Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.

The study presented here was performed in order to create a rule that identifies subjects at high risk for invasive candidiasis in the intensive care setting. Retrospective review and statistical modelling were carried out on 2,890 patients who stayed at least 4 days in nine hospitals in the USA and Brazil; the overall incidence of invasive candidiasis in this group was 3% (88 cases). The best performing rule was as follows: Any systemic antibiotic (days 1-3) OR presence of a central venous catheter (days 1-3) AND at least TWO of the following-total parenteral nutrition (days 1-3), any dialysis (days 1-3), any major surgery (days -7-0), pancreatitis (days -7-0), any use of steroids (days -7-3), or use of other immunosuppressive agents (days -7-0). The rate of invasive candidiasis among patients meeting the rule was 9.9%, capturing 34% of cases in the units, with the following performance: relative risk 4.36, sensitivity 0.34, specificity 0.90, positive predictive value 0.01, and negative predictive value 0.97. The rule may identify patients at high risk of invasive candidiasis.

Infections in the neutropenic patient--new views of an old problem.

Infection in the neutropenic patient has remained a major clinical challenge for over three decades. While diagnostic and therapeutic interventions have improved greatly during this period, increases in the number of patients with neutropenia, changes in the etiologic agents involved, and growing antibiotic resistance have continued to be problematic. The evolving etiology of infections in this patient population is reviewed by Dr. Donowitz. Presently accepted antibiotic regimens and practices are discussed, along with ongoing controversies. In Section II, Drs. Maki and Crnich discuss line-related infection, which is a major infectious source in the neutropenic. Defining true line-related bloodstream infection remains a challenge despite the fact that various methods to do so exist. Means of prevention of line related infection, diagnosis, and therapy are reviewed. Fungal infection continues to perplex the infectious disease clinician and hematologist/oncologist. Diagnosis is difficult, and many fungal infections will lead to increased mortality even with rapid diagnosis and therapy. In Section III, Dr. Pappas reviews the major fungal etiologies of infection in the neutropenic patient and the new anti-fungals that are available to treat them. Finally, Dr. Rolston reviews the possibility of outpatient management of neutropenic fever. Recognizing that neutropenics represent a heterogeneous group of patients, identification of who can be treated as an outpatient and with what antibiotics are discussed.

Algorithm-based decision rules to safely reduce laboratory test ordering.

PURPOSE: Our study develops decision rules to define appropriate intervals at which repeat tests might be indicated for commonly ordered laboratory tests for hospitalized patients. METHODS: The final data set includes 5,632 adult patients admitted to the University of Virginia Hospital between July 1995 and December 1999. These patients had a hospital length of stay of five days or more and had results recorded for three routinely ordered laboratory tests for each of the first five days of their hospitalization. We use the serum potassium test to illustrate our algorithm-based decision rule methodology. RESULTS: Our decision rule begins with testing on the first two days of hospitalization and allows for repeat testing after observation of any non-normal values. The results show that the algorithm-based decision rule would lead to a 34% reduction for serum potassium tests for the first five days of hospitalization. Only one out of the 5,632 patients in our sample had a critical value that occurred only on a non-test day and, thus, was missed by the algorithm. CONCLUSIONS: The algorithm results are encouraging. We demonstrate that the number of tests can be reduced while missing critical values in only a small fraction of patients. Testing algorithms such as these can be used to reduce laboratory test ordering without compromising the quality of patient care.

Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study.

Community-acquired pneumonia remains an important infectious disease problem, with more than 4 million cases occurring in the United States annually. Although Streptococcus pneumoniae remains the most commonly identified organism, a variety of bacterial and nonbacterial pathogens may be involved. Hospitalization is unnecessary in most cases, and oral antibiotic therapy is common. In the majority of cases, the etiology of pneumonia is unknown at the time of presentation, necessitating the use of empiric therapy. Quinolones have not been utilized in this setting in the past because of their inconsistent coverage of S pneumoniae. Sparfloxacin (RP 64206) is a broad-spectrum fluoroquinolone with excellent activity in vitro against the majority of bacteria involved in community-acquired pneumonia, including pneumococcus. We therefore studied the efficacy and safety of sparfloxacin compared with the second-generation cephalosporin cefaclor as empiric therapy for patients with community-acquired pneumonia in a double-masked, double-dummy, multicenter trial. Three hundred thirty patients aged 18 years or older with community-acquired pneumonia suspected of being bacterial in etiology were enrolled at 74 centers in the United States from June 1, 1992, to March 4, 1995. Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once followed by sparfloxacin 200 mg orally daily (n = 168), or cefaclor 500 mg orally every 8 hours (n = 162). There were no significant differences between groups with regard to baseline characteristics. Patients were followed up serially at 4 +/- 1 days, 20 +/- 3 days, and 38 +/- 7 days after the beginning of therapy. Patients were evaluated for clinical response, clinical recurrence of infection, and eradication of baseline pathogens. The primary efficacy variable was the clinical response (cured or improved) in the subgroup of patients meeting the definition of clinically assessable. Responses were also evaluated in the intent-to-treat population. In the intent-to-treat population, 35.7% of patients receiving sparfloxacin were clinically cured, compared with 32.1% of patients receiving cefaclor. Clinical successes (patients clinically cured plus improved) were also comparable (72.6% of patients in the sparfloxacin group and 71.0% of patients in the cefaclor group). Similar clinical success rates were noted using only the clinically assessable population (primary efficacy variable). Forty-four percent of patients receiving sparfloxacin and 39.1% of patients receiving cefaclor were clinically cured. In the sparfloxacin group, 86.6% of patients were clinical successes, compared with 84.4% of patients in the cefaclor group. Microbiologic cures were comparable in both groups. There was no difference in the incidence of recurrence of infection or superinfection. Adverse events thought to be due to study drug occurred equally in both groups (14.3% in the sparfloxacin group vs 14.8% in the cefaclor group). Results show that sparfloxacin is a safe and effective empiric therapy for patients with community-acquired pneumonia and is comparable to cefaclor.

