John P. Flaherty

Fever of unknown origin

ostensibly due to improved diagnostic imaging, but in a contemporaneous series the proportion was 24%. In our hospital neoplasia, in particular lymphoma, remains an important cause of FUO. The role of certain individual diseases has changed considerably. For example, rheumatic fever and systemic lupus erythematosus (SLE) were common in early series but are unusual today, probably because of the sharp decline in rheumatic fever in the developed world and the wide availability of accurate tests for SLE that permit early diagnosis. Infective endocarditis has decreased in frequency since the 1950s as blood culture techniques have improved, but new pathogens that are difficult to isolate (eg, Bartonella quintana) ensure that it will not disappear as a cause of FUO. A few diagnoses in recent series were unknown four decades ago, including Lyme disease, acute HIV infection, Sweet’s syndrome, and Bartonella endocarditis. Early series also failed to report drug fever as a cause of FUO.

Nosocomial infection caused by antibiotic-resistant organisms in the intensive-care unit.

Resistance to antimicrobial agents is an evolving process, driven by the selective pressure of heavy antibiotic use in individuals living in close proximity to others. The intensive care unit (ICU), crowded with debilitated patients who are receiving broad-spectrum antibiotics and being cared for by busy physicians, nurses, and technicians, serves as an ideal environment for the emergence of antibiotic resistance. Problem pathogens presently include multiply resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, and the recently emerged vancomycin-resistant enterococci. The prevention of antimicrobial resistance in ICUs should focus on recognition via routine unit-based surveillance, improved compliance with handwashing and barrier precautions, and antibiotic-use policies tailored to individual units within hospitals.

Treatment of Vancomycin-Resistant Enterococcus faecium Infections with Quinupristin/Dalfopristin

Clinicians caring for patients with vancomycin-resistant Enterococcus faecium (VREF) infections face severe constraints in the selection of treatment. Quinupristin/dalfopristin (Synercid) is active in vitro against VREF, with a MIC(90) of 1.0 microg/mL. We investigated the clinical efficacy and safety of this agent in a multicenter, prospective, noncomparative, emergency-use study of 396 patients. Patients were included if they had signs and symptoms of active infection, including bacteremia of unknown origin, intra-abdominal infection, and skin and skin-structure infection, with no alternative antibiotic therapy available. The mean duration of treatment was 20 days (range, 4-40 days). The clinical response rate was 68.8% in the evaluable subset, and the overall response rate was 65.6%. The most common adverse events related to quinupristin/dalfopristin were arthralgias and myalgias. Related laboratory abnormalities were rare. In this severely ill patient population, quinupristin/dalfopristin was efficacious and demonstrated an acceptable safety profile in the treatment of VREF infection.

An Outbreak of Gram-Negative Bacteremia Traced to Contaminated O-Rings in Reprocessed Dialyzers

