Inhibitors of DNA polymerases of murine leukemia viruses: activity of ethidium bromide.

Ethidium bromide, compared on a molar basis, was a more effective inhibitor of the DNA polymerases of the Rauscher and Moloney murine leukemia viruses than either 4-N-demethylrifampicin or 4-N-benzyldemethylrifampicin. Daunomycin inhibited the polymerases weakly, and chromomycin A(3) inhibited almost not at all. 4-N-Benzyldemethylrifampicin was a more active inhibitor than the 4-N-demethyl congener.

Hepatic dysfunction in acute measles infection of adults.

Hepatitis has rarely been recognized as a complication of acute measles infection. Two adult patients are reported in whom abnormal liver function was a prominent clinical feature during acute measles infection. Hepatic function returned to normal in both patients as the measles infection resolved. Hepatitis may be a salient clinical manifestation of acute measles infection of adults.

Necrotizing fasciitis complicating intravenous drug abuse.

Two cases of necrotizing fasciitis in intravenous cocaine abusers are presented to alert the medical community to the possibility of these severe infections in such addicts. Antimicrobial therapy should include agents effective against Bacteroides species, streptococci, and Gram-negative aerobes; therapy directed only against staphylococci and Gram-negative aerobes is not sufficient.

Rhinocerebral mucormycosis: premortem diagnosis and therapy.

The diagnosis of rhinocerebral mucormycosis is most often made at autopsy. We report a series of nine patients in whom the diagnosis was established premortem. Six of the patients had underlying diabetes mellitus and three had acute leukemia. Facial or ocular pain was the complaint found in all patients, and frequently was the initial symptom. The diagnosis was established by examination and culture of infected tissue obtained by biopsy. In seven patients, identification of hyphal elements in smears of biopsy material allowed the immediate institution of amphotericin B therapy. Four of the seven patients treated with amphotericin B survived. All surviving patients had underlying diabetes mellitus and had undergone surgical debridement. Early diagnosis leading to immediate institution of appropriate therapy is most important for survival of patients with mucormycosis.

Use of antimicrobial agents in a university teaching hospital. Evolution of a comprehensive control program.

A comprehensive control program for utilization of anti-microbial agents in a large tertiary university teaching hospital regulates both dosage and duration of therapy and requires the prior approval of an infectious disease specialist for utilization of restricted antimicrobial agents. Benefits of the program include more cost-effective antimicrobial therapy and increased physician education in the use of these drugs. Gross savings in pharmacy costs for antibiotics during the first year of the program (1985) amounted to +483,032 for an average monthly savings of +40,252. Gross savings for 1986 were +211,786 with monthly savings of +17,648. The control of the use of one agent may lead to overuse of another agent. Antimicrobial prescribing patterns of physicians are quickly influenced by changing regulations of the program. An ongoing surveillance and review program of in-hospital utilization of antimicrobial agents is necessary to maintain effective and flexible controls.

Clostridium difficile diarrhea induced by cancer chemotherapy.

Four patients had diarrhea due to Clostridium difficile after receiving chemotherapy for cancer. None of the patients had received antibiotics for at least 4 weeks before the onset of diarrhea. At the time of admission of any of these four patients no outbreak of diarrhea was noted on the ward. Each patient was admitted with the acute onset of diarrhea after receiving chemotherapy, at different times of the year. Diarrhea was clinically important and was associated with dehydration, toxemia, and blood in the stool in all cases. Diagnosis of C difficile was confirmed by endoscopic examination, positive biopsy specimen, and positive test for toxin in the stool. All patients recovered after undergoing specific treatment. Drugs not believed to carry serious risk to the bowel mucosa may facilitate proliferation of C difficile. Patients with severe diarrhea after receiving chemotherapy, particularly those with blood in the stool, should be promptly tested for C difficile even in the absence of a history of antibiotic administration. Early and specific treatment can prevent additional morbidity and reduce cost of care.

Central nervous system infections in the elderly.

Review of records of patients aged 65 years and older admitted to The Mount Sinai Hospital, New York, NY, during the period from 1970 through 1985 revealed 57 episodes of central nervous system infections, including 50 meningitides, 5 brain abscesses, 1 subdural empyema, and 1 epidural abscess. Predisposing conditions were present in 17 patients with meningitis, and concurrent infections occurred in 19 patients. Streptococcus pneumoniae accounted for 43% of all isolates; 25% were gram-negative organisms. Of the patients in this sample, fever was present in 100%, meningismus was present in 58%, and change in mental status was present in 86%. Sixty-five percent of patients with meningitis survived; increased mortality was associated with altered mental status, inappropriate initial antibiotic therapy, and hypoglycorrhachia. Delay in diagnosis, underlying disease, and bacteremia did not significantly alter outcome. All patients with focal infections presented with localizing signs and all survived.

