David R. Snydman

Increasing Mortality Due to End-Stage Liver Disease in Patients with Human Immunodeficiency Virus Infection

Highly active antiretroviral therapy has decreased human immunodeficiency virus (HIV)-associated mortality; other comorbidities, such as chronic liver disease, are assuming greater importance. We retrospectively examined the causes of death of HIV-seropositive patients at our institution in 1991, 1996, and 1998-1999. In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P=.003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm(3) within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P=NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.

Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation

Cytomegalovirus (CMV) remains one of the most common infections after solid organ transplantation, resulting in significant morbidity, graft loss, and occasional mortality. Management of CMV varies considerably among transplant centers. A panel of experts on CMV and solid organ transplant was convened by The Infectious Diseases Section of The Transplantation Society to develop evidence and expert opinion-based consensus guidelines on CMV management including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues.

The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance

OBJECTIVES To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration. DESIGN Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata. SETTING Four tertiary care medical centers. RESULTS Four hundred twenty-seven consecutive patients were enrolled. The frequency of candidemia due to non-C. albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01). Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents. Candidemias developing while receiving antifungal therapy were more likely caused by non-C. albicans species than by C. albicans species (P = 0.0005). C. parapsilosis and C. krusei were more commonly seen with prior fluconazole therapy, whereas T. glabrata was more commonly seen with prior amphotericin B therapy. Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001). CONCLUSION In this large scale study, the non-C. albicans species, especially T. glabrata, emerged as important and frequent pathogens causing fungemia. This finding has major clinical implications given the higher complication and mortality rate associated with the non-C. albicans species. The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy. This is an ominous sign given the in vitro resistance of the non-C. albicans species to currently available antifungal agents.

Use of Cytomegalovirus Immune Globulin to Prevent Cytomegalovirus Disease in Renal-Transplant Recipients

We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from patients.

An International Prospective Study of Pneumococcal Bacteremia: Correlation with In Vitro Resistance, Antibiotics Administered, and Clinical Outcome

We performed a prospective, international, observational study of 844 hospitalized patients with blood cultures positive for Streptococcus pneumoniae. Fifteen percent of isolates had in vitro intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC], 0.12-1 microg/mL), and 9.6% of isolates were resistant (MIC, >or=2 microg/mL). Age, severity of illness, and underlying disease with immunosuppression were significantly associated with mortality; penicillin resistance was not a risk factor for mortality. The impact of concordant antibiotic therapy (i.e., receipt of a single antibiotic with in vitro activity against S. pneumoniae) versus discordant therapy (inactive in vitro) on mortality was assessed at 14 days. Discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. Similarly, time required for defervescence and frequency of suppurative complications were not associated with concordance of beta-lactam antibiotic therapy. beta-Lactam antibiotics should still be useful for treatment of pneumococcal infections that do not involve cerebrospinal fluid, regardless of in vitro susceptibility, as determined by current NCCLS breakpoints.

Determinants of Vancomycin Resistance and Mortality Rates in Enterococcal Bacteremia: A Prospective Multicenter Study