Reprocessing of hemodialyzers has become a common practice in the United States because of decreased costs, improved biocompatibility, and fewer patient symptoms [1-3]. Reuse generally has been safe, but pyrogenic reactions and bacteremia occasionally have occurred [4-11]. These problems have been attributed to improper disinfection procedures [4, 7, 9] or inadequate potency of the solution used to disinfect the dialyzer [5-7, 9]. Treated water used to prepare dialysate and rinse dialyzers has been implicated as the reservoir for organisms causing bacteremia [4, 9, 11], but the exact means by which bacteria from the treated water reach the bloodstream of patients has not been elucidated. We investigated a cluster of cases of gram-negative bacteremia in patients receiving long-term hemodialysis at our institution. Using epidemiologic and laboratory studies, we identified the mechanism by which bacteria were transmitted from treated water to the bloodstream of patients receiving hemodialysis treatment. Methods Hemodialysis Unit The outpatient hemodialysis unit at the University of Chicago Hospital was opened in July 1985 in a building separate from the hospital. At the time of the outbreak, approximately 130 patients were receiving long-term hemodialysis treatment there. The unit operated three shifts per day, 6 days per week, and administered approximately 390 hemodialysis treatments per week. In September 1987, the center introduced high-flux dialysis, and in October 1987 the unit began a program of dialyzer reuse. Reprocessing was done by an automated procedure (Renatron; Minntech, Minneapolis, Minnesota) using a hydrogen peroxide-peracetic acid germicide (Renalin, Minntech). The long-term hemodialysis unit has two rooms for patient treatment and a separate room for the water treatment system, supplies, and dialyzer reprocessing. The main treatment room contains 16 stations, and the other treatment room (annex) contains 3 stations. The use of high-flux dialysis increased dramatically during March 1988, so that at the time of the investigation in July 1988, approximately 50% of all patients at the center were receiving high-flux dialysis. Recovery of Pseudomonas cepacia from blood culture specimens taken during dialysis on 30 June 1988 from 2 patients receiving long-term hemodialysis prompted an investigation that continued from July 1988 to April 1989. Case Definition and Case Detection A case was defined as an episode of primary gram-negative bacteremia occurring in a patient receiving long-term hemodialysis. To detect cases, results of all blood culture specimens from patients receiving long-term hemodialysis were reviewed retrospectively for the period 1 July 1987 to 30 June 1988 and then prospectively through April 1989. Blood Cultures Specimens for blood culture were obtained during hemodialysis from the venous return port after it was wiped with an iodophor antiseptic and then with 70% alcohol. Specimens were inoculated into an enrichment medium (Bactec, NR660; Becton-Dickinson Diagnostic Instrument Systems, Towson, Maryland). All organisms isolated were identified by an automated method (AutoMicrobic Systems; Vitek, Hazelwood, Missouri), confirmed by conventional biochemical methods, and tested for susceptibility to antimicrobial agents using a broth microdilution method. Matched-Pair Study We did a casecontrol study to identify risk factors for the development of primary gram-negative bacteremia. For each case, a matched control of the same sex and closest age was selected from among patients having outpatient hemodialysis on the same day who did not have signs or symptoms of gram-negative bacteremia. Medical records were reviewed to identify underlying renal disease; years on long-term dialysis; type of dialyzer (high-flux or conventional); type of vascular access; dialysis shift, station number, and location; dialysis machine; number of times dialyzer had been reused; dialyzer reprocessing technician; and recent antibiotic use. Data were analyzed using the McNemar chi-square test and the Wilcoxon signed-rank test. Evaluation of the Hemodialysis Unit and Hemodialyzers Techniques used to disinfect water-distribution lines and hemodialysis machines, to reprocess dialyzers, and to dialyze patients were observed to determine compliance with written procedures. The results of cultures routinely done each month to monitor treated water were reviewed, and, during the first 3 months of the investigation, additional 100-mL samples of treated water were cultured weekly from seven sites throughout the water-distribution system. Total bacterial counts were determined using a standard membrane filter technique [12]. On 7 July 1988 and 18 October 1988, cultures were taken of moist environmental surfaces and of antiseptics and solutions used in the dialysis unit for hemodialysis and dialyzer reprocessing. Serial volumes (1, 0.1, and 0.01 mL) of solution were plated on blood agar and incubated for 48 hours at 35 