Lesson 22, Volume 15—Treatment of Fungal Pneumonia

By Michael W. Owens, MD, FCCP; David S. Green, MD; Ronald B. George, MD, FCCP

Objectives

1. Be familiar with the available antifungal therapeutic agents.
2. Understand the clinical and radiographic presentations of the various fungal pneumonias.
3. Recognize the appropriate choice of therapeutic agents for the fungal pneumonias in the normal host and the immunosuppressed patient.
4. Know the alternative agents available for use in patients with fungal pneumonias.

Key words

Abbreviation

AmB = amphotericin B

Although fungi have been recognized as important pathogens for the last century, they were for many years considered unusual and limited to certain endemic areas. As a result, the development of antifungal agents has lagged far behind that of antibacterial agents.¹ The first important antifungal drug, amphotericin B (AmB), introduced in 1955, was the mainstay of therapy until the 1980s when the first generation of triazole antifungal agents—ketaconazole, fluconazole, and itraconazole—was introduced.²

During the last two decades, the incidence of systemic fungal infections has increased dramatically, associated with the development of transplantation techniques, advances in chemotherapy, and the appearance of the AIDS epidemic. Currently, systemic fungal infections are recognized as a major cause of morbidity and mortality.³ At present, a large number of new azole derivatives are undergoing evaluation, and new unrelated agents are being developed.¹ We will review the current status of available antifungal agents (Table 1 and Table 2), and will mention some of the new agents on the horizon. Standard therapeutic regimens will be considered briefly.

Antifungal Agents

Polyene Antibiotics

Polyene antibiotics, such as AmB and nystatin, target ergosterol in the outer cell membrane of the fungus. In the case of AmB, aqueous pores are produced that result in increased membrane permeability, leakage of cell contents, and ultimately cell death. AmB has a very narrow therapeutic index, and doses that are clinically useful are associated with significant side effects in most patients. These include fever, chills, nausea, vomiting, headaches, electrolyte imbalance, and renal failure.

A variety of lipid formulations of AmB are available for clinical use.⁴ These include AmB lipid complex (Abelcet; The Liposome Co, Inc; Princeton, NJ), AmB colloidal dispersion (Amphotec; Sequus Pharmaceuticals Inc; Menlo Park, CA), and AmB liposomal preparation (AmBisome; Fujisawa Healthcare, Inc; Deerfield, IL). Abelcet is a large lipid complex with a configuration of sheets. It is rapidly removed from the blood by the liver and spleen, resulting overall in lower serum concentrations than AmB. Ambisome is a small (diameter of 80 nm), unilamellar vesicle. Its small size allows it to escape the macrophage-phagocyte system, resulting in higher serum concentrations than AmB. Amphotec is a colloidal dispersion of AmB complexed with cholesteryl sulfate shaped into flat disks. It achieves a lower peak concentration but has a longer half-life than AmB. Doses of these agents at 5 mg/kg/d are roughly equivalent to AmB at 1 mg/kg/d. They are not associated with an improved clinical efficacy compared with AmB but have fewer serious side effects, such as nephrotoxicity. The lipid formulations of AmB are all very expensive; therefore, conventional AmB is preferred unless significant toxicity develops with its use.

Nystatin cannot be used parenterally secondary to significant toxicity. Nystatin in multilamellar liposomes is currently undergoing study.⁵ It is active against clinical isolates of Aspergillus spp, including itraconazole-resistant isolates in vitro. When used in neutropenic rabbits with invasive pulmonary aspergillosis, it caused a reduction in the tissue burden of aspergillus and an improvement in survival.⁵

Azoles

The azoles used to treat fungal lung infections include an imidazole, ketoconazole, and the triazoles, fluconazole and itraconazole. These agents exert their fungistatic effect by inhibiting sterol biosynthesis. They inhibit the fungal cytochrome P-450–dependent enzyme, lanosterol demethylase, which is responsible for the conversion of lanosterol to ergosterol. Inhibition of this enzyme leads to depletion of ergosterol in the fungal cell plasma membrane and alterations in the membrane fluidity. These agents have an increased selectivity for fungal cell membranes over mammalian cell membranes.

Ketoconazole was developed in 1978. It has efficacy against histoplasmosis, blastomycosis, candidiasis, coccidioidomycosis, and paracoccidioidomycosis. It has been replaced for the most part by the newer azoles, which have fewer side effects and are generally better tolerated.