Mycobacterial meningitis. Retrospective analysis from 1970 to 1983.

The clinical presentation and course of tuberculous meningitis in 21 patients treated between 1970 and 1983 are analyzed. Tuberculous meningitis may present as acute, subacute, or chronic meningitis. Although characteristic cerebrospinal fluid findings of lymphocytic pleocytosis, low glucose level, and elevated protein level occur in the majority of cases, there are many atypical presentations. The protein level, glucose level, and white blood cell count may be normal, and there may be a predominance of polymorphonuclear cells rather than lymphocytes in the cerebrospinal fluid. Poor prognostic factors in this series were age greater than 65, underlying diseases, and stage 3 presentation. Incorrect or inadequate therapy had a disastrous outcome. Nontuberculous mycobacteria rarely are involved in central nervous system disease. Tuberculous meningitis must be considered in the differential diagnosis of any patient with fever and change in sensorium. A deteriorating mental status and falling cerebrospinal fluid glucose level in the presence of negative findings on bacterial culture and india ink preparation should lead to strong consideration for empiric initiation of anti-tuberculous therapy.

Infections associated with transhepatic biliary drainage devices.

To determine the infectious complications associated with transhepatic biliary drainage devices, an analysis of the records of 38 patients who underwent placement of a pigtail catheter (n = 11), a Ring catheter/feeding tube (n = 13), or a Carey-Coons endoprosthesis (n = 15) was carried out. Nineteen infectious events occurred in 38 patients with 39 biliary devices. Infections consisted of bacteremia, cholangitis with and without documented bacteribilia, and intrahepatic abscesses and were frequently associated with obstruction (66.7 percent of infectious episodes). The most frequent organisms isolated from blood were Escherichia coli and Pseudomonas aeruginosa, and the most frequent organisms isolated from bile were P. aeruginosa, Klebsiella pneumoniae and Streptococcus faecalis. Trends for more frequent occurrence of neoplasms involving the gallbladder or biliary tract, recent surgical procedures and catheter manipulations in infected as compared with noninfected patients, and a delayed time to infection were noted in patients with an endoprosthesis.

Renal aspergilloma: an unusual cause of infection in a patient with the acquired immunodeficiency syndrome.

The case of a 36-year-old man with the acquired immunodeficiency syndrome (AIDS) and a renal aspergilloma is reported. Aspergillus infections are uncommon in patients with AIDS. Isolated renal aspergillomas have rarely been reported in the non-AIDS population (14 cases) and have never been reported in a patient with AIDS. The patient we describe was clinically symptomatic and initially treated medically, but he did not respond to intravenous amphotericin and oral itraconazole. He eventually required nephrectomy; however, there was local recurrence of the aspergilloma postoperatively. We comment on some issues in the spectrum of Aspergillus infections in AIDS and review the literature on the manifestations and treatment of renal aspergillomas.

Bloodstream infections in the elderly.

PURPOSE: Bacteremia in the elderly is associated with a different clinical course and a higher mortality rate when compared with that in younger age groups. In order to examine these issues in the aged, we reviewed the clinical course and factors involved in the outcome of 100 episodes of bloodstream infections in patients over 65 years of age. PATIENTS AND METHODS: The hospital records of all patients over 65 years of age at The Mount Sinai Hospital with a positive blood culture result during the period October 1984 to October 1986 were reviewed. Place of residence before hospital admission, site of acquisition of infection, source of bloodstream infection, and microorganism were analyzed. Antimicrobial therapy was defined as appropriate if initial therapy included one agent to which the isolate was sensitive, or inappropriate if the isolate was resistant. The following factors affecting survival were analyzed: age, sex, underlying diseases, clinical parameters on admission, white blood cell count, mental status, source of infection, microorganism isolated, antibiotic toxicity, and appropriate versus inappropriate antibiotic therapy. RESULTS: Most patients were female (63 percent), were febrile (90 percent), had an altered mental status (52 percent), and had a neutrophilic response (61 percent). Eighty-three percent of patients were admitted from the community (home), 14 percent were from long-term-care facilities, and 3 percent were transferred from other hospitals. Fifty percent of infections were nosocomial, and 44 percent were community (home and nursing home)-acquired. Gram-negative organisms accounted for 60 percent of isolates, with Escherichia coli (22 percent) and Klebsiella species (11 percent) predominating; 30 percent were gram-positive organisms, with Staphylococcus aureus (13 percent) and Streptococcus faecalis (10 percent) the most common. The overall survival was 60 percent; the survival rate was 65.8 percent for community-acquired (home) bacteremia, 75 percent for nursing home-acquired bacteremia, and 52.8 percent for hospital-acquired bacteremia. Survival for gram-negative isolates was 65 percent, versus 51.7 percent for gram-positive isolates. Survival was greatest in patients whose source of bacteremia was either the genitourinary tract (70 percent) or an intravascular device (78 percent) and poorest in patients with lower respiratory tract source (42 percent); all three patients with endocarditis died. Increased survival was observed in patients treated with appropriate antimicrobial agents regardless of age, source of infection, or bloodstream isolates.(ABSTRACT TRUNCATED AT 400 WORDS)