C, and growth was assessed quantitatively. Swab samples were plated on blood agar and assessed semi-quantitatively. All isolated organisms were identified using a commercially available kit (API test-strips; Analylab Products, Inc., Plainview, New York) or by conventional biochemical methods. When available, hemodialyzers (associated with patients who had bacteremia) were examined and cultured. Dialysis and blood pathway fluids were cultured using standard membrane filter techniques and were assayed for the presence of Renalin using Renalin residual test strips (Renal Systems, Inc.; Minneapolis, Minnesota). Screw-top headers (when present) were removed, and the fiber-bundle ends and header O-rings were cultured by impression onto blood agar. During 7 July to 6 September, 47 dialyzers used in patients without bacteremia were similarly cultured and assayed for Renalin concentration. O-Ring Contamination To determine whether O-rings were adequately decontaminated during reprocessing, O-rings from Hemoflow F-80 hemodialyzers (Fresenius AG; Bad Homburg, Germany) Figure 1 were deliberately contaminated by being dipped in a bacterial suspension and were then replaced in dialyzers that were reprocessed. Strains of bacteria used in these experiments were the isolates of P. cepacia, Xanthomonas maltophilia, Citrobacter freundii, Enterobacter cloacae, and Acinetobacter calcoaceticus var. anitratus from patients receiving hemodialysis who had gram-negative bacteremia. Bacterial concentrations ranged from 102 to 105 colony-forming units (CFU)/mL. After the dialyzers had been disinfected with Renalin and stored for 48 hours, sterile saline was flushed through the blood and dialysis compartments and was then cultured quantitatively by plating 0.1-, 1.0-, and 10-mL aliquots onto blood agar. Also, O-rings were removed and cultured by impression onto blood agar. Growth was assessed semi-quantitatively at 48 hours as light when a faint or partial outline of a ring was visible, moderate when a complete circle was present with bleeding onto the surrounding agar, and heavy when a lawn of growth was present. Dialyzers showing persistent bacterial contamination after initial disinfection were processed a second time using the standard method. Several dialyzers with positive cultures after a second attempted disinfection were disinfected a third time with the additional step of removing the O-rings, dipping them in Renalin, and replacing them in the header before reuse. Figure 1. Schematic representation of the Hemoflow F-80 dialyzer. Simulated Dialysis Simulated hemodialysis was done after F-80 dialyzer O-rings were contaminated by dipping them in a suspension of 104 to 105 CFU/mL of bacteria. Dialyzers were reprocessed and stored at room temperature for 48 hours. To simulate dialysis, each dialyzer was connected to a dialysis machine, and 800 mL of sterile saline was circulated through the blood compartment, whereas 600 mL of bicarbonate solution was circulated through the dialysis compartment. This simulation was continued for approximately 20 minutes for each dialyzer. The saline circulating through the blood pathway was cultured, the dialyzers were then disconnected, and the O-rings were cultured. Next, these dialyzers were reprocessed with the additional step of removing the O-ring and dipping it in Renalin before automated reprocessed. The O-rings were replaced, and the dialyzer was reprocessed by the automated method. After storage at room temperature for 48 hours, the dialyzers again were used for simulated dialysis, and cultures were repeated. Results Description of Cases During January to October 1988, 12 episodes of primary gram-negative bacteremia were identified in 11 patients receiving long-term hemodialysis (Table 1). One episode was caused by two different organisms, and the pathogens in the 12 episodes were P. cepacia (6 episodes), X. maltophilia (4 episodes), C. freundii (1 episode), Acinetobacter calcoaceticus var. anitratus (1 episode), and E. cloacae (1 episode). During the course of the outbreak, gram-negative bacteremia occurred at a rate of about 0.77 episodes per 1000 hemodialysis sessions. Table 1. Characteristics of Patients Receiving Long-Term Hemodialysis in Whom Primary Gram-Negative Bacteremia Developed The most common clinical manifestations of bacteremia were chills (11 episodes) and temperature greater than 37.5 C (8 episodes). In 11 episodes, symptoms began about 30 minutes to 3 hours after the start of treatment. In the remaining episode, chills began shortly after the patient had completed treatment and left the dialysis unit. Intravenous antibiotic treatment was administered for 11 episodes, and 3 episodes required that the patient be admitted to the hospital. All of the patients recovered, including one who received no treatment for X. maltophilia bacteremia. One patient had bacteremia first with C. freundii and then 6 weeks later with P. cepacia. Pseudomonas cepacia bacteremia was documented

