Incidence, timing and site of infections among pancreas transplant recipients.

The incidence, timing and site of infections among the different categories of pancreas transplant recipients were investigated. Patients were divided into three groups: pancreas transplant alone (PTA), pancreas after kidney transplant (PAK), or simultaneous pancreas and kidney (SPK) transplants. Length of follow-up, time to death, pancreas graft survival, incidence, timing and site of bacterial infections were noted. Our study showed that at least 75% of pancreas transplant recipients experienced at least one infection (range from 77.8% in the PTA group to 86.7% in the PAK group). The SPK group presented the highest rate of infections with 35.1 infections per 1000/patient-days. Symptomatic urinary tract infections were the most common cause of infection in all patients. The incidence of infections was higher during the first month after transplantation, except for the SPK transplant group, where infections occurred over a longer time period.

Aspergillus vertebral osteomyelitis after simultaneous kidney-pancreas transplantation.

Aspergillus osteomyelitis is a rare complication of invasive aspergillosis after organ transplantation. This is the report of a 46-year-old man who underwent a simultaneous pancreas and kidney transplantation, complicated by an Aspergillus osteomyelitis and diskitis of the lumbar spine. Prompt diagnosis with needle biopsy, followed by antifungal therapy using caspofungin, a new antifungal agent recommended for the treatment of refractory aspergillosis, in combination with amphotericin B and an early surgical intervention led to clinical resolution of the infection. Reported cases of spinal aspergillosis after transplantation are reviewed in terms of clinical presentation, risk factors, therapeutic options, and outcome.

Comparative antimicrobial activity of gatifloxacin with ciprofloxacin and beta-lactams against gram-positive bacteria.

Gatifloxacin is a new 8-methoxy fluoroquinolone. The in-vitro antibacterial activity of gatifloxacin was compared to that of ciprofloxacin, ceftriaxone, imipenem, piperacillin/tazobactam and amoxicillin/clavulanic acid against 165 streptococcal isolates, 369 staphylococcal isolates, and 50 enterococcal isolates recently recovered from clinical isolates. Gatifloxacin was the most active agent tested against streptococci including penicillin-nonsusceptible Streptococcus pneumoniae (MIC(90) 0.5 microg/mL). Imipenem and gatifloxacin (MIC(90) 0.5 microg/mL) were the most active agents tested against viridans group streptococci. All the agents demonstrated excellent activity against methicillin-susceptible S. aureus. Imipenem, piperacillin/tazobactam, amoxicillin/clavulanic acid, and gatifloxacin had good activity against methicillin-sensitive S. epidermidis. Among the methicillin-sensitive and methicillin-resistant coagulase-negative staphylococci tested, gatifloxacin was the most active agent. Amoxicillin/clavulanic acid and gatifloxacin were the most active agents against E. faecalis. Thus, gatifloxacin possesses equal or superior activity when compared to ciprofloxacin and beta-lactams making it a promising new fluoroquinolone for clinical use in treating Gram-positive infections.

Current and future antifungal therapy: new targets for antifungal therapy.

Invasive fungal infections will continue to cause major complications in immunocompromized patients. At the moment, the expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive fungal infections. The overview of the development of antifungal therapy which is provided here demonstrates the increased interest in this very special area of infectious diseases. Although we now have some newer and less toxic antifungal agents that are currently available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not very good. Intense efforts in antifungal drug discovery are urgently needed to develop more promising and effective antifungal agents for use in the clinical arena.

Efficacies of two new antifungal agents, the triazole ravuconazole and the echinocandin LY-303366, in an experimental model of invasive aspergillosis.

