In vitro activities of beta-lactam and aminoglycoside antibiotics. A comparative study of 20 parenterally administered drugs.

In vitro susceptibilities of 552 recent clinical isolates to 20 parenterally administered beta-lactam and aminoglycoside antibiotics were studied. Newer beta-lactam antibiotics had no increased activity over well-known penicillins and cephalosporins against Gram-positive cocci. All showed greater activity, a broadened spectrum, or both against Gram-negative bacilli; azlocillin, mezlocillin, mecillinam, cefamandole, and cefoxitin each had unique advantages. Against Bacteroides fragilis, mezlocillin was more active than available penicillins, and cefoxitin was more active than available cephalosporins, but neither provided any advantages against other anaerobes. All the aminoglycosides studied were inactive against streptococci and anaerobes but had broad spectrums of activity against staphylococci and Enterobacteriaceae. Activity against Pseudomonas aeruginosa was variable. Sisomicin was the most active aminoglycoside against aminoglycoside-susceptible Gram-negative bacilli, but amikacin inhibited the largest percentage (99.2%) of Enterobacteriaceae and P aeruginosa.

Comparative in vitro activities of third-generation cephalosporins.

The in vitro susceptibilities of 823 clinical isolates to eight third-generation cephalosporin and cephalosporinlike antibiotics were studied. All eight antibiotics were more active and had broader spectrums of activity against gram-negative bacilli and anaerobes than older derivatives; however, they were less active against gram-positive cocci. Cefotaxime sodium, cefmenoxime hydrochloride, ceftriaxone disodium, and ceftizoxime sodium had similar activities. Cefoperazone sodium was more active than those drugs against Pseudomonas aeruginosa but less active against Enterobacteriaceae and Acinetobacter. Ceftazidime pentahydrate was more active against P aeruginosa but less active against gram-positive cocci. Moxalactam disodium was more active against some Enterobacteriaceae, Pseudomonas maltophilia, and Bacteroides fragilis but less active against gram-positive cocci. Thienamycin formamidide monohydrate had the broadest spectrum of activity and was the only antibiotic active against Streptococcus faecalis; the only resistant species were P maltophilia and Pseudomonas cepacia.

St Louis encephalitis in Ohio, September 1975: clinical and EEG studies in 16 cases.

In 1975, during the largest epidemic of St Louis encephalitis (SLE) in the United States, 416 cases were diagnosed in Ohio. Persons who were admitted to two Columbus (Ohio) hospitals with suspected acute viral CNS infection were prospectively studied to define the virologic and clinical aspects of SLE. Sixteen cases of SLE were diagnosed serologically. Fifteen patients had signs of encephalitis and one had aseptic meningitis. Six patients had the syndrome of inappropriate antidiuretic hormone secretion. Other frequent findings included moderate peripheral leukocytosis and CSF pleocytosis, with mild elevation of CSF protein levels but normal glucose levels. Severe neurologic sequelae were infrequent. The EEG proved valuable in diagnosis and prognosis. Results of brain scans were normal. Virus in CSF or urine was not demonstrated, nor was viral antigen in CSF or urine sediments. Specific antibody was found in the sera and CSF of all patients who were tested, but interferon was not detected.

Clindamycin and gentamicin for aerobic and anaerobic sepsis.

Thirty-eight adult patients with serious pleuropulmonary, soft-tissue, bone, and intra-abdominal infections caused by combinations of aerobic, facultative, and anaerobic bacteria were treated with parenterally given clindamycin phosphate and gentamicin sulfate and surgery when appropriate. Nine had associated bacteremia. In 29, infections failed to respond to other therapeutic regimens, which included penicillins, cephalosporins, aminoglycosides, and chloramphenicol. Results with clindamycin and gentamicin were excellent and were attributed primarily to the activity of clindamycin against anaerobes, particularly Bacteroides fragilis. Serum concentrations of clindamycin surpassed by manyfold the minimal inhibitory concentrations (MICs) for anaerobes. Serum concentrations of gentamicin did not consistently surpass the MICs for Enterobacteriaceae and Pseudomonas aeruginosa, although those organisms were consistently gentamicinsusceptible by disk diffusion susceptibility tests. Persistent colonization with Enterobacteriaceae, P aeruginosa, enterococci, or Candida were common, and occasionally they were significant in prolonging the clinical courses of patients with extensive infections.