Multicenter, randomized trial of ciprofloxacin plus azlocillin versus ceftrazidime plus amikacin for empiric treatment of febrile neutropenic patients

In a multicenter, randomized clinical trial, the efficacy of ciprofloxacin plus azlocillin was compared with that of a standard regimen of ceftazidime plus amikacin for the initial empiric treatment of fever in neutropenic cancer patients. In addition, the efficacy of early conversion from intravenous therapy to orally administered ciprofloxacin was compared with that of continued ceftazidime plus amikacin. Seventy-one oncology patients with 79 episodes of fever and neutropenia were randomly assigned to receive initial empiric antibiotic therapy with either intravenously administered ciprofloxacin and azlocillin followed by orally administered ciprofloxacin (regimen 1, 25 episodes); ceftazidime and amikacin (regimen 2, 30 episodes); or ceftazidime and amikacin followed by oral ciprofloxacin (regimen 3, 24 episodes). Microbiologically documented infections were the cause of fever in 10 (40 percent), seven (23 percent), and nine (38 percent) episodes in regimens 1, 2, and 3, respectively, including six, five, and four episodes of bacteremia. Patient survival was 90 to 92 percent in each regimen; however, some modification of antimicrobial therapy occurred in 65, 44, and 41 percent of surviving patients in regimens 1, 2, and 3, respectively. The rate of clearance of initial bacteremia was 67 percent (four of six) in regimen 1, 100 percent (five of five) in regimen 2 and 50 percent (two of four) in regimen 3. Patients in regimens 1 and 3 were able to convert to orally administered ciprofloxacin in 32 (65 percent) of 49 episodes after a mean of six days of intravenous therapy. Superinfections occurred in 24, 10, and 12 percent of patients receiving regimens 1, 2, and 3, respectively, and occurred similarly for patients receiving orally administered ciprofloxacin, 12 percent (four of 32), and intravenous therapy, 17 percent (eight of 47). Parenteral ciprofloxacin was generally well tolerated. One (4 percent) of 25 patients receiving regimen 1 experienced oto- or nephrotoxicity, compared with eight (15 percent) of 54 patients receiving regimens 1, 2, and 3 (p = 0.15), including three patients who required premature termination of aminoglycoside therapy. Our data suggest that the combination of ciprofloxacin and azlocillin is an effective alternative to ceftazidime and amikacin for the initial empiric therapy of febrile neutropenic patients, is generally well tolerated, and avoids the oto- and nephrotoxicity associated with aminoglycoside use. In addition, a majority of patients could change to orally administered ciprofloxacin alone after six days of parenteral therapy.

Impact of Switching Virologically Suppressed, HIV-1-Infected Patients from Twice-Daily Fixed-Dose Zidovudine/Lamivudine to Once-Daily Fixed-Dose Tenofovir Disoproxil Fumarate/Emtricitabine

Abstract Objective: Evaluate the impact of switching from twice-daily zidovudine/lamivudine (AZT/3TC) to once-daily tenofovir DF plus emtricitabine (TDF/FTC) with efavirenz (EFV). Design: Prospective, multicenter, single-arm 24-week trial. Methods: Patients on EFV + AZT/3TC for =8 weeks with HIV-1 RNA <400 copies/mL were switched to EFV + TDF/FTC and assessed for safety/tolerability, virologic and immunologic responses, adherence, and quality of life at 4, 12, and 24 weeks. Results: Of 402 patients, 2% discontinued for an adverse event (AE) and 1 patient for virologic failure. At 24 weeks, 87% had HIV RNA <400 copies/mL, and 74% versus 71% at baseline had undetectable (HIV RNA <50 copies/mL) viral load (ITT; M=F). Treatment-emergent AEs were infrequent (≤5%) with gastrointestinal complaints being the most common. At 24 weeks compared to baseline, hemoglobin (Hb) increased by a median of 0.6 g/dL (p < .001), and a decrease in creatinine clearance of 7.6 mL/min (p < .001) was observed. Fasting lipids decreased slightly (p < .02) in a subset of patients studied (n = 160). A higher percentage of patients reported being “very satisfied” with treatment and the absence of regimen side effects at 24 weeks versus baseline (p < .001). At 24 weeks, 86% of patients took ≥95% of doses versus 78% at baseline (p = .002). Conclusion: Patients switched to EFV + TDF/FTC maintained virologic suppression and the regimen was well tolerated. Patients reported increased satisfaction with treatment and fewer were bothered by side effects.