CXCR4 and CCR5 expression by H9 T-cells is downregulated by a peptide-nucleic acid immunomodulator.

Product R (Reticulose(TM)) is a peptide-nucleic acid immunomodulator with broad-spectrum antiviral activity that was recently shown to increase expression of mRNAs encoding the proinflammatory cytokines, IFN-gamma, IL-1beta, IL-6 and TNF-alpha. Since these cytokines induce expression of the chemokines, MIP-1alpha, MIP-1beta, RANTES, and SDF-1, all of which inhibit viral infectivity, we were interested to determine if Product R also alters chemokine expression. In addition, the finding, that Product R decreases HIV-1 RNA and extracellular p24 antigen in H9 T-lymphoma cells, suggested to us that this drug may block viral infection by reducing the expression of chemokine receptors on target cells. We have therefore utilized H9 cells to test the effects of Product R on expression of mRNAs encoding the chemokine receptors, CD4, CXCR4 and CCR5, as well as their ligands, IL-16, SDF-1, MIP-1alpha, MIP-1beta, and RANTES, by RT-PCR. We also assayed the effect of Product R on surface receptor expression by flow cytometry, and on the chemotactic activity of these cells towards the CXCR4 ligand, SDF-1, and the CCR5 ligands, MIP-1alpha and RANTES. H9 cells were cultured for 3-21 days in medium containing 5% or 10% Product R, or 5% or 10% PBS. We found that, compared to control cultures, cells cultured in media containing Product R expressed lower amounts of CXCR4 and CCR5 mRNA and surface antigen at all time points. Culture for 3 days in media containing Product R also reduced the ability of cells to migrate towards 10-20 ng/ml SDF-1 and 100-250 ng/ml RANTES. In contrast, Product R had no effect on the expression of CD4 mRNA and receptor protein, or on expression of IL-16 mRNA. These findings suggest that Product R may have clinical efficacy in HIV-1-infected patients by downregulating viral coreceptors on target T-cells.

Study of a needleless intermittent intravenous-access system for peripheral infusions: analysis of staff, patient, and institutional outcomes.

OBJECTIVE: To assess the effect on staff- and patient-related complications of a needleless intermittent intravenous access system with a reflux valve for peripheral infusions. DESIGN: A 6-month cross-over clinical trial (phase I, 13 weeks; phase II, 12 weeks) of a needleless intermittent intravenous access system (NL; study device) compared to a conventional heparin-lock system (CHL, control device) was performed during 1991 on 16 medical and surgical units. A random selection of patients was assessed for local intravenous-site complications; all patients were assessed for the development of nosocomial bacteremia and device-related complications. Staff were assessed for percutaneous injuries and participated in completion of product evaluations. A cost analysis of the study compared to the control device was performed. SETTING: A 1,100-bed, teaching, referral medical center. PATIENTS AND STAFF PARTICIPANTS: 594 patients during 602 patient admissions, comprising a random sample of all patients with a study or control device inserted within a previous 24-hour period on study and control units, were assessed for local complications. The 16 units included adult inpatient general medicine, surgical, and subspecialty units. Pediatrics, obstetrics-gynecology, and intensive-care units were excluded. All patients on study and control units were assessed for development of nosocomial bacteremia and device-related complications. All staff who utilized, manipulated, or may have been exposed to sharps on study and control units were assessed for percutaneous injuries. Nursing staff completed product evaluations. INTERVENTION: The study device, a needleless intermittent intravenous access system with a reflux valve, was compared to the control device, a conventional heparin lock, for peripheral infusions. RESULTS: During the study, 35 percutaneous injuries were reported. Eight injuries were CHL-related; no NL-related injuries were reported (P=.007). An evaluation of 602 patient admissions, 1,134 intermittent access devices, and 2,268 observed indwelling device days demonstrated more pain at the insertion site for CHL than NL; however, no differences in objective signs of phlebitis were noted. Of 773 episodes of positive blood cultures on study and control units, 6 (0.8%) were device-related (assessed by blinded investigator), with no difference between NL and CHL. Complications, including difficulty with infusion (P<.001) and disconnection of intravenous tubing from device (P<.001), were reported more frequently with CHL than with NL. Of nursing staff responding to a product evaluation survey, 95.2% preferred the study over control device. The projected annual incremental cost to our institution for hospitalwide implementation of NL for intermittent access for peripheral infusions was estimated at $82,845, or $230 per 1,000 patient days. CONCLUSIONS: A needleless intermittent intravenous access system with a reflux valve for peripheral infusions is effective in reducing percutaneous injuries to staff and is not associated with an increase in either insertion-site complications or nosocomial bacteremia. Institutions should consider these data, available institutional resources, and institution-specific data regarding the frequency and risk of intermittent access-device-related injuries and other types of sharps injuries in their staff when selecting the above or other safety devices.