Change in neuropsychological performance in asymptomatic HIV infection: 1-year follow-up.

OBJECTIVE: To examine the stability of cognitive function in patients with asymptomatic HIV infection. DESIGN: Previous longitudinal studies of cognitive function have focused on patients who progress in terms of disease stage. The present study avoided this potential confounding factor by including only subjects who remained in the asymptomatic stage of infection over the follow-up period. METHOD: Subjects were administered an extensive neuropsychological test battery at baseline and 1 year follow-up. Overall performance was characterized as normal or abnormal based on the performance of a well-matched HIV-negative control group. RESULTS: A significantly higher proportion of HIV-positive subjects became abnormal at the follow-up examination. Comparison of the seropositive subjects who remained normal with those who became abnormal revealed no differences at baseline on age, education, depression or CD4 levels. Subjects who became abnormal had worse performance at baseline on measures of information processing, verbal learning and memory, and reaction time. CONCLUSIONS: These data indicate that cognitive function may decline in some patients who continue to be in the asymptomatic stage of infection. Patients with a pattern of cognitive abnormalities at baseline, which includes information processing and reaction time deficits, may be at increased risk for declines in function during early stages of infection.

Neuropsychological performance in symptomatic and asymptomatic HIV infection.

OBJECTIVE: To examine cognitive function in patients at various stages of HIV infection, and to determine the nature and severity associated with stage of illness. DESIGN: Subjects were administered an extensive battery of neuropsychological tests. SUBJECTS: Two hundred and thirty-three HIV-1-infected homosexual/bisexual men and 77 HIV-negative control subjects who had been screened for previous neurological illness. All subjects were volunteers in a longitudinal study of neurobehavioral complications of HIV infection. RESULTS: Patients with symptomatic infection differed from controls on a large number of measures, and asymptomatic patients had a more circumscribed pattern of deficit. On a summary measure of cognitive impairment, there was a twofold increase in the prevalence of impairment in asymptomatic patients relative to controls, and a fourfold increase in symptomatic patients. Memory and dexterity problems appear to be early features of neurobehavioral dysfunction, and frontal lobe deficits were found in patients with symptomatic infection. CONCLUSION: These data indicate that there is a steady increase in the prevalence of neurobehavioral abnormalities associated with stage of infection. The pattern of abnormality also varies with disease stage.

Aerobic exercise: effects on parameters related to fatigue, dyspnea, weight and body composition in HIV-infected adults.

OBJECTIVES: The purpose of the study was to examine the effects of aerobic exercise on physiological fatigue (time on treadmill), dyspnea [rate of perceived exertion (RPE) and forced expiratory volume at 1 s (FEV1)], weight, and body composition in HIV-1-infected adults (200-499 x 106 CD4+ cells/l). DESIGN: The study was a randomized, wait-listed, controlled clinical trial of aerobic exercise in HIV-1-infected adults on signs and symptoms associated with HIV-1 infection or its treatment. METHODS: Sixty subjects were recruited and randomized to two groups. Experimental subjects completed a 12-week supervised exercise program. Control subjects continued usual activity from baseline to week 12 and were then were enrolled in the exercise program. RESULTS: At baseline, the groups were similar in age, weight, body mass index [mean body mass index (BMI) > 27], time since diagnosis, number of symptoms, CD4+ cell count, and number on protease inhibitor therapy (n = 7). Despite disproportionate attrition from the exercise group (38%), exercise subjects were able to remain on the treadmill longer, lost weight, decreased BMI, subcutaneous fat, and abdominal girth when compared to controls. The improvement in weight and body composition occurred without a decrease in kilocalories consumed. Exercise did not seem to have an effect on RPE, a surrogate for dyspnea, and FEV1. There was no significant difference in either the change in CD4+ cell count, percentage or copies of plasma HIV-1 RNA between groups. CONCLUSIONS: We conclude that supervised aerobic exercise training safely decreases fatigue, weight, BMI, subcutaneous fat and abdominal girth (central fat) in HIV-1-infected individuals. It did not appear to have an effect on dyspnea.