Evaluation of Efficacy, Safety, Pharmacokinetics, and Adherence in HIV-1—Infected, Antiretroviral-Naïve Patients Treated with Ritonavir-Boosted Atazanavir Plus Fixed-Dose Tenofovir DF/Emtricitabine Given Once Daily

Abstract Objectives: Evaluate efficacy, safety, tolerability, pharmacokinetics, adherence, and treatment satisfaction of atazanavir/ritonavir (ATV/r) 300mg/100mg and tenofovir DF/emtricitabine (TDF/FTC) 300mg/200mg once daily in antiretroviral-naïve HIV-infected patients. Method: Single-arm, open-label, multicenter 48−week study. Results: 100 patients were evaluated; 17 patients discontinued early including 6 for adverse events. There were 2 deaths (multi-organ failure, lactic acidosis). At 48 weeks, 81% achieved HIV−1 RNA <50 copies/mL (ITT, M=F). No K65R or ATV/r associated mutations emerged; M184V developed in one patient. Median CD4 increase was 217 cells/mm3. The most common adverse events (≥10%) were diarrhea, nausea, scleral icterus, fatigue, upper respiratory tract infection, headache, and vomiting. Grade 4 hyperbilirubinemia occurred in 5%. Median increases at 48 weeks in total cholesterol, HDL, LDL, and triglycerides were 11, 3, 2, and 5 mg/dL, respectively. Two patients had confirmed graded increases in serum creatinine (one grade 1, one grade 2). Median (IQR) creatinine clearance change from baseline at 48 weeks was −7 (−19, 2) mL/min. Geometric mean (95% CI) ATV trough concentrations exceeded suggested therapeutic range. At 48 weeks, 92% of patients reported complete adherence by 1−week recall and 90% reported being “very satisfied” with the regimen. Conclusion: ATV/r+TDF/FTC was safe, well tolerated, and convenient for patients. Larger comparative trials are ongoing.

Absence of xenotropic murine leukemia virus-related virus in blood cells of men at risk for and infected with HIV

Xenotropic murine leukemia virus-related virus has been detected in blood cells of patients with chronic fatigue syndrome and in 3.7% of healthy controls from the same geographic region. We evaluated 996 men who were participants in the Multicenter AIDS Cohort Study for xenotropic murine leukemia virus-related virus sequences in blood cells by means of a real-time quantitative PCR assay. Xenotropic murine leukemia virus-related virus was detected in none of the men on the basis of the absence of xenotropic murine leukemia virus-related virus DNA, suggesting that infection may be population-specific.

Suboptimal Nevirapine Steady-state Pharmacokinetics During Intrapartum Compared With Postpartum in Hiv-1-seropositive Ugandan Women

Background: Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. Methods: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. Results: The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipants C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. Conclusions: Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.

Breakthrough Candida Infections in Patients Receiving Voriconazole

OBJECTIVE To describe 2 instances of breakthrough Candida infection in 2 patients on treatment doses of voriconazole. CASE SUMMARIES A 27-year-old woman with systemic lupus erythematosus was receiving high-dose voriconazole (400 mg twice daily) for central nervous system lesions of unknown origin and developed oral thrush. The patient was receiving concomitant therapy with phenytoin 400 mg/day. The voriconazole dose was increased to 400 mg 3 times daily, and the thrush resolved. A 50-year-old man with HIV infection was receiving enfuvirtide, lamivudine, tenofovir, and efavirenz 600 mg/day, as well as prophylactic trimethoprim/sulfamethoxazole and azithromycin. He was started on voriconazole 200 mg twice daily for pulmonary aspergillosis and developed esophageal candidiasis. The voriconazole dose was increased to 350 mg twice daily, and the thrush eventually resolved. DISCUSSION Both reactions were probable according to the Naranjo probability scale. Significant drug interactions may have played a role in the development of breakthrough infections in these patients, specifically with phenytoin and efavirenz. Voriconazole is metabolized primarily by CYP2C19, as well as CYP2C9 and CYP3A4. Voriconazole is also known to inhibit these enzymes, and the manufacturer reports an extensive list of drugs that interact with voriconazole. CONCLUSIONS Although requiring systematic evaluation, there may be a role for voriconazole serum concentration monitoring to ensure therapeutic efficacy when significant drug interactions are suspected.