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Planned progressive antimicrobial therapy in neutropenic patients

Major advances have been achieved in medical science in recent decades, such that patients with illnesses previously considered untreatable now receive appropriate therapy and may survive. However, this achievement has usually been obtained with aggressive and invasive procedures, which in turn lead to multiple disruptions in immunological protection and therefore to increased susceptibility to opportunistic infections. The net results is that patients surviving severe underlying diseases may succumb to bacterial, fungal, viral or protozoan infections. This is particularly true for cancer patients, where infectious complications represents a major cause of morbidity and mortality (Meyers & Thomas, 1988; Morittu et al, 1989; Pizzo & Meyers, 1989). In recent years the management of infectious complications in cancer patients has improved substantially, especially in the field of bacterial infections. For example, among about 800 documented bacteraemia cases observed in the eight therapeutic trials (I, II, III, IV, V, VIII, IX and XI) performed by the International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organisation for Research and Treatment of Cancer (EORTC) from 1978 to 1994, the overall mortality rate decreased from 21% to 7%. In particular, the 30-day mortality rate from any cause in patients with Gram-negative and Gram-positive bacteraemia is now as low as 10% and 6%, respectively (personal communication, Marianne Paesmans, Statistician, EORTC– International Antimicrobial Therapy Co-operative Group). This represents a dramatic improvement with respect to, for example, a classic study of Gram-negative rod bacteraemias performed in 1962, in which the mortality rate was approaching 90% (McCabe & Jackson, 1962) and to the first study of the International Antimicrobial Therapy Cooperative Group (IATCG) of the EORTC performed in 1978, in which more than 20% of the patients with Gram-negative sepsis and about 15% of those with Gram-positive sepsis died (EORTC–International Antimicrobial Therapy Project Group, 1978). Reasons for this improvement are probably multiple, although the strategy of the rapid institution of empirical broad-spectrum antibacterial therapy with very active antimicrobial compounds at the commencement of fever has probably played a major role. The pattern of infective pathogens has also changed significantly over time. Whereas in the early days of antineoplastic chemotherapy, Gram-negative rods were the most common pathogens in neutropenic patients, nowadays Gram-positive micro-organisms are prevalent and cause about 60% of documented bacteraemias (EORTC–International Antimicrobial Therapy Cooperative Group, 1990; Klastersky et al, 1988; Brown et al, 1995). The reasons for this modification in the pattern of infecting pathogens remain unclear. The treatment of cancer has become more intensive and it is now associated with more severe oral mucositis and diarrhoea, leading to major damage of mucosal barriers and increasing risk of infection due to the resident Gram-positive oral flora. Herpes simplex oral lesions, frequently observed in granulocytopenic cancer patients, may further compromise mucous membrane integrity, allowing bacteria to enter the bloodstream (Corey & Spear, 1986). In addition, patients with cancer are often fitted with indwelling catheters (especially Broviac or Hickman type and Port-a-Cath), which can easily become colonized with skin bacteria and constitute a wellrecognized risk factor for Gram-positive infections (Viscoli et al, 1988, 1994; Viscoli & Castagnola, 1995). Finally, the selective pressure of antibiotics, such as third-generation cephalosporins and fluoroquinolones, more active against Gram-negative than Gram-positive bacteria, may also have played a role. Elting et al (1992) showed that the use of fluoroquinolones was one of the factors significantly associated with the development of streptococcal bacteraemia, especially when used in combination with H2-blockers and other antacids, probably due to increased colonization of the gastric and oesophageal flora by oral streptococci. Interestingly, in the trials performed by the IATCG of the EORTC the respective proportion of Gramnegative and Gram-positive organisms causing bacteraemia have remained stable over the last 5 years and there are reports suggesting that Gram-negative infections are again increasing, especially in paediatric populations (Aquino et al, 1995). In a recent surveillance study of bacteraemia in neutropenic and non-neutropenic children with cancer performed by the Italian Association for Paediatric Haematology and Oncology, 46% of the isolated pathogens were Grampositive cocci, versus 44% Gram-negative rods and 10% fungi (Castagnola et al, unpublished observation). In recent years several reports have emphasized the increasing role of fungal infections as a cause of morbidity and mortality in compromised patients, including those with cancer. For example, a national survey of nosocomial fungal infections in American hospitals (Hospital Infection Program, CDC, Atlanta, U.S.A.) showed that the incidence of these infections increased from 2·0 to 3·8 infections/1000 discharges form 1980 to 1990, with the incidence of nosocomial candidaemia increasing from 1·0 to 4·9 infections/1000 discharges (Beck-Saguè & Jarvis, 1993). There are studies (including autopsy studies) performed on both sides of the Atlantic showing that the increase in fungal infections is well documented in cancer patients (Bodey et al, 1992; Groll et al, 1996; Meunier et al, 1992; Martino et al, 1993). For years, Candida albicans was the most frequently British Journal of Haematology, 1998, 102, 879–888