The efficacy of ravuconazole, a new triazole antifungal agent, and the echinocandin LY-303366 were evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with ravuconazole at a dosage of 30 mg/kg of body weight per day or the echinocandin LY-303366, given intravenously in a dosage of 5 or 10 mg/kg, was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. Prophylaxis was also studied with LY-303366 given at a dosage of 5 or 10 mg/kg/day 48 h before lethal or sublethal challenge. Ravuconazole eliminated mortality, cleared aspergillus antigen from the serum, and eliminated Aspergillus fumigatus organisms from tissues of both lethally and sublethally challenged immunosuppressed animals with invasive aspergillosis. Although LY-303366, at both doses, prolonged survival and reduced aspergillus antigenemia, it did not eliminate aspergillus organisms from organ tissues. The half-lives of ravuconazole and LY-303366 in rabbits were 13 and 12.5 h, respectively, and no accumulation of either drug was seen after 6 days of treatment. Although LY-303366 showed activity in this rabbit model of invasive aspergillosis, ravuconazole was the more active agent, comparable to amphotericin B. Additional studies are needed to determine the potential of ravuconazole for use in the treatment of this infection.

Lipid formulations of amphotericin B.

The incidence of systemic fungal infections, especially in immunocompromised patients, has continued to increase during the past few decades. Treatment with conventional amphotericin B has been the standard care for the majority of patients with invasive fungal infections, despite its associated toxicity. Three lipid formulations of amphotericin B have now been approved for use in the United States. The pharmacology, pharmacokinetics, clinical experience, toxicity, dosing strategies, and cost of these three preparations--amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B--were reviewed in detail in this chapter. The clinical data indicate that lipid formulations of amphotericin B represent an important therapeutic modality in the management of invasive fungal infections.

The future of the quinolones.

This review emphasises the advances in the development of newer quinolones: their broader antimicrobial activity particularly their increased activity against Pneumococcus and anaerobes; their longer half-life and tissue penetration including activity in cerebrospinal fluid; and their excellent efficacy in respiratory, intra-abdominal, pelvic, and skin and soft tissue infections. Also, considerable progress has been made in our understanding of the development of bacterial resistance to the newer quinolones. Additional advances in quinolone development are likely to provide better compounds for clinical use.

The 1998 Garrod lecture. Current and future antifungal therapy: new targets for antifungal agents.

Invasive fungal infections are a major problem in immunocompromised patients. The recent expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive infections. The overview of the development of antifungal therapy which is provided herein reflects the increased interest in this very special area of infectious diseases. Although we have newer, less toxic, antifungal agents that are available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not optimal. Thus, intense efforts in antifungal drug discovery are still needed to develop more promising and effective antifungal agents for use in the clinical arena.

When to do culture in urinary tract infections.

A brief review of the value of quantitative bacteriology of the urine in patients with symptoms of urinary tract infections is presented. Changes in our approach to the diagnosis of urinary tract infections are briefly discussed. The economic value of empiric treatment without urine cultures in young women with dysuria and frequency is presented along with our approach to patients with asymptomatic bacteriuria in the presence of an indwelling bladder catheter. In addition, specific groups of patients with symptomatic urinary tract infections who require urine cultures in order to receive optimal antimicrobial therapy is reviewed. Although these suggestions may not be appropriate for all patients in each category, their use in some patients is likely to result in economic benefits without reducing the quality of their health care.

Current and future therapy of invasive fungal infections.

Major increases in the incidence of systemic fungal infections have been observed during the past three decades, particularly in immunocompromised patients. A critical need exists for new antifungal agents to treat these life-threatening invasive fungal infections. The review of the development of antifungal therapy provided in this chapter indicates the increased interest in this very special area of infectious diseases. Even though newer and less toxic antifungal agents are currently available for clinical use, innovative research in antifungal drug discovery may eventually produce more promising antifungal agents.

Comparison of in vitro activity of trovafloxacin against gram-positive and gram-negative organisms with quinolones and beta-lactam antimicrobial agents.

