, P. carinii predominates. The primary site of infection is the lung. Clinical disease represents reactivation of endogenous infection usually acquired in childhood. Typical symptoms include progressive shortness of breath with or without a relatively unproductive cough, progressive hypoxaemia, and diffuse bilateral chest radiograph infiltrates. The diagnosis has been greatly facilitated by the availability of a fluorescent antibody to P. carinii,which can be applied to expectorated sputum or to a saline lavage obtained by bronchoscopy.
Table 28.4 Common opportunist pathogens complicating HIV disease
The treatment of choice is high-dose co-trimoxazole, by mouth or intravenously, for 3 weeks. The risk of hypersensitivity to the sulphonamide component is greatly increased in HIV disease and alternative regimens, such as intravenous pentamidine or oral atovaquone, or a combination of clindamycin and primaquine may be necessary. Intravenous trimetrexate has also been used in patients intolerant of or unresponsive to other drugs.
Once the patient has recovered it is necessary to continue with life-long prophylaxis with low-dose co-trimoxazole. Alternative agents that can be used in those intolerant of the standard regimens include dapsone, clindamycin, and primaquine. Nebulized pentamidine given once monthly as an aerosol inhalation provides another choice. In view of the seriousness of P. carinii pneumonia, patients with HIV infection are now offered primary prophylaxis when their CD4 lymphocyte counts fall below 200/µl in order to prevent infection. The choice of agent and frequency of administration is the same as for secondary prophylaxis.
The protozoon Toxoplasma gondii can cause serious disease in people with HIV infection. This may occur as a primary infection, although it more usually represents reactivation of dormant parasites. The disease presents most frequently as a space-occupying lesion of the brain with focal neurological features. The diagnosis is based on clinical suspicion and computed tomography scan. Serodiagnosis is difficult. The presence of tachyzoites in brain biopsy is confirmatory. However, it is more usual to carry out a trial of chemotherapy in the first instance since this can avoid potentially dangerous neurosurgery.
Toxoplasmosis is treated with pyrimethamine and sulfadiazine in high dosage for 6 weeks before reducing to a maintenance dose. This regimen often results in bone marrow suppression or is complicated by an allergic skin eruption. Alternative drugs include high-dose clindamycin or the azalide azithromycin, which also exhibits useful activity. The principles of treatment are similar to those for controlling P. carinii pneumonia in that initial control is followed by lifelong maintenance therapy. There is evidence that cotrimoxazole given as prophylaxis for P. carinii may also be suppressive for toxoplasmosis.
Cytomegalovirus infection is extremely common. In those with HIV infection, reactivation is associated with a range of manifestations, which may involve the gastrointestinal tract, lung, liver, and in particular the eye, where a progressive retinopathy may lead to loss of vision or total blindness. Treatment with ganciclovir, foscarnet, or cidofovir is suppressive but not curative (see Chapter 27).
Patients with HIV infection are at increased risk of mycobacterial infection. This may be newly acquired but is more usually the result of endogenous reactivation as cell-mediated immunity steadily declines. Mycobacterium tuberculosis is the infecting organism, but disease may present atypically owing to altered host immunity. In many parts of the world drug-resistant tuberculosis has emerged as an important problem, and there have been instances of spread within prisons and hospitals (see p. 353). Where there is good evidence for previous tuberculosis, chemoprophylaxis with isoniazid is recommended for 1-2 years.
Infection with organisms of the Mycobacterium avium complex is a common problem in patients with AIDS. Disease presents with fever, sweats, weight loss, and diarrhoea. Patients are frequently bacillaemic and have high bacterial loads within the gut and bone marrow. The organisms are extremely resistant to conventional antituberculosis regimens and a combination of clarithromycin with rifabutin and ethambutol is recommended. Response to treatment may, unfortunately, be short-lived. Attempts have therefore been directed at preventing disease with rifabutin, alone or in combination with azithromycin.
The spleen is an important site of host defences, rich in lymphoid follicles and phagocytic cells. In its absence the patient is at increased risk of infection, including fulminating bacteraemia. Apart from splenectomy, a variety of medical conditions can cause hyposplenism. These include hereditary conditions such as sickle cell anaemia and hereditary spherocytosis. The risk of serious infections is greatest in early childhood but declines with age, although the risk remains throughout life. Among the fulminant infections are those caused byStreptococcus pneumoniae, Haemophilus influenzae, Esch. coli, Neisseria meningitidis, and a rare pathogen of man, Capnocytophaga canimorsus. Hyposplenic or asplenic patients should be alerted to their increased risk and recommended to seek early medical attention in the presence of symptoms suggestive of severe infection. Immunization against pneumococcal infections is possible in those over 2 years of age and is the best form of prevention. Likewise, children should be immunized against H. influenzae and group C meningococcal infection. Long-term chemoprophylaxis with phenoxymethylpenicillin (penicillin V) is of proven benefit in children with sickle cell disease. However, the additional benefit of life-long prophylaxis in those who have been actively immunized is marginal. Compliance with lifelong penicillin V prophylaxis is a further problem, as is the steady increase in resistance to penicillin among pneumococci, especially in parts of Europe and North America.