Fever in the compromised host.

Fever in the compromised host remains a significant clinical problem. Multiple potential pathogens, subtle physical findings, and a variety of noninfectious problems that may masquerade as infection contribute to this clinical challenge. A review of host defense defects along with a careful physical examination will begin to narrow the etiologic possibilities for fever. Recognizing that the majority of infections will represent as fevers of unknown etiology, a consistent approach to the patient who responds to empiric antibiotic therapy as well as to the patient who fails to respond should be developed.

Risk factors for infection of adult patients with cancer who have tunnelled central venous catheters.

BACKGROUND: Long-dwelling tunnelled central venous catheters provide reliable access for infusion therapy of patients with cancer, but can result in serious bloodstream infections. The incidence of such infections has been documented, but few studies have assessed potential risk factors, and to the authors' knowledge, none have measured the effect of neutropenia upon the incidence of these infections. METHODS: A cohort of 71 adult patients with cancer with long-dwelling tunnelled central venous catheters was followed for a total of 12,410 catheter days until catheter removal, death, or end of study for the occurrence of catheter-related infection or sepsis of unknown origin. Fifteen factors were assessed for association with these infections. RESULTS: Thirteen patients (18%) experienced a catheter-related infection (1.0/1000 catheter days), and 23 (32%) experienced sepsis of unknown origin. Neutropenia was associated significantly with risk for catheter-related infection (relative risk [RR] = 15.1, 95% confidence interval [CI] 2.7-86.9) and sepsis of unknown origin (RR = 10.3, 95% CI 4.0-26.8). Inpatient status, acute leukemia, and cytosine arabinoside therapy also were associated with sepsis of unknown origin, but not when adjusted for neutropenia. CONCLUSION: Of the 15 potential risk factors studied, neutropenia was the only independent risk factor for infection related to long-dwelling tunnelled central venous catheters and for sepsis of unknown origin.

Tissue-directed antibiotics and intracellular parasites: complex interaction of phagocytes, pathogens, and drugs.

Antibiotics with significant tissue penetration and intracellular accumulation may have an important role in the treatment of intracellular infections. However, clinically relevant evaluation of these antibiotics in vitro remains a challenge. Measurement of serum drug concentrations or serum bactericidal levels may not be relevant. Measurement of intracellular drug concentrations may be simplistic, given the complex interaction of drug, microbe, and phagocyte. The effect of an antibiotic on an intracellular organism depends on the drug's penetration into the cell, its intracellular location, its metabolism within the cell, and its antimicrobial activity within the organism's specific intracellular microenvironment. Legionella micdadei, an intracellular parasite that grows within monocytes, has been used for the evaluation of drugs like azithromycin that are concentrated intracellularly.

Azithromycin inhibition of intracellular Legionella micdadei.

Legionella micdadei is an intracellular parasite that is ingested, but not killed, by leukocytes. Within monocytes, the organism has been shown to grow 1.0 to 2.0 log10 units over 48 h (D. L. Weinbaum, R. R. Benner, J. N. Dowling, A. Alpern, A. W. Pasculle, and G. R. Donowitz, Infect. Immun. 46:68-73, 1984). Intracellular L. micdadei would appear to be a useful model in which to study the effect of antibiotics which accumulate intracellularly. Azithromycin, a newly introduced azalide, is highly concentrated within leukocytes and was therefore studied to determine its effect on a single strain of L. micdadei that had been ingested by human monocytes. Peripheral blood monocytes were allowed to ingest L. micdadei and extracellular, nonadherent organisms were subsequently removed by washing. Cells and cell-associated bacteria were then incubated at 0, 24, and 48 h in media with serial concentrations of azithromycin at sub-MIC levels (less than 1.0 microgram/ml). L. micdadei in cells not exposed to azithromycin grew 0.8 +/- 0.1 log10 units (mean +/- standard deviation) at 24 h and 1.7 +/- 0.4 log10 units at 48 h. At both 24 and 48 h, the lowest concentrations of azithromycin tested (0.02 microgram/ml) significantly inhibited bacterial growth in monocytes (P = 0.02). A stepwise inhibition of L. micdadei CFUs was noted with increasing azithromycin concentrations. In contrast, when cells were exposed to antibiotic before ingesting L. micdadei, a less effective antibacterial effect was noted. Under certain in vitro conditions, azithromycin is a potent agent against intracellular L. micdadei.

