Biomedical subjects
Publications and source records attributed to W R Wilson.
Candida lusitaniae is a newly recognized opportunistic pathogen amongst immunocompromised patients. The epidemiology and pathology remain largely unknown. This case report describes a 27-year-old female with vasculitis who acquired a fatal C. lusitaniae fungemia.
Erythromycin is a macrolide that acts by inhibiting the translocation reaction during protein synthesis. Erythromycin is inactive against the Enterobacteriaceae and Pseudomonas aeruginosa except under alkaline conditions. Erythromycin is active against most gram-positive bacteria; some gram-negative bacteria, including Neisseria, Bordetella, Brucella, Campylobacter, and Legionella; and Treponema, Chlamydia, and Mycoplasma. The emergence of resistance to erythromycin is closely associated with its use and is often plasmid mediated. After its oral or parenteral administration, erythromycin diffuses readily into intracellular fluids and is actively concentrated intracellularly by polymorphonuclear leukocytes and alveolar macrophages.
Erythromycin, first introduced for clinical use 30 years ago, was found to be effective for the treatment of gram-positive bacterial infections. Emergence of resistance and the advent of penicillinase-resistant penicillins limited the use of erythromycin for serious staphylococcal infections; however, erythromycin remains among the drugs of choice for the treatment of acne, infections of the skin and soft tissues, streptococcal pharyngitis, bronchitis, pneumonitis, diphtheria, carriers of pertussis, and, when administered with a sulfonamide, otitis media. Erythromycin is the drug of choice for the empiric treatment of outpatients with pneumonitis. Erythromycin is also the drug of choice for the treatment of Legionella pneumonia and is effective therapy for Chlamydia infections. Other uses of erythromycin include prophylaxis for elective colon operations and treatment of Campylobacter enteritis, genitourinary infections, and some sexually transmitted diseases.
Pseudallescheria boydii is a recognized cause of mycetoma, a chronic fungal disease that usually affects the extremities. Isolated case reports have also implicated P. boydii in infections of other sites. We report the first large series (83 isolates) of P. boydii in 46 patients, including the second report of P. boydii brain abscess and disseminated infection in a noncompromised host. Between 1974 and 1984 at our institution, P. boydii was cultured from a variety of sites: respiratory tract, 36; soft tissue, 25; bone, 9; gastric aspirate, 4; maxillary sinus, 2; wound, 2; urine, 2; brain abscess, 1; ear, 1; and toenail, 1. Pulmonary colonization proved to be the most common form of pseudallescheriasis of the lung (34 of 36 cultures in this category); 28 of the 32 patients with pulmonary infections had received immunosuppressive therapy or had an underlying disorder. The importance of isolation of P. boydii from bone and soft tissue is supported in this series because all 9 cultures from bone and 21 of 25 cultures from soft tissue were associated with infection. Of 10 cases of infection, 5 were osteomyelitis and 2 were infected wounds; in addition, maxillary sinusitis, disseminated infection, and a lung abscess occurred in 1 patient each.
With few exceptions, pulmonary complications in the immunocompromised host will proceed to death unless the clinician intercedes. The differential diagnosis of diffuse pulmonary disease in this setting includes (1) infection, most commonly from opportunistic organisms; (2) recurrence or extension of the basic underlying disease process to involve the lungs; (3) adverse pulmonary reaction to drugs; (4) a new, unrelated disease process such as cardiac pulmonary edema or pulmonary emboli; and (5) any combination of these categories. Up to a third of these patients have two or more complications, such as pneumonitis from two different opportunistic organisms or an opportunistic infection and a drug-induced pulmonary complication. An understanding of the host defense that is compromised enables the clinician to narrow the differential diagnosis. The most common types of impairment of defense mechanisms are reductions in the number of granulocytes, B-lymphocytes, or T-lymphocytes, and not uncommonly, two or all three of these types of cells are involved. Impairment of each of these cell types is associated with an increased frequency of infection by a particular group of organisms. Consequently, the clinician can be somewhat selective if empiric therapy is being considered. In the immunocompromised patient, most pulmonary complications, including drug-induced pulmonary disease and pulmonary emboli, are associated with fever that mimics an infection. Up to 25% of the pulmonary complications in these patients are noninfectious.