The in vitro activity of trovafloxacin against 721 Gram-negative and 498 Gram-positive organisms was determined by the standard microdilution broth method using commercially prepared frozen microtiter plates. The activity of trovafloxacin was compared to ofloxacin, ciprofloxacin, amoxicillin/clavulanate, ampicillin/sulbactam (1:1), piperacillin/tazobactam, ceftriaxone, and imipenem. Trovafloxacin had equal or greater activity compared with the other agents tested against Citrobacter diversus, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Stenotrophomonas maltophilia, Serratia marcescens, staphylococci, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, group G streptococci, Enterococcus faecalis, and E. faecium. The reliability of the commercially prepared plates for testing the in vitro activity of the quinolones was evaluated by comparing identical isolates also tested by broth microdilution using laboratory prepared plates. The commercially prepared plates generally correlated, within one- to twofold dilutions, with the laboratory prepared plates. There was, however, a large discrepancy obtained when testing Enterobacter agglomerans and E. cloacae, where the commercially prepared plates yielded a significantly higher MIC90 value.

Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era.

Profound physiologic and anatomic changes of the urinary tract during pregnancy contribute to the increased risk for symptomatic urinary tract infection in women with bacteriuria. Asymptomatic bacteriuria is the major risk factor for developing symptomatic UTIs during pregnancy and may be associated with adverse effects on maternal and fetal health. Because most symptomatic UTIs develop in women with bacteriuria earlier in pregnancy, treatment of bacteriuria is undertaken to prevent symptomatic infections. All pregnant women should be screened at the first antenatal visit, which is reliably and inexpensively done with a dipstick culture. Short-course therapy should be given to women with bacteriuria and clearance of bacteriuria should be documented after therapy is complete. Failure to eliminate bacteriuria with repeated therapy or recurrence with the same organism is indicative of renal parenchymal infection or a structural abnormality. All women with persistent bacteriuria or recurrent infection should have follow-up cultures and a urologic evaluation after delivery.

Renal and perirenal abscesses.

Our knowledge of the spectrum of renal abscesses has evolved as a result of more sensitive radiologic techniques. The classification of intrarenal abscesses currently includes acute focal bacterial nephritis, acute multifocal bacterial nephritis, renal cortical abscess, renal corticomedullary abscess, and xanthogranulomatous pyelonephritis. The clinical presentation of these entities does not differentiate them, however, and various radiographic studies are helpful in making the diagnosis. The intrarenal abscess is usually treated successfully with antibiotic therapy alone. Antistaphylococcal therapy is indicated for the renal cortical abscess, whereas therapy directed against the common gram-negative uropathogens is indicated for most of the other entities. The perinephric abscess is often an elusive diagnosis, has a more serious prognosis, and is more difficult to treat. Drainage of the abscess and sometimes partial or complete nephrectomy, in addition to antibiotic therapy, are required for resolution.

Bacterial urinary tract infections in diabetes.

Diabetes mellitus has a number of long-term effects on the genitourinary system. These effects predispose to bacterial urinary tract infections in the patient with diabetes mellitus. Bacteriuria is more common in diabetic women than in nondiabetic women because of a combination of host and local risk factors. Upper tract infection complications are also more common in this group. Diabetic patients are at higher risk for intrarenal abscess, with a spectrum of disease ranging from acute focal bacterial pyelonephritis to renal corticomedullary abscess, to the renal carbuncle. A number of uncommon complicated urinary tract infection complications occur more frequently in diabetics, such as emphysematous pyelonephritis and emphysematous pyelitis. Because of the frequency and severity of urinary tract infection in diabetic patients, prompt diagnosis and early therapy is warranted. A plain abdominal radiograph is recommended as a minimum radiographic screening tool in the patient with diabetes presenting with systemic signs of urinary tract infection. Ultrasonography or further radiographic studies such as CT scanning may also be warranted, depending on the clinical picture, to identify upper urinary tract complications early for appropriate intervention.

In-vitro activity of trovafloxacin against sensitive and resistant aerobic bacteria using the standard microdilution broth method and Etest.