Candidal endophthalmitis after lithotripsy of renal calculi.

Candidal endophthalmitis is most commonly due to hematogenous seeding of the eye by Candida albicans. Although it is most often seen as a manifestation of disseminated candidiasis in patients who are seriously ill, other patients may have candidal endophthalmitis as the only evidence of fungal infection. We have presented a case of endophthalmitis due to C albicans in a patient who had bilateral renal calculi and who had received multiple antibiotics and extracorporeal shock wave lithotripsy.

The role of the chest roentgenogram in febrile neutropenic patients.

In a retrospective review of patients with neutropenia and fever, we sought to determine how often roentgenograms detected pulmonary disease, especially pneumonia, not suggested by signs and symptoms. Further, we sought to determine how often therapy was changed as a result of roentgenographic findings. Overall, 41 (22%) of 187 chest roentgenograms obtained during initial febrile episodes, recurrent fevers, or persistent fevers were abnormal. While most patients had signs and symptoms suggesting the presence of pulmonary disease, 17% had roentgenographic abnormalities detected in the absence of such findings. During initial febrile episodes, therapy was not changed in response to findings on the chest roentgenogram. However, during episodes of persistent or recurrent fever, findings on chest roentgenograms led to changes in therapy in eight (61%) of 13 episodes of which six (40%) resulted in clinical improvement. Chest roentgenograms were therefore found to be an important diagnostic tool in evaluating recurrent or persistent fever in the neutropenic patient but of little use during initial febrile episodes.

Ingestion of Legionella micdadei inhibits human neutrophil function.

Legionella micdadei is a human pathogen which survives within leukocytes. To determine how this organism escapes intracellular destruction, we examined its effect on human neutrophil activity. Neutrophils were allowed to ingest L. micdadei prior to evaluation of functional activity. Compared with control cells which did not ingest organisms, cells ingesting L. micdadei showed significantly depressed production of superoxide anion (24.5 +/- 9.0 nmol/10(6) cells per 15 min versus 6.9 +/- 3.2 nmol/10(6) cells per 15 min, respectively; P = 0.002), chemotaxis (43.9 +/- 0.8 mm versus 0.9 +/- 1.3 mm of directed migration, respectively; P = 0.001) and bactericidal activity against Staphylococcus aureus (97.9% versus 37.6% of ingested organisms killed, respectively; P = 0.001). Similar degrees of inhibition could not be demonstrated when either Staphylococcus aureus or Escherichia coli was ingested by cells prior to evaluation. Inhibition of neutrophil function did not occur when phagocytosis of L. micdadei was prevented. However, inhibition occurred with heat-killed as well as with viable organisms. The inhibition of neutrophil function by ingested L. micdadei may help explain the bacterium's ability to survive intracellularly and may begin to explain the pathogenesis of this disease.

Cunninghamella bertholletiae: an unusual agent of zygomycosis.

Cunninghamella bertholletiae shares many of the features typical of the other agents causing zygomycoses. Those who are immunocompromised constitute the major patient population at risk; the agents as a group are aggressive, the disease is often disseminated, and the pathologic picture of vascular invasion and tissue infarction is common. Unlike other agents of zygomycoses, Cunninghamella bertholletiae infection remains difficult to treat successfully even after early diagnosis and appropriate therapy.

Polymorphonuclear neutrophils: an effective antimicrobial force.

The production and deployment of polymorphonuclear neutrophils (PMNs) are under close regulation. PMNs interact through cytokines with a number of cell types, including macrophages, lymphocytes, and endothelial cells. PMNs are guided by bacterial products and cytokines to target sites, where microbes are recognized and killed. Killing occurs through oxygen-dependent and oxygen-independent mechanisms. The frequent and severe infections seen in patients with defects (either congenital or acquired) in PMN function demonstrate the importance of PMNs in host defense against infection. PMNs are potent inflammatory cells and can exacerbate disease states such as myocardial ischemia, gram-negative bacterial sepsis, and the adult respiratory distress syndrome.

Third generation cephalosporins.