In this second segment of our article on pulmonary disease in the immunocompromised host (ICH), we review the infections associated with pulmonary infiltrates in the ICH and the diagnostic approaches for both infectious and noninfectious conditions. Although certain immunologic defects may predispose patients to specific infectious agents, virtually any infectious agent can cause pulmonary disease in any ICH. Physical findings and laboratory observations may give the clinician clues about probable causes of infection. Nevertheless, invasive diagnostic procedures-in particular, open-lung biopsy-are often necessary to diagnose pulmonary disease in the ICH. The relatively new technique of bronchoalveolar lavage is useful in diagnosing pulmonary disease in the patients with acquired immunodeficiency syndrome (AIDS). Further studies are necessary to confirm the reliability of this procedure as a diagnostic method in the ICH who does not have AIDS.
The recovery of viruses and Chlamydia trachomatis from cell cultures and the detection of their antigens in impression smears prepared from open-lung biopsy (OLB) specimens from immunocompromised adults were compared. Touch impression smears were prepared on three slides, each containing eight wells. OLB tissue was homogenized (Stomacher) and inoculated into MRC-5, primary monkey kidney, and McCoy cell cultures. The direct and indirect immunofluorescence (IF) tests were used to detect antigens to the following organisms: herpes simplex virus, adenovirus, parainfluenza types 1 and 3, respiratory syncytial virus, cytomegalovirus (CMV), Chlamydia trachomatis, influenza types A and B, and varicella-zoster virus. Of 105 OLB specimens, 21 viral isolates (20%) were recovered in cell culture; 20 were CMV and one was an influenza virus type A (H3N2). Both culture and IF results were positive with 12 specimens, but in nine instances a virus was isolated and IF was negative or eight times culture results did not yield the organism but IF test results were positive. Chlamydia trachomatis was never isolated or detected by IF. The authors recommend that for optimal detection of CMV from OLB specimens a new rapid centrifugation-enhanced cell culture system be used in preference, or in conjunction with a preliminary IF screen of impression smears for CMV detection.
We studied the efficacy of penicillin and penicillin combined with streptomycin in the treatment of experimental endocarditis caused by viridans streptococci that are susceptible, tolerant, or relatively resistant to penicillin. Rabbits with experimental endocarditis were treated with procaine penicillin (1.5 X 10(5) U/kg) administered twice daily or with procaine penicillin (1.5 X 10(5) U/kg) plus streptomycin (20 mg/kg) administered twice daily for five days. Compared with control animals, animals treated with penicillin alone experienced a significant reduction (P less than .001) of colony forming units per gram of cardiac valve vegetations when infected with streptococci that are susceptible, tolerant, or resistant to penicillin. This antibiotic alone was less effective against streptococci that were tolerant or resistant to penicillin than against streptococci susceptible to the drug (P less than .01). The combination of penicillin and streptomycin was more effective therapy than was penicillin alone in animals with penicillin-tolerant or penicillin-resistant streptococci causing endocarditis (P less than .01). Penicillin-streptomycin therapy was less active against penicillin-resistant strains than against either penicillin-tolerant (P less than .04) or penicillin-susceptible (P less than .01) strains. The results of our study suggest that tolerance or relative resistance to penicillin in strains of viridans streptococci influences the response to therapy with penicillin alone or penicillin combined with streptomycin in the treatment of experimental endocarditis caused by viridans streptococci.
From January 1978 through December 1980, ninety-five immunocompromised patients underwent diagnostic open lung biopsy (OLB) at the Mayo Clinic, Rochester, Minn. A specific causative diagnosis was made in 77 patients (81%); 12 patients (13%) had more than one specific causative diagnosis. Of the 77 patients with a specific causative diagnosis, 52 patients (68%) had infections, 19 patients (24%) had malignant pulmonary disease, 12 patients (15%) had cytotoxic lung disease, ten patients (13%) had interstitial fibrosis (not related to cytotoxins), and one patient (1%) had vasculitis. In 36 (47%) of the 77 patients with a specific causative diagnosis, the diagnosis was made, by frozen sections or stains, within three hours of OLB. In 35 additional patients (45%), the diagnosis was established within 24 hours. Twelve patients (13%) had minor complications of OLB; no deaths were attributed to the OLB procedure.