Enterococcus species have become increasingly prominent as etiologic agents of nosocomial bacteremia (19). Enterococcal bacteremia has a mortality rate of 42% to 73% (10, 11) and is common among debilitated patients and those with severe underlying illnesses (5, 6, 1217). Enterococci have low-level resistance to penicillins, aminoglycosides, and clindamycin and are intrinsically resistant to cephalosporins. Enterococci may acquire resistance to additional antibiotics, including -lactams, aminoglycosides, and glycopeptides (18). Resistance to multiple antibiotics, in particular vancomycin coupled with high-level ampicillin and aminoglycoside, has been reported with increasing frequency (19). At present, more than 20% of enterococci isolated from intensive care units exhibit vancomycin resistance. The addition of vancomycin resistance to high-level ampicillin and aminoglycoside resistance limits available therapeutic options (20). To investigate the clinical implications of antibiotic resistance in enterococci, we instituted a prospective, multicenter observational study of outcome in patients with enterococcal bacteremia. We sought to determine 1) factors associated with infection with vancomycin-resistant enterococci [VRE], 2) factors predictive of death in patients with enterococcal bacteremia, 3) the effect of vancomycin resistance on mortality rates, and 4) the effect of antibiotic therapy on outcome. Methods All patients with enterococcal bacteremia were hospitalized at the University of Pittsburgh Medical Center and the Veterans Affairs (VA) Medical Center (Pittsburgh, Pennsylvania), Detroit Medical Center and John D. Dingell VA Medical Center (Detroit, Michigan), Rush-Presbyterian-St. Lukes Medical Center (Chicago, Illinois), New England Medical Center (Boston, Massachusetts), and William Beaumont Hospital (Royal Oak, Michigan). Clinical data were obtained from review of medical records. The institutional review boards of four participating institutions approved the study. At the fifth institution, the study was considered exempt from review because it involved confidential use of existing records and bacterial isolates. Microbiology Blood for culture was obtained by venipuncture or through central venous catheters. Enterococcal species were determined by using either VITEK (bioMerieux Vitek, Inc., Hazelwood, Missouri) or MicroScan (MicroScan, Inc., West Sacramento, California) systems according to the manufacturers recommendations. Identification of species other than E. faecalis and E. faecium was confirmed as reported elsewhere (21). One of the authors standardized antimicrobial susceptibilities by using Etest strips (AB BIODISK North America, Inc., Piscataway, New Jersey). Enterococcus faecium isolates showing resistance or intermediate susceptibility to quinupristindalfopristin were tested by broth microdilution and disk diffusion to confirm reduced susceptibility. If the isolate was unavailable, antimicrobial susceptibilities reported by the submitting microbiology laboratories were used. Minimum inhibitory concentration (MIC) breakpoints from the Ninth National Committee for Clinical Laboratory Standards (NCCLS) were used (22). Because imipenem MIC values for enterococci are not defined, NCCLS breakpoints for Enterobacteriaceae were used (22). Quality control was monitored by using E. faecalis American Type Culture Collection (ATCC) 29212. Nine enterococcal isolates displayed intermediate susceptibility to vancomycin (MIC, 8 to 16 g/mL) but were considered resistant for the purposes of analysis. Vancomycin resistance genotypes of selected clinical isolates were determined by using polymerase chain reaction (PCR) amplification with primers specific for intragenic sequences of the vanA and vanB genes (23, 24). Control strains included vancomycin-susceptible E. faecalis ATCC 29212, E. faecium BM4147 (vanA) (25), and E. faecalis V583 (vanB) (26). For determination of aminoglycoside resistance genes, genomic DNA for PCR amplification was prepared with the InstaGene Matrix kit (BioRad Laboratories, Hercules, California) and PCR performed as reported elsewhere (27). Aminoglycoside resistance genes detected included aac(6)-Ie-aph(2)-Ia (28), aph(2)-Ic (29), aph(2)-Id (30), and aph(2)-Ib (31). Definitions Clinically significant bacteremia was defined as isolation of enterococci in two or more separately obtained blood cultures or from a single blood culture and from a concomitant site of infection in a clinical scenario compatible with bacteremic infection (6). Endocarditis was defined by using the Duke criteria (32). Polymicrobial bacteremia was defined as isolation from blood culture of one or more additional species of bacteria concomitantly with enterococci (same blood culture or another blood culture within 24 hours of the initial blood culture yielding enterococci). A single concomitant isolation of another bacterial species was sufficient, except for isolation of coagulase-negative staphylococci, diphtheroids, -hemolytic streptococci, and Bacillus species that required isolation from two blood cultures. Length of hospitalization was defined as the time in days from hospital admission to development of clinically significant enterococcal bacteremia. Enterococcal bacteremia occurring 60 days or more from a previous episode in patients already enrolled was counted as a separate episode. The end point was survival at 14 days from the first positive blood culture. Patients discharged from the hospital before 14 days were considered survivors. Medical records were reviewed at entry, at 2 weeks, at 4 weeks, and at 6 weeks (or at time of discharge or death if earlier than 6 weeks). We collected information on patient demographic characteristics, underlying disease, Acute Physiology and Chronic Health Evaluation (APACHE) II scores at bacteremia onset, antibiotic use, use of glucocorticosteroids and other immunosuppressive drugs, and receipt of invasive devices and procedures in the 2 weeks before bacteremia onset. Antibiotic therapy during the 6 weeks after the onset of bacteremia was recorded. Beyond 6 weeks, patients were followed for evidence of relapse of bacteremia and for survival to discharge or death. Immunosuppressive drugs included cyclosporine, cyclophosphamide, azathioprine, tacrolimus, methotrexate, and cytotoxic chemotherapy. Appropriate antibiotic therapy was defined as treatment with at least one antibiotic that had in vitro activity (as defined by Etest) against the enterococcal isolate, initiated within 48 hours of the initial positive enterococcal blood culture and continuing for at least 72 hours. Antibiotics considered potentially active included penicillin, ampicillin, ureidopenicillin, vancomycin, quinupristindalfopristin, chloramphenicol, doxycycline, and rifampin. Statistical Analysis For categorical variables, proportions were compared by using the Fisher exact test. Continuous variables were analyzed with the MannWhitney rank-sum test. Multivariate analysis was done by using logistic regression. Variables with a two-tailed P value of 0.05 were included in stepwise logistic regression models for vancomycin resistance and 14-day mortality. The initial bacteremic episode for each patient (n = 398) was used for the evaluation of risk factors for bacteremia caused by VRE. Patients who were alive 14 days after the onset of enterococcal bacteremia (n = 321) were evaluated for factors associated with microbiological failure. Statistical analysis of the data was performed by using the Prophet system (MarketMiner, Inc., Charlottesville, Virginia) and Epistat (Epistat Services, Richardson, Texas). Results Enterococcal Bacteremia We studied hospitalized patients 16 years of age or older with clinically significant hospital- or community-acquired enterococcal bacteremia. From February 1995 through March 1997, 391 consecutive patients from five participating institutions were entered into the study. An additional 9 patients from Pittsburgh were entered into the study over a 6-month period (October 1998 through March 1999) to increase the total number of patients to 400. These patients were consecutive and unselected. Two patients younger than 16 years of age were excluded, leaving 398 patients for evaluation. Eighty-nine patients were from the University of Pittsburgh Medical Center and the VA Medical Center, 97 were from Rush-Presbyterian-St. Lukes Medical Center, 95 were from the Detroit Medical Center and John D. Dingell VA Medical Center, 61 were from New England Medical Center, and 56 were from the William Beaumont Hospital. Blood cultures yielded 398 enterococcal isolates. Of these, 60% (239 of 398) were E. faecalis and 37% (148 of 398) were E. faecium. Three percent (10 of 398) of the isolates belonged to the less common enterococcal species, which include E. avium, E. casseliflavus, E. durans, E. gallinarum, and E. raffinosus. The species of one isolate could not be identified. Seventeen recurrences were seen at 60 or more days after the initial bacteremia. Of these, 14 were caused by the same enterococcal species as the initial episode. In 12 of these 14 episodes, the pair of isolates had the same susceptibilities to vancomycin. Overall, 35% of the 398 enterococcal isolates were resistant to vancomycin (MIC 32 g/mL), 63% were susceptible to vancomycin (MIC 4 g/mL), and 2% displayed intermediate susceptibility (MIC, 8 to 16 g/mL). Table 1 shows the susceptibility patterns of the two major Enterococcus species. Eight percent of the E. faecalis isolates were resistant to vancomycin, 91% were susceptible, and 1% displayed intermediate susceptibility. In contrast, 80% of the E. faecium isolates were resistant to vancomycin, 18% were susceptible, and 2% displayed intermediate susceptibility. Of the 11 isolates of other species, none were resistant to vancomycin, 73% (8 of 11) were susceptible to vancomycin, and 27% (3 of 11) displayed intermediate susceptibility to vancomycin. Table 1. Pr