Fluconazole was developed in 1981. It is available in oral and IV formulations. It is well-tolerated, with nausea and vomiting and other GI side effects occurring in < 5% of patients, skin rashes and headaches in < 2% of patients, and an increase in hepatic transaminases in approximately 7% of patients. Fluconazole is effective in pulmonary and disseminated cryptococcosis. It is not recommended for the treatment of pulmonary or disseminated candidiasis. Its widespread use has led to an increased incidence of resistance. Torulopsis glabrata and Candida krusei are less susceptible to fluconazole than Candida albicans, Candida tropicalis, and Candida parapsilosis.

Itraconazole was developed in 1986. It is available in oral and IV formulations. It is also well-tolerated, with nausea and vomiting and other GI side effects occurring in < 10% of patients, skin rashes and headaches in < 2% of patients, and an increase in hepatic transaminases in approximately 5% of patients. It is useful against filamentous fungi. It is useful in nonlife-threatening, nonmeningeal pulmonary and extrapulmonary blastomycosis and histoplasmosis, including chronic cavitary pulmonary disease and disseminated nonmeningeal histoplasmosis. It is also useful in the treatment of pulmonary sporotrichosis in immunocompetent patients. Itraconazole was the first azole to have activity against Aspergillus spp. It can be used in Aspergillus infections as discussed above, but resistance to Aspergillus spp may occur. It is not as good as fluconazole against acute cryptococcal infection.

Itraconazole may be erratically absorbed from the GI tract when taken orally. It takes approximately 7 to 10 days when given orally to reach a steady-state serum level that exceeds the minimum inhibitory concentration of most Aspergillus spp. It interferes with the cytochrome P-450 system, and use of itraconazole simultaneously with terfenadine, astemizole, midazolam, cisapride, and triazolam is contraindicated. It also alters the metabolism of cyclosporin A, tacrolimus, and vincristine. Rifampin significantly increases the metabolism of itraconazole. Drugs that decrease gastric acidity significantly decrease the absorption of itraconazole. This effect can by overcome by combining itraconazole with cyclodextrin, an oligosaccharide, which increases the absorption of itraconazole.⁶ The IV formulation of itraconazole, hydroxyitraconazole, possesses activity similar to that of oral itraconazole and can reach therapeutic concentrations rapidly in the critically ill patient.

Some new third-generation azoles are being developed. Voriconazole is structurally related to itraconazole and fluconazole.⁷ It will be available in oral and IV formulations. It is active against Candida spp resistant to fluconazole, including C krusei and T glabrata. It is more potent than fluconazole or itraconazole against Cryptococcus neoformans. Posaconazole, a hydroxylated analogue of itraconazole, and ravuconazole, a derivative of fluconazole, are currently undergoing study.⁷ They appear to have activity similar to itraconazole against Aspergillus spp.

Pyrimidine Analogues

Flucytosine (5-fluorocytosine) enters the fungal cell via a permease enzyme, where it is converted to 5-fluorouracil by cytosine deaminase. Flucytosine has no antifungal activity itself; it is the 5-fluorouracil that has antifungal activity. The 5-fluorouracil is incorporated into RNA and disrupts protein synthesis. It is also converted into 5-fluorodeoxyuridine monophosphate, a potent inhibitor of thymidine synthase, which is involved in DNA synthesis and nuclear division. Monotherapy with flucytosine is generally not recommended because of resistance, particularly with cryptococcal infections. It is usually used in combination with AmB. Side effects include nausea and vomiting, anorexia, bone marrow suppression, and renal toxicity.

Echinocandins and Pneumocandins

These agents inhibit fungal cell wall production. Mammalian cells do not have a cell wall, making the fungal cell wall an attractive target for these antifungal agents. They inhibit the fungal beta-(1,3)-D-glucan synthase complex, leading to depletion of glucan in the cell wall with subsequent osmotic fragility and lysis. Caspofungin has recently become commercially available. It has potent activity in vitro against Candida spp, Aspergillus spp, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis.⁸ It lacks activity against cryptococcus due to the low content of beta-(1,3)-D-glucan in this fungus. At present it is only approved for use in patients with invasive aspergillosis.⁸ Its clinical utility for other fungal infections remains to be established.