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

Depression and neuropsychological performance in asymptomatic HIV infection.

OBJECTIVE: The authors examined the effect of depression on neuropsychological performance in HIV-infected men. Previous studies have suggested that depression may account for the neuropsychological abnormalities observed in some patients with HIV infection, but few studies have specifically examined this question. METHOD: An extensive neuropsychological test battery was administered to 121 HIV-seropositive asymptomatic men and 42 HIV-seronegative comparison subjects. The seropositive subjects were grouped into depressed and non-depressed groups on the basis of scores on the Beck Depression Inventory, Hamilton Rating Scale for Depression, and Structured Clinical Interview for DSM-III-R. RESULTS: Statistical comparisons revealed very few measures on which the depressed seropositive subjects scored significantly worse than either of the nondepressed comparison groups. The nondepressed seropositive group differed consistently from the seronegative comparison subjects on measures of verbal memory and dexterity. CONCLUSIONS: These data indicate that the subtle neuropsychological abnormalities observed in some asymptomatic HIV-seropositive subjects cannot be attributed to depression. These data also indicate the advantages of a multifaceted approach to assessment of depression.

Rate of CD4 decline and neuropsychological performance in HIV infection.

This study examined the relationship between performance on a battery of neuropsychologic tasks and rate of CD4 lymphocyte decline in 47 gay or bisexual men infected with the human immunodeficiency virus type 1. Subjects were volunteers for a longitudinal study of the human immunodeficiency virus infection and were not selected because of neuropsychiatric symptoms. Subjects were at all stages of illness, although most were asymptomatic. Faster rates of decline in percent CD4 lymphocyte were related to poorer performance on measures of memory and reaction time. This relationship was independent of stage of illness and CD4 level at the time of neuropsychologic examination, and was not due to medication effects. The rate of percent CD4 lymphocyte cell loss is associated with and may represent a risk factor for the development of the human immunodeficiency virus-related neurobehavioral deficit.

The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.

We conducted a double-blind, randomized phase II study to evaluate the safety and activity of combination therapy with N-butyl-deoxynojirimycin (SC-48334) (an alpha-glucosidase I inhibitor) and zidovudine versus zidovudine alone. Patients with 200 to 500 CD4 cells/mm3 who tolerated < or = 12 weeks of prior zidovudine therapy received SC-48334 (1000 mg every 8 h) and zidovudine (100 mg every 8 h) or zidovudine and placebo. Sixty patients received combination therapy and 58, zidovudine and placebo. Twenty-three patients (38%) and 15 (26%), in the combination and zidovudine groups, respectively, discontinued therapy (p = 0.15). The mean SC-48334 steady-state trough level (4.04 +/- 0.99 micrograms/ml) was below the in vitro inhibitory concentration for human immunodeficiency virus (HIV). The mean increase in CD4 cells at week 4 was 73.8 cells/mm3 and 52.4 cells/mm3 for the combination and zidovudine groups, respectively (p > 0.36). For patients with prior zidovudine therapy, the mean change in CD4 cells in the combination and zidovudine groups was 63.7 cells/mm3 and 4.9 cells/mm3 at week 8 and 6.8 cells/mm3 and -45.1 cells/mm3 at week 16, respectively. The number of patients with suppression of HIV p24 antigenemia in the combination and zidovudine groups was six (40%) and two (11%) at week 4 (p = 0.10) and five (45%) and two (14%) at week 24 (p = 0.08), respectively. Diarrhea, flatulence, abdominal pain, and weight loss were common for combination recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of oral ciprofloxacin in the treatment of serious respiratory infections.