The Independent Role of Cytomegalovirus as a Risk Factor for Invasive Fungal Disease in Orthotopic Liver Transplant Recipients

PURPOSE To assess impact of cytomegalovirus (CMV) donor-recipient serostatus, infection, or disease on development of invasive fungal infection in orthotopic liver transplant recipients. PATIENTS AND METHODS An analysis of prospectively collected data in 146 liver transplant recipients (intention to treat cohort) from 4 tertiary care, university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation). Patients were observed for 1 year after transplantation for the development of CMV infection, CMV disease, CMV pneumonia, as well as for the development of opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine and throat and every other week of buffy coat for CMV for 2 months, then monthly for 6 months, at 1 year, and at the time of any clinical illness. Pre- and posttransplant variables including CMV-serostatus of donor and recipient, fungal isolation from sterile body sites, fungemia, bacteremia, antibiotic use, immunosuppression, treatment for rejection, and volumes of blood products were measured. RESULTS Survival analysis demonstrated that 36% of patients with CMV disease developed invasive fungal disease within the first year post-transplant compared with 8% of those without CMV disease (P < 0.0001). One-year mortality in patients with invasive fungal disease was 15 of 22 (68%) compared with 23 of 124 (19%) in those without invasive fungal disease (P < 0.001). A multivariable, time-dependent analysis demonstrated that being a CMV-seronegative recipient of a CMV-seropositive donor organ (P < 0.001), having bacteremia (P = 0.001), UNOS (United Network for Organ Sharing) status 4 (need for life support measures) at transplant (P = 0.002), and volume of platelets (P = 0.002) were independently associated with invasive fungal disease. Restriction of cases of invasive fungal disease to those that occurred more than 2 weeks after transplant demonstrated an association with CMV disease (P = 0.003), bacteremia (P = 0.003), need for life support (P = 0.03), and volume of blood products transfused (P = 0.02). CONCLUSION CMV disease or being a CMV-seronegative recipient of a CMV-seropositive donor organ is an important predictor for invasive fungal disease following orthotopic liver transplantation.

Daptomycin-Resistant, Methicillin-Resistant Staphylococcus aureus Bacteremia

We describe a patient who developed daptomycin-resistant, methicillin-resistant Staphylococcus aureus (MRSA) during an episode of presumed septic thrombophlebitis of the portal vein. Although daptomycin is an alternative agent for treatment of drug-resistant gram-positive bacterial infections, development of resistance during prolonged use may occur with MRSA bacteremia from a persistent focus.

Prevention of Cytomegalovirus Infection by Cytomegalovirus Immune Globulin After Marrow Transplantation

In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fishers exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.