A comparison of MICs of trovafloxacin (CP-99,219) determined by the standard microdilution broth method versus the Etest was performed for multiple strains of Gram-positive and Gram-negative bacteria. A comparison was also made of the in-vitro activity of trovafloxacin versus ciprofloxacin and ofloxacin. The MIC50 and MIC90 were determined by both methods for each species tested. The Etest resulted in MICs one to two dilutions higher than the microdilution broth method. Trovafloxacin was the most active agent against Gram-positive organisms. Ciprofloxacin was the most active agent against Citrobacter freundii, Proteus mirabilis, Proteus vulgaris, Morganella morganii and Serratia marcescens, while trovafloxacin had equal or greater activity compared with ciprofloxacin and ofloxacin against the other Gram-negative organisms tested. Overall, ofloxacin was the least active agent tested. In addition, the in-vitro activity of trovafloxacin or ciprofloxacin in combination with ampicillin/sulbactam, gentamicin or vancomycin was evaluated. The combination of trovafloxacin and gentamicin was synergic against two of 20 Enterococcus faecium isolates, the combination of trovafloxacin and ampicillin/sulbactam was synergic against two of 24 Enterococcus faecalis isolates, and the combination of ciprofloxacin and gentamicin was synergic against one of 25 Stenotrophomonas maltophilia isolates. All other antibiotic combinations resulted in an additive or indifferent effect.

Hospital epidemiologic surveillance for invasive aspergillosis: patient demographics and the utility of antigen detection.

OBJECTIVE: To monitor the epidemiology of invasive aspergillosis at a university hospital during a period of hospital construction. To compare the efficacy of active epidemiologic surveillance for invasive aspergillosis using Aspergillus cultures with the efficacy of surveillance using Aspergillus antigen detection. DESIGN: A prospective surveillance study. SETTING: An 850-bed, tertiary-care, university-based hospital. PATIENTS: A convenience sample of 153 patients with Aspergillus antigen testing and culture. RESULTS: 24 cases were identified over a 12-month period; 7 were nosocomial, and 17 were community-acquired. Cases occurred primarily in patients with hematologic malignancy, but also occurred in patients with solid tumor, steroid treatment, cardiac transplant, and acquired immunodeficiency syndrome. Culture techniques identified only 14 (58%) of 24 cases, whereas Aspergillus antigen was positive in 19 (79%) of 24 cases tested. Epidemiological surveillance using either antigen or culture positivity detected 22 (92%) of 24 cases. In addition, antigen detection was 98% specific for the detection of aspergillosis, as compared to 91% for culture and 88% for antigen and culture combined. CONCLUSIONS: Hospital surveillance for aspergillosis should include determination of whether cases are nosocomial or community-acquired, because many may be the latter. Patients at risk for aspergillosis include patients without hematologic malignancies. Enhanced case detection occurred with active surveillance of patients considered to be at risk using both fungal serology and traditional microbiological techniques. Antigen detection was more sensitive and specific for the detection of invasive aspergillosis and may improve epidemiological surveillance for aspergillosis.

Systemic Candida infections.

Over the past two decades, Candida species have come to be regarded as important agents of nosocomial infection. In this paper, initially presented as a teaching conference at the Yale University School of Medicine, we summarize recent information pertaining to the epidemiology, diagnosis, and treatment of systemic Candida infections.

Efficacy of UK-109496, a new azole antifungal agent, in an experimental model of invasive aspergillosis.

The efficacy of UK-109496, a new azole antifungal agent, was evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with UK-109496 at a dosage of 10 or 15 mg/kg of body weight every 8 h was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. UK-109496 eliminated mortality and also reduced the tissue burden of Aspergillus fumigatus 10- to 100-fold in liver and kidney tissues and to a lesser degree in lung tissue, and at the higher dose, no viable organisms were recovered from brain tissue from these animals. Both dosages of UK-109496 decreased or eliminated circulating antigen. The half-life of UK-109496 in rabbits was 2.5 to 3 h, and no accumulation of drug was seen even after 15 doses in either uninfected or infected animals. Thus, UK-109496 shows activity in this rabbit model of invasive aspergillosis. Additional studies are needed to determine the potential of the drug for use in the treatment of this infection.