Mucormycosis in a transplant recipient.

Mucormycosis classically occurs in patients who have uncontrolled diabetes who develop rhinocerebral disease. A fatal case of rhinocerebral infection caused by Rhizopus arrhizus in a 53-year-old man who had received a renal homograft three years previously is reported. Only five similar cases have been documented, all since 1970. Although direct smears of the purulent nasal exudate revealed the presence of numerous Gram-negative bacilli, later identified as Haemophilus influenzae, the diagnosis of mucormycosis was made by demonstrating the typical broad, nonseptate branched hyphae in the necrotic tissue obtained by surgical debridement of the paranasal sinuses. Culture of this material revealed growth of mold-like fungus which, upon direct microscopic examination, showed sporangiophores bearing spherical sporangia arising directly from a cluster of root-like structures of rhizoids. Despite the immediate institution of therapy with amphotericin B postoperatively, the patient died 48 hours later. Subsequently, the Rhizopus isolated was shown to be resistant to both amphotericin B and 5-fluorocytosine. The present case and two others stress the importance of an aggressive diagnostic approach to patients suspected of having mucormycosis, because the usual microbiologic technics are frequently, inexplicably, unsuccessful, and possibly even misleading in this disease.

The hepatitis B virus as a molecular model for chronic infection: synthesis of hepatitis B surface and e antigens in mouse L cells transfected with closed circular viral DNA.

Linear hepatitis B virus (HBV) DNA, excised from a recombinant plasmid with EcoR1, was purified by preparative electrophoresis on agarose gels and incubated with phage T4 ligase to form either monomeric or dimeric closed circles. Thymidine kinase deficient mouse L cells were cotransfected with thymidine kinase (tk) and circular HBV DNAs and grown in hypoxanthine medium. Colonies of tk-transformed cells, selected after 3-4 weeks of incubation and subcultured in HAT medium, synthesized either hepatitis B surface antigen (HBsAg) alone or HBsAg in combination with hepatitis B e antigen (HBeAg). The various cell colonies differed in plating efficiency, growth rates, cellular appearance, and extent of viral antigen synthesis. Southern hybridization analysis showed the presence of HBV-related sequences in high molecular weight DNA prepared from cells expressing viral antigens. Digestion of cellular DNAs with restriction endonucleases indicated integration of the entire viral genome.

Antimicrobial activity in vitro of cefaclor, a new oral cephalosporin.

The antimicrobial activity of cefaclor, a new orally administered cephalosporin derivative, was studied in vitro against a variety of Gram-positive and Gram-negative clinical isolates. Both penicillin-resistant and penicillin-susceptible strains of Staphylococcus aureus were susceptible to cefaclor, with mean MICs of 1.44 and 0.93 microgram/ml, respectively. However, the MBC for penicillin-resistant S. aureus was higher than that for the penicillin-susceptible strains. All strains of Streptococcus pyogenes, Streptococcus viridans, and Streptococcus pneumoniae tested were highly susceptible to cefaclor; all strains of Streptococcus faecalis were highly resistant to cefaclor. Strains of Escherichia coli, Klebsiella sp., Proteus mirabilis, and Hemophilus influenzae were susceptible to cefaclor. Eighty per cent of strains of H. influenzae were inhibited by 5 micrograms/ml of cefaclor. Most strains of Enterobacter sp., indole-positive Proteus, Pseudomonas sp., and Serratia sp. were resistant to cefaclor.

Pharmacokinetic properties of mezlocillin in ambulatory elderly subjects.