Amsacrine [m-AMSA; 4'-(9-acridinylamino)methanesulfon-m-anisidide] is a synthetic intercalating agent with clinical utility in the treatment of acute leukemias and lymphomas. However, as with other intercalators, its mechanism of action is uncertain. We have examined structural changes induced by amsacrine and other intercalators (actinomycin D, Adriamycin, mitoxantrone, 9-aminoacridine) in cultured Chinese hamster (V79-171b) and rat kangaroo kidney epithelial (PtK2) cells, using light- and electron microscopy with simultaneous assessment of cell survival. During chronic exposure at low concentrations, amsacrine causes cell and nuclear enlargement, lobulation of the nucleus, and nucleolar segregation. Nucleolar segregation was also induced by the other four intercalators. The cytotoxic potency of these drugs, as measured by cell survival after 1-hr exposure, was compared with potency of induction of nucleolar segregation. Relative potencies in the two assays varied by more than 10(4)-fold, with actinomycin D the most effective and amsacrine the least effective inducer of nucleolar segregation relative to cytotoxic potency. Thus, although all five intercalators induced nucleolar segregation with high specificity, this lesion does not correlate with cell killing by these drugs. However, interference with nucleolar function (i.e., ribosomal RNA synthesis) may be responsible for the reversible cytostatic effect observed on chronic exposure to some intercalators (actinomycin D, 9-aminoacridine) at low concentrations.
From 1970 to 1983, five patients with group B streptococcal endocarditis were treated at the Mayo Clinic, Rochester, Minn. The minimal inhibitory concentration and the minimal bactericidal concentration of penicillin were 0.09 microgram/mL or less and 1.56 micrograms/mL or less, respectively. The in vitro activity of cefazolin against group B streptococci was similar to that of penicillin. In three of the five cases, penicillin and streptomycin acted synergistically in vitro against group B streptococci. Four of the five patients were cured, three by use of an aminoglycoside combined with penicillin, ampicillin, or vancomycin. Three of the five patients had multiple large systemic emboli, and one of the three died of brain-stem infarct. Penicillin alone or in combination with an aminoglycoside is effective therapy for group B streptococcal endocarditis. Patients unable to tolerate penicillin may be treated with cefazolin or vancomycin. Clindamycin therapy should be avoided in patients with endocarditis caused by strains that are tolerant in vitro to clindamycin.
A method is described by which the growth inhibitory effects of cytotoxic compounds on exponentially growing adherent cell lines can be quantitated. Cultures are established in microtiter plates and the cytotoxic compounds to be tested are added after 2 days. Dilution series are constructed within the microcultures using 8-channel micropipets designed for use with microtiter plates. To measure growth after several days of drug exposure, adherent cell layers are fixed, stained, and the plates washed in water to remove excess stain. After stained cells are air-dried and solubilized, absorbance is determined using spectrophotometers designed for reading of microtiter trays. This method is reproducible and offers the advantage that any adherent cell line can be utilized without the need for tedious cell-counting procedures.
The growth-inhibitory potencies in culture of a variety of clinical antitumour drugs have been compared using two widely studied cell lines: L1210 murine leukaemia and V79 Chinese hamster fibroblasts. Marked variations in the relative sensitivities of these two lines were observed with individual antimetabolites and DNA intercalating agents, while activities of alkylating agents and vinca alkaloids were similar for both cell lines. This experimental system was used to evaluate the possibility of designing intercalating drugs selective for a particular target cell. Results with derivatives of the antileukaemia agent amsacrine indicate that relative cytotoxicity can be modulated by simple monosubstitution within the 9-anilinoacridine ring system. The variation in ratios of inhibitory potencies within the latter series is similar to that observed for the structurally diverse group of clinically-utilized intercalators tested. These results suggest that amsacrine analogue development may provide agents having a different tumour spectrum and greater therapeutic utility than the parent drug.