The third generation cephalosporins demonstrate greater potency, broader antibacterial spectrum, and more favorable pharmacologic characteristics than other cephalosporins. The majority of strains of E. coli, Klebsiella pneumoniae, and Proteus are susceptible, including strains resistant to aminoglycosides, anti-Pseudomonas penicillins, and other cephalosporins. Pseudomonas aeruginosa is susceptible to a subgroup of third generation agents including ceftazidime, cefoperazone, and the experimental agents cefpirome and cefpiramide. Penetration into the cerebrospinal fluid is excellent especially for cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime. These agents are safe, sharing most of the known toxicities of other beta-lactam compounds. Their greatest use is in the therapy of difficult to treat gram-negative bacterial infections, including meningitis, nosocomial infections, and infections caused by Pseudomonas aeruginosa.

Comparison of once-daily cephalosporin regimens for community-acquired lower respiratory tract infections in patients with chronic lung disease.

The efficacy of cefonicid and of ceftriaxone, administered once daily for the treatment of lower respiratory tract bacterial infections (pneumonia or bronchitis), was evaluated and compared in 118 patients with chronic lung disease. The patients were randomly assigned to receive 1 gm of either drug, intravenously or intramuscularly, daily for three to 11 days (mean, seven days). Pathogenic bacteria were isolated from sputum in 59% of patients; Haemophilus influenzae and Streptococcus pneumoniae predominated. Clinical cure or improvement was noted in 95% and 93% of patients treated with cefonicid and ceftriaxone, respectively, and bacteriologic cure or improvement in 69% and 81% (the differences were not significant). Side effects were infrequent and similar in the two treatment groups, except that diarrhea was more common in the ceftriaxone group (11%, versus 4.4% in the cefonicid group). It is concluded that patients with chronic lung disease who experience acute exacerbations associated with infection caused by H influenzae or S pneumoniae, or other susceptible organisms, can be effectively treated with once-daily administration of either cefonicid or ceftriaxone.

Human nasal mucosal responses to topically applied recombinant leukocyte A interferon.

Healthy adults were randomly assigned to receive intranasal sprays of recombinant leukocyte A interferon (IFN; 9 X 10(6) U per day) or placebo once daily for four or 10 days. Scrape nasal biopsy specimens stained by hematoxylin and eosin and mucosal punch biopsy specimens stained by immunoperoxidase techniques with monoclonal antibodies to lymphocyte subsets were collected before and after exposure. Blinded analysis of the punch biopsy specimens by two pathologists found increased degrees of lymphocyte infiltration compared with preexposure samples in 56% of IFN vs. 0% of placebo recipients at four days (P = .008) and 60% of IFN vs. 10% of placebo recipients at 10 days (P = .057). By immunoperoxidase staining the cellular infiltrates were primarily in the subepithelium and comprised principally (mean, greater than or equal to 84%) T lymphocytes. In the 10-day IFN recipients, subepithelial T helper (Leu-3):T suppressor (Leu-2) cell ratios ranged from 2:1 to 5:1. The number of distribution of B (Leu-14) or natural killer (Leu-7) cells did not appear affected by IFN.

5-Fluorouracil effect on cultured murine stem cell progeny and peripheral leukocytes.

Pretreatment of mice with 5-fluorouracil (5-FU) depletes total marrow cellularity but leaves a residual population of cells with enhanced regenerative capability. Using the long-term Dexter liquid culture system, we studied the effects of 5-FU on murine marrow cells and their production of pluripotent stem cells (CFU-S) and monocyte-granulocyte precursors (CFU-C). We also examined oxidative and bactericidal activity of neutrophil progeny of marrow cells in culture to determine the effect of 5-FU on effector cell activity. As an in vivo comparison, effector cell activity of neutrophils from peritoneal exudates of 5-FU treated animals was examined. C57B1/6J mice were treated with 5-FU, 100 mg/kg or 150 mg/kg, 4-7 days prior to marrow cell harvest and culture. Total cell counts, CFU-S, and CFU-C were all reduced compared with values from saline-treated controls. Over time, cell production from 5-FU marrow increased, reaching supranormal levels by 2-3 weeks of culture. The neutrophil progeny obtained from these marrow cultures showed normal reduction of nitroblue tetrazolium dye (NBT), but abnormally low chemiluminescence. In contrast, neutrophils from peritoneal exudate of 5-FU-treated animals showed normal chemiluminescence, but abnormally low reduction of NBT. Normal bactericidal activity was exhibited by both neutrophil progeny from marrow cultures and by neutrophils from peritoneal exudates of 5-FU-treated animals. The present data indicate that mouse marrow cells surviving 5-FU have an enhanced proliferative capacity in vitro and are capable of producing neutrophil progeny that, despite some abnormalities of oxidative function, have normal bactericidal capability.