Twelve healthy ambulatory elderly subjects (mean age, 73-78 years) randomly received either a 4-g or 5-g dose of mezlocillin intravenously. One week later the regimen was repeated and patients crossed over to the other dose. Peak serum concentrations were 165 mg/L and 281 mg/L for the 4-g and 5-g doses, respectively. For both doses, differences in t1/2 beta (1.32 hr vs 1.13 hr), AUC (275 mg.hr/L vs 403 mg.hr/L), CL (207 mL/min vs 174 mL/min), CLR (59 mL/min vs 45 mL/min), CLNR (152 mL/min vs 130 mL/min) were not statistically significant. The differences in Varea (22.4L vs 168.8L, P less than or equal to .01) and Cmax (216.6 mg/L vs 317 mg/L, P less than or equal to .05) were statistically significant. Comparison with pharmacokinetic parameters obtained in younger subjects following the 5-g dose reveals that in the elderly the AUC, Varea, and CLNR are higher whereas the CL and CLR are lower. The elderly demonstrated an increase in nonrenal clearance compared with young subjects that is not fully compensatory. The increased AUC in the elderly group suggests that clinical studies examining mezlocillin doses and dose intervals in the treatment of serious infections are warranted in infected elderly patients.

Pharmacokinetics of aztreonam in healthy elderly and young adult volunteers.

Aztreonam is a monobactam exhibiting an antibacterial spectrum similar to that of the aminoglycosides, with activity against aerobic gram-negative bacilli, and is the only related drug that may be given to patients hypersensitive to beta-lactams. The pharmacokinetics of aztreonam were compared in two groups of healthy volunteers. The young group comprised 10 adults between the ages of 18 and 30 years, and the elderly group included 10 adults older than 65 years of age. The two groups each received two doses (1 and 2 g) aztreonam, separated by 1 week. Although the mean peak serum concentrations of aztreonam for the two groups were similar, there were differences in other pharmacokinetic parameters. For example, for the 2-g dose the mean half-life (1.8 +/- .51 versus 3.1 +/- .9 hour), and area under the curve (AUC) (294.42 +/- 64.08 versus 469.01 +/- 144.02 micrograms x hour/mL per 1.73 m2) were less for the younger group compared with the elderly group. The mean total body clearance of aztreonam was greater for the younger than the elderly group. The results were similar to the pharmacokinetic parameters derived from the 1-g dose. These results mirror the lower creatinine clearances and higher serum creatinine levels found in the elderly group. The data suggest that lower doses of aztreonam given at less frequent intervals may be appropriate in the elderly population.

Pharmacologic studies with cefaclor, a new oral cephalosporin.

Cefaclor, a new oral cephalosporin, was administered to 18 normal human volunteers in either single or multiple doses of 250 and 500 mg. Mean serum concentrations of 6.09 and 12.8 microgram/ml were achieved 1 hour after single oral doses of 250 and 500 mg, respectively. The serum concentrations declined rapidly and no drug was detected at 4 hours. Very high concentrations of cefaclor were found in urine during the first 8 hours after ingestion of the drug. Forty-three per cent of the total dose was excreted in urine during the first 8 hours. There was no accumulation of drug in serum during the multiple-dose studies.

Peptide nucleic acids stimulate gamma interferon and inhibit the replication of the human immunodeficiency virus.

BACKGROUND: Peptide nucleic acids (PNAs) are newly appreciated molecules consisting of both amino acids and nucleotides that already have been shown to have interesting properties; for example, they are very stable and have antisense activity. Reticulose, a peptide nucleic acid preparation that had been used for many years to treat human viral infections such as influenza, was investigated for inhibitory effects on the replication of the human immunodeficiency virus (HIV) in cell culture systems. METHODS: H9 and peripheral blood mononuclear cells (PBMCs) were treated with reticulose before, during, and after infection with HIV-1 at various multiplicities. Treatment of cells with PNA significantly inhibited replication of HIV-1 as measured by synthesis of viral mRNA and p24 protein, reverse transcriptase activity, and syncitial cell formation. Exposure of cells to PNA under conditions that favor transfection of DNA, such as electroporation, markedly enhanced the inhibition of HIV replication. RESULTS: In experiments to examine the mechanism of inhibition, it was found that PNA stimulated production of a distinctive cassette of chemokine mRNAs in PBMC cultures. Cytokines stimulated by reticulose included gamma interferon, interleukin-6, interleukin-1, and tissue necrosis factor-alpha. CONCLUSIONS: These results offer new tools for the study of immune functions and, moreover, open new approaches to the therapy of HIV infection and AIDS.