Aerococcus viridans organisms are gram-positive cocci with a strong tendency to form tetrads. These bacteria have infrequently been encountered as a human pathogen, particularly in bacterial endocarditis. A review of the literature suggests that treatment of A. viridans endocarditis should be similar to that for endocarditis caused by penicillin-susceptible streptococci.
Moxalactam was administered (20 mg/kg intravenously every 8 hours) as single-drug empiric antimicrobial therapy to 63 patients with bacteremia who were neither neutropenic nor immunosuppressed. Six patients (10%) had microorganisms that were susceptible to moxalactam and resistant to all other antimicrobial agents tested; two patients (3%) had microorganisms that were resistant to moxalactam and other agents tested. Of these 63 patients, 47 (75%) were cured with moxalactam therapy. Nine patients (14%) had breakthrough bacteremia while receiving other antimicrobial therapy and were cured subsequently with moxalactam therapy alone. The two major risk factors for failure of moxalactam therapy were polymicrobial bacteremia and an extrahepatic intra-abdominal source of infection; these two conditions frequently coexisted. Six of nine patients with polymicrobial bacteremia died. Superinfection (one pseudomonal, five enterococcal) was responsible for 6 of the 16 treatment failures. Enterococcal superinfection occurred exclusively among patients who had received relatively prolonged therapy with moxalactam for extrahepatic intra-abdominal infection, especially intraabdominal abscess. These five patients died, and postmortem examination showed that enterococcal superinfection was the major cause of death in all. Mild, reversible adverse reactions associated with use of moxalactam occurred in 14 of the 63 patients (22%). None had clinically overt bleeding. The use of moxalactam alone seems to be safe and effective and a cost-effective alternative empiric antimicrobial therapy for most patients with bacteremia who are not immunosuppressed or neutropenic and who are not at high risk of having Pseudomonas or polymicrobial bacteremia.
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.
Detection thresholds for pure tones (1000 Hz and 4000 Hz) in noise and in quiet were estimated for infants at 6 months and 12 months of age and for adults. A visually reinforced head-turn procedure under control of a PDP-11/03 minicomputer was used. An adaptive protocol with a 5-dB step size was employed for the threshold estimates. Infant thresholds were poorer than adult thresholds in each condition. In noise, infant-adult differences were 8 dB (6-month-old infants) and 6 dB (12-month-old infants) at each frequency. In quiet, infant-adult differences were 14 dB (6-month-old infants) and 12 dB (12-month-old infants) at 1000 Hz but were only 7 dB (6-month-old infants) and 5 dB (12-month-old infants) at 4000 Hz. The masking data suggest that infants are at only a slight disadvantage in detecting a target in a background of noise and are consistent with a frequency selectivity mechanism that is proportional to that of adults. The detection-in-quiet data, with greater correspondence among the groups at 4000 Hz than at 1000 Hz, support the notion that hearing sensitivity varies with frequency in a different way in infants than in adults. Data on task performance reveal significant age effects, and the possibility that such effects have biased the observed differences in the estimates of sensory function among the groups is considered.
Clinical and microbiologic aspects of fungal sinusitis occurring in six patients are presented. Three of the six patients were immunosuppressed. Fatal disseminated fungal disease developed in two of those immunosuppressed. The three patients with normal immune function had fungal infections confined to the nasal sinuses. Aspergillus fumigatus and Aspergillus flavus were recovered from the immunosuppressed patients and Sporothrix schenckii, Alternaria species, and Pseudallescheria boydii were recovered from the immunocompetent patients. Surgical debridement was performed on all patients; however, anti-fungal therapy only was prescribed in patients who were at risk of progressive fungal disease. The microbiology laboratory aids in the diagnosis of fungal sinusitis by examining surgical biopsy material for fungal organisms and by culturing the material for recovery of the fungal pathogen.