Fifty-two patients with serious respiratory infections were treated with orally administered ciprofloxacin; 42 patients were evaluable for the efficacy analysis and all were evaluable for determining adverse reactions. Cures were achieved in 24 patients with infections (14 with bronchitis, 10 with pneumonia) caused by Hemophilus influenzae, Streptococcus pneumoniae, or Branhamella catarrhalis, and pathogens were rapidly eradicated from respiratory secretions. Seventeen patients had infections (seven bronchitis, 10 pneumonia) caused by Enterobacteriaceae or Pseudomonas aeruginosa; many of these patients were critically ill and were enrolled in the study because their pathogens were resistant to multiple drugs or because their infections had not responded to alternate antimicrobial therapy. All patients had favorable clinical responses, and members of the Enterobacteriaceae were rapidly eradicated from respiratory secretions. However, five of 12 strains of P. aeruginosa persisted during treatment; minimal inhibitory concentrations for these strains increased 4- to 16-fold as infections continued to resolve. One patient with Staphylococcus aureus infection also showed a response. Ciprofloxacin probably caused nausea, vomiting, or both in three of the 52 patients and possibly contributed to similar symptoms in another three patients (6 to 12 percent). Other possible adverse reactions, including central nervous system symptoms, were also observed but were not clearly drug-related.

Intravenous/oral ciprofloxacin versus ceftazidime in the treatment of serious infections.

Seventy-one adult patients with 72 infections were treated, by random selection, with intravenous/oral ciprofloxacin or intravenously administered ceftazidime. Twenty-seven additional patients with 29 infections who were not appropriate for random assignment were treated in an open study with intravenously administered ciprofloxacin only; the latter infections were generally more serious or were caused by ceftazidime-resistant organisms. The most common doses were ciprofloxacin, 200 mg intravenously and 500 mg orally every 12 hours and ceftazidime, 1 to 2 g intravenously every eight to 12 hours. Forty-seven ciprofloxacin-treated infections and 31 ceftazidime-treated infections were evaluable for determination of efficacy. Infections included lower respiratory tract (21 infections), urinary (37 infections), skin/soft tissue (14 infections), bacteremia/endocarditis (four infections), colitis (one infection), and mastoiditis (one infection). Median minimal inhibitory concentrations of ciprofloxacin and ceftazidime were, respectively: for Enterobacteriaceae, Haemophilus influenzae, and Branhamella catarrhalis, no more than 0.06 and no more than 0.25 micrograms/ml; for Pseudomonas aeruginosa, 0.25 and 4 micrograms/ml; for Enterococcus faecalis, 1 and more than 32 micrograms/ml; and for Staphylococcus aureus, 0.25 and 8 micrograms/ml. Ciprofloxacin, 200 mg intravenously, yielded mean serum concentrations 0.5 and eight hours post-intravenous infusion of 2.3 and 0.7 micrograms/ml, respectively. Satisfactory clinical responses were achieved in 17 (81 percent) of 21 patients with intravenous/oral ciprofloxacin, 22 (71 percent) of 31 patients with ceftazidime, and 20 (77 percent) of 26 patients with intravenous ciprofloxacin. The most common treatment failures occurred in complicated skin/soft-tissue infections treated with intravenous/oral ciprofloxacin, complicated urinary tract infections treated with ceftazidime, and necrotizing P. aeruginosa pneumonia treated with intravenous ciprofloxacin; the pneumonia patients all had respiratory failure and had been previously unresponsive to treatment with other appropriate drugs. Serious adverse reactions were observed in three patients, seizures with intravenous ciprofloxacin in two patients, and Clostridium difficile diarrhea with ceftazidime in one patient. We conclude that sequential intravenous/oral ciprofloxacin and ceftazidime were comparable in efficacy and safety; the ability to change from intravenous to oral therapy is a major convenience. Intravenous ciprofloxacin was useful for more serious infections, often caused by ceftazidime-resistant organisms.

Treatment of skin and soft tissue infections with imipenem/cilastatin.