Pulmonary Mycoses in the Normal Host

The endemic mycoses, histoplasmosis, blastomycosis, and coccidioidomycosis, have been recognized for many years as causes of pulmonary infections in nonimmunocompromised people living in endemic areas. They commonly infect young people and those moving from nonendemic areas, and cause mild, usually unrecognized disease. It is thought that the three major endemic mycoses affect a large percentage of the population, probably the majority, based upon serologic studies and skin test results. Occasionally, they will cause more serious pulmonary infections requiring specific antifungal therapy.

For many years, the agent of choice for histoplasmosis, blastomycosis, and coccidioidomycosis was AmB, and in some cases it is still recommended. For mild to moderate illnesses, the triazole antifungals, which are effective orally, are preferred (Table 1). More recently, sequential therapy with IV AmB initially, followed by oral azole therapy when the patient's symptoms are relieved, has become popular. The following dosage recommendations for adults are based upon common usage; however, it is important to note that these are chronic infections of varying severity. As in other chronic infections, the treatment guidelines should be altered to fit the specific patient's needs.

Histoplasmosis

Primary histoplasmosis in a previously normal host usually presents on the chest radiograph as patchy pulmonary infiltrates associated with hilar and mediastinal lymph node enlargement. Symptoms are nonspecific, including malaise, fatigue, low-grade fever, cough, and occasionally rheumatologic symptoms, serositis, or erythema nodosum. These infections usually resolve over a period of weeks, and observation alone is indicated. For arthralgias or serositis, nonsteroidal anti-inflammatory agents without specific antifungal therapy are useful. If symptoms persist over several weeks, or if there is progression on serial chest radiographs, most authorities recommend a 3- to 6-week course of itraconazole (5 mg/kg/d for children, 200 mg once or twice a day for adults), although clinical studies are lacking.⁹

Acute severe pulmonary histoplasmosis occurs rarely in patients exposed to large concentrations of inhaled spores, eg, in construction workers clearing heavily infested sites. They present with fever, severe dyspnea, hypoxemia, and diffuse chest radiograph consolidation, similar to other forms of acute lung injury.¹⁰ Such cases require emergent therapy with oxygen, parenteral corticosteroids, and AmB, 0.7 mg/kg/d for a total dose of about 500 mg. Clinical response is usually rapid, and corticosteroids may be tapered rapidly when hypoxemia resolves.

Patients with chronic cavitary histoplasmosis should be treated with oral itraconazole, 200 mg twice daily, for a period of at least 6 months, but up to a year or more, depending upon response. If the disease is responding well, or if there are mild side effects to therapy, the dose of itraconazole may be lowered to 200 mg daily in one dose. An important consideration with itraconazole therapy is its cost, since it must be given for long periods. Ketoconazole, a related agent, is also effective in doses of 400 to 800 mg daily, and costs less, but has more side effects. Patients who do not respond to azole therapy after a few weeks should be given AmB using a total dose of 35 mg/kg over a period of 12 to 16 weeks. AmB should also be given in patients with CNS involvement.

Blastomycosis

Most patients with acute pulmonary blastomycosis recover over a period of weeks with no antifungal therapy. However, late relapse may occur after initial recovery, and may be manifest in the lungs or elsewhere. Reliable patients with mild disease should receive only close observation over a period of several months. For less reliable patients and those with more severe infections, a course of itraconazole, 200 to 400 mg/d, for > 6 months, is curative and prevents late relapses. In one multicenter study involving immunocompetent patients without meningeal involvement, itraconazole 200 mg once or twice daily was curative in 90% of patients treated for a median period of 6.2 months.¹¹ Ketoconazole 400 to 800 mg/d was also moderately effective, but was associated with toxicity in nearly half the patients.¹² For patients with severe pulmonary blastomycosis, CNS involvement, or a lack of response to azole therapy, AmB should be initiated at a dose of 0.7 mg/kg/d, for a total dose of 2 g. A higher total dose may be necessary for those with CNS infections, depending upon response.

Coccidioidomycosis

Coccidioidomycosis is endemic to the southwestern United States and northern Mexico. It is usually seen in individuals living in the lower Sonoran desert and in the Central Valley of California, or in people visiting these areas. As in the other endemic mycoses, most infections are asymptomatic or clinically mild, consisting of an influenza-like illness with cough, fever, fatigue, and pleuritic chest pain. Patchy infiltrates on a chest radiograph may be accompanied by hilar adenopathy or a pleural effusion. In chronic disease, cell-mediated immunity is associated with necrosis of the infiltrates and the appearance of thin-walled and thick-walled cavities. In the absence of therapy, these cavities may enlarge and rupture through the pleural surface, resulting in a pneumothorax.

Most cases of pulmonary coccidioidomycosis are self-limited and resolve without therapy. In patients who do not recover, and in those with moderate to severe symptoms, a course of oral antifungal therapy is indicated. Fluconazole, 400 mg/d, is considered the drug of choice, and should be continued for 1 to 3 months after the active infection has resolved.⁹ Ketoconazole, 200 to 400 mg/d, and itraconazole, 400 mg/d daily, have also been used for this infection, although clinical comparisons with fluconazole have not been reported.

For more severe acute disease, AmB is recommended initially, for a total dose of 1 to 1.5 g. If response occurs, treatment may be switched to oral fluconazole, and continued to completion of therapy. For patients with more severe progressive pulmonary disease, AmB is the treatment of choice, reaching a total dose of 30 mg/kg.⁹ This may be followed by a course of fluconazole, continued for 6 months after the illness resolves.

Cryptococcosis

C neoformans is a ubiquitous fungus, and cases of cryptococcosis are reported from throughout the world. The organism may reside in the lungs in the absence of clinical disease. The symptoms of acute pulmonary cryptococcosis are similar to those of other acute pulmonary mycoses, including cough, fever, and chest pain. Chest radiographs typically demonstrate multiple small patchy areas of infiltration, usually in one or more lower lobes. In the normal host, the infection resolves over a period of days to weeks without specific therapy. The fungus has a natural trophism for the CNS, and often the initial pulmonary disease is missed and the patient presents with cryptococcal meningitis.

Because of the frequency of dissemination to the CNS, it is now considered appropriate to treat acute pulmonary cryptococcosis with oral fluconazole, 400 mg/d, until symptoms and chest radiograph abnormalities have resolved. Patients with pulmonary cryptococcosis should have cryptococcal antigen titers measured in the blood and spinal fluid; if meningitis is present, they should receive a course of AmB, either alone or combined with flucytosine. For patients who are immunocompromised but HIV-negative, therapy should be initiated with AmB, 0.7 mg/kg/d, with or without flucytosine, 100 mg/kg/d. Following resolution of symptoms, if meningitis is not present, oral fluconazole, 400 mg/d, may be substituted for a total course of > 3 months. In HIV-positive patients, oral fluconazole should be continued for life.

Sporotrichosis

Sporotrichosis is an uncommon disease caused by the dimorphic fungus, Sporotrichium schenckii. It is most often seen as a localized infection of the skin and soft tissues following a minor injury. Occasionally, sporotrichosis may present as an isolated pulmonary infection, following inhalation of airborne conidia.¹³ The pulmonary infection may be acute and self-limited, or may persist as a cavitary pneumonia. Patients with chronic pulmonary sporotrichosis should receive oral itraconazole, 200 to 400 mg/d, until the pneumonia has radiologically resolved.¹³

Pulmonary Mycoses in the Immunocompromised Host

With the advent of aggressive treatment of malignancies, the prevalence of new immune-altering diseases such as HIV, and the availability of powerful antirejection medications used in transplant medicine, pulmonary fungal infections in immunosuppressed patients have become more prevalent and clinically important.¹⁴ Besides the endemic fungi described in the preceding section, immunocompromised patients may become infected with a variety of opportunistic fungi, with resulting pulmonary candidiasis, aspergillosis, mucormycosis, and pseudallescheriasis.

The agent of choice for severe pulmonary fungal disease in immune-suppressed patients is IV AmB. The triazole antifungal agents have a limited role in the management of seriously ill immunocompromised patients. However, lipid-based formulations of AmB may be useful in this group of patients, particularly if the patient cannot tolerate the side effects of standard AmB.⁴

Pulmonary Candidiasis

Candidal infections of the lung are quite rare, even in patients with deficient immune systems. Candida spp involved in pulmonary infections include C albicans, C tropicalis, and T glabrata (formerly Candida glabrata). Although candida is ubiquitous in nature and part of the normal flora of the GI tract and skin, pulmonary disease due to Candida spp may be seen in patients who are neutropenic, either because of a primary malignancy or secondarily because of chemotherapeutic agents. Patients who are taking a prolonged course of corticosteroids, as well as those who are taking prolonged antibiotic therapy for bacterial infections, are also at increased risk. Diabetes mellitus is a common underlying illness that predisposes some patients to develop candida infections. Patients who undergo lung transplantation are at risk for developing opportunistic pulmonary infections, including infections due to Candida spp.¹⁵ A significant risk factor that may lead to the development of candida infection is the widespread and prolonged use of IV catheters, in which the Candida spp may disseminate into the bloodstream and spread to other organs including the lungs.

Pulmonary candidiasis may present as a localized infiltrate, a diffuse bilateral miliary process in patients with hematogenous disease, and, rarely, as a fungus ball indistinguishable from an aspergilloma. Other signs and symptoms include cough, fever, shortness of breath, and occasionally hemoptysis. Patients with disseminated disease may have skin lesions, ophthalmitis, and liver metastases. Patients may present with a sepsis-like picture when severely ill. Diagnosis rests on demonstrating tissue invasion of the fungus or on positive blood cultures in disseminated disease.

Management of candidal pneumonia includes supportive measures with supplemental oxygen and removal of any obvious source of infection, such as indwelling catheters. Although fluconazole is an effective antifungal agent for treating some candidal infections, it is not recommended for the treatment of disseminated or pulmonary candidiasis. IV AmB is the standard treatment of pulmonary candidiasis, and should be given in doses of 0.5 to 0.7 mg/kg/d up to a total dose of 1 to 2 g.¹⁴ Although fluconazole may be as effective as AmB in the treatment of candidemia in immunocompetent patients, its use cannot be recommended in seriously ill immunosuppressed patients. The presence of a candidal fungus ball often requires surgical removal for resolution of symptoms and prevention of complications such as massive hemoptysis.

Pulmonary Aspergillosis

Pulmonary infections due to Aspergillus spp are not uncommon and may be life-threatening in certain groups of patients. Aspergillus spp responsible for human infection include Aspergillus fumigatus, Aspergillus niger, and Aspergillus flavus, as well as other lesser-known species. Diagnosing aspergillosis depends on finding the organism in tissue (lung) by biopsy and not solely on the identifying the organism by stains or cultures of sputum. Classic clinical and radiographic features, such as the presence of a fungus ball, may lead one to make a presumptive diagnosis and begin empiric therapy. Invasive aspergillosis is seen mostly in patients who have hematologic malignancies or are posttransplantation, who are rendered neutropenic due to chemotherapy. A form of aspergillus infection that may be seen in patients who undergo lung resection is bronchial-stump aspergillosis, in which the stump that remains after resection becomes infected. Lung transplant patients may develop ulcerative tracheobronchitis.¹⁵

Management of pulmonary aspergillosis depends on the form encountered. Aspergillomas usually require surgical excision for life-threatening complications. Other therapeutic options that have been tried include oral and systemic antifungals as well as intracavitary installation of chemotherapeutic agents. Although case reports have described some success using these therapies, surgical resection is the treatment of choice for an aspergilloma. Invasive pulmonary aspergillosis requires therapy with AmB (total dose, 1 to 2 g). A longer course of therapy may be necessary to achieve eradication of the organism. Once stable, the patient may be switched to oral itraconazole, 400 mg/d. Therapy is usually continued until the absolute neutrophil count is > 500 cells/mm and both clinical and radiographic signs of infection have improved or stabilized.¹⁶ Severe necrotizing lobar aspergillosis may require emergency surgical removal to avoid fatal hemoptysis.

A new class of antifungal agents has recently been approved for the treatment of invasive apergillosis infections for patients who cannot tolerate other medications (AmB, amphotericin lipid formulations, itraconazole) or those whose disease is refractory. Caspofungin is an echinocandin is currently only approved for invasive aspergillosis infections.⁸ Its use in other systemic fungal infections remains to be defined.

Pulmonary Mucormycosis

Pulmonary infections due to fungi of the order Mucor are quite rare yet are associated with a poor outcome. In a recent review of pulmonary mucormycosis, risk factors listed for development of the infection include organ transplantation, renal failure, diabetes mellitus, and hematologic cancers.¹⁷ Patients infected with pulmonary mucormycosis (zygomycosis) usually present with symptoms similar to invasive aspergillosis, although the sinuses and upper respiratory tract are more often involved.

Treatment of pulmonary mucormycosis is with high-dose AmB, up to 1 mg/kg/d. Surgical excision may be required in cases of massive hemoptysis. Prognosis of patients with pulmonary mucormycosis is poor despite medical and surgical therapy.

Pseudallescheriasis

Pulmonary infections due to Pseudallescheria boydii are unique in their rarity and in their treatment. Pseudallescheriasis pulmonary infections are histologically and clinically similar to aspergillosis, and may even present as a fungus ball.¹⁸ Diagnosis rests on culture of the organism from infected tissue. Pseudallescheriasis is unique in that it is resistant to AmB. Historically, the antifungal agent of choice for this rare infection has been miconazole. However, because IV miconazole is not available in the United States, oral itraconazole 400 mg/d is recommended (this usage is not approved by the Food and Drug Administration).¹⁹ Surgical excision may also be required, especially in cases of life-threatening hemoptysis.

References

1. Hossain MA, Ghannoum MA. New investigational antifungal agents for treating invasive fungal infections. Expert Opin Investig Drugs 2000; 9:1797–1813
2. Pomerantz S, Singh VR, Sarosi GA. The role of new drugs in the treatment of fungal diseases. Pulm Crit Care Update 1993; 8(29):1–5
3. Anaissie E, Bodey P. Nosocomial fungal infections. Old problems and new challenges. Infect Dis Clin North Am 1989; 3:867–882
4. Hann IM, Prentice HG. Lipid-based amphotericin B: a review of the last 10 years of use. Int J Antimicrob Agents 2001; 17:161–169
5. Andriole VT. Current and future antifungal therapy: new targets for antifungal agents. J Antimicrob Chemother 1999; 44:151–162
6. Willems L, Van Der Geest R, De Beule K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther 2001; 26:159–169
7. Hoffman HL, Ernst EJ, Klepser ME. Novel triazole antifungal agents. Expert Opin Investig Drugs 2000; 9:593–605
8. Georgopapadakou NH. Update on antifungals targeted to the cell wall: focus on beta-1,3-glucan synthase inhibitors. Expert Opin Investig Drugs 2001; 10:269–280
9. Goldman M, Johnson PC, Sarosi GA. Fungal pneumonias: the endemic mycoses. Clin Chest Med 1999; 20:507–519
10. Storch G, Burford JG, George RB, et al:. An outbreak of acute histoplasmosis in northern Louisiana. Chest 1980; 77:38–42
11. Dismukes WF, Bradsher RW Jr, Kauffman CA, et al. Itraconazole therapy for blastomycosis and histoplasmosis. Am J Med 1992; 93:489–497
12. Pappas PG, Brasher RW, Kauffman CA, et al. Treatment of blastomycosis with higher doses of fluconazole. Clin Infect Dis 1997; 25:200–205
13. Sang MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30:710–718
14. Davies SF, Sarosi GA. Fungal pulmonary complications. Clin Chest Med 1996; 17:725–744
15. Levine SM, Peters JI. Fungal infection in the lung transplant recipient: clinical presentation, diagnosis, treatment, and prophylaxis. Pulmonary and Critical Care Update 1998; 12:1–11. Available at: www.chestnet.org/downloads/education/online/Vol12_13_18.pdf. Accessed May 2001.
16. Sugar AM. Treatment of invasive aspergillosis. In: UpToDate, version 9.1. Available at: www.uptodate.com. Accessed May 2001.
17. Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med 1999; 159:1301–1309
18. Travis LB, Roberts GD, Wilson WR. Clinical significance of Pseudallescheria boydii: a review of 10 years experience. Mayo Clin Proc 1985; 60:531–537
19. Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 31st ed. Vienna, VA: Antimicrobial Therapy, Inc, 2001; 75

3300 Dundee Road • Northbrook, Illinois 60062-2348 • (847) 498-1400 • (800) 343-2227
Copyright ©1999-2008 American College of Chest Physicians. All Rights Reserved.
ACCP Privacy Policy | ACCP Web Site Terms of Use