Ninety-eight adult patients with skin and soft tissue infections caused by a variety of bacterial pathogens were treated with imipenem/cilastatin (71), cefazolin (21), or moxalactam (six) at three medical centers. Favorable clinical responses were observed in 87 of the 90 evaluable cases (97 percent). Most etiologic pathogens were eradicated during treatment including five of seven which demonstrated in vitro resistance to the therapeutic agent. Strains that persisted during treatment were not associated with therapeutic failure except in one cefazolin-treated patient who was infected with Bacteroides fragilis. All three drugs were well tolerated and no specific patterns of adverse reactions were observed.

Regression-line analysis of trimethoprim-sulfamethoxazole activity against Neisseria gonorrhoeae.

A standardized disk diffusion test was developed and used to test the susceptibility of 102 strains of Neisseria gonorrhoeae to combinations of trimethoprim and sulfamethoxazole (TMP/SMX) by relating zone diameters of inhibition to minimal inhibitory concentrations (MIC's). MIC's for TMP/SMX in ratios of 1:20 ranged from 0.08/1.52 to 2.5/47.5 mug/ml and zones of inhibition ranged from 34 to 10 mm. The coefficient of correlation (r) was -0.75. For comparison, a regression line was similarly calculated for ampicillin. MIC's ranged from 0.02 to 0.32 mug/ml and zones of inhibition ranged from 50 to 31 mm; r was -0.71. With establishment of MIC breakpoints to define the categories, susceptible, intermediate, and resistant, the disk duffusion test would be as reliable for estimating susceptibility of gonococci to TMP/SMX as for estimating susceptiblity to ampicillin.

In vitro activity of RO 23-6240 (AM-833): a new fluoroquinolone.

The in vitro activities of RO 23-6240 (AM-833) and four comparative fluoroquinolones were studied. Minimal inhibitory concentrations (MICs) of RO 23-6240, which inhibited at least 90% of strains, were less than or equal to 0.03-1 microgram/ml for Staphylococcus aureus, Staphylococcus epidermidis, Enterobacteriaceae, Acinetobacter anitratus Aeromonas hydrophila, Branhamella catarrhalis, and Haemophilus influenzae, 2-8 micrograms/ml for Staphylococcus saprophyticus, streptococci, diphtheroids, and Pseudomonas spp., and 1-32 micrograms/ml for anaerobic species. MICs of ofloxacin, pefloxacin, norfloxacin, and ciprofloxacin paralleled those of RO 23-6240. With all five drugs, MICs were minimally affected by inoculum size and minimal bacterial concentrations (MBCs) were always within two dilution steps (log2) of MICs.

In vitro activity of cefpiramide (SM-1652) against gram-negative bacilli.

The susceptibilities of 317 gram-negative bacilli to cefpiramide, cefotaxime, and piperacillin were determined by standardized microdilution and disk diffusion tests. Cefpiramide and piperacillin were more consistently active against nonfermenters than against Enterobacteriaceae, whereas cefotaxime was more active against Enterobacteriaceae. Inhibitory zone diameters of approximately 75-micrograms cefpiramide disks correlated well with minimal inhibitory concentrations (r = 0.85); breakpoints for defining susceptibility and resistance were recommended.

In vitro activity of DNA gyrase inhibitors, singly and in combination, against Mycobacterium avium complex.

The in vitro activities of the DNA gyrase inhibitors ciprofloxacin, coumermycin, and novobiocin against 31 clinical isolates of Mycobacterium avium complex were studied using a microdilution technique. Minimal inhibitory concentrations (MICs) were determined in 4 days using Middlebrook 7H9 broth, and minimal bactericidal concentrations (MBCs) were determined by subculturing to Middlebrook 7H10 agar. MICs were: ciprofloxacin, 0.5-greater than 16 (mean, 4.1) micrograms/ml; novobiocin, 4-greater than 128 (mean, 54.7) micrograms/ml; and coumermycin, 2-greater than 16 (mean, 17.5) micrograms/ml. MBCs were usually more than two dilution steps higher than MICs. Checkerboard studies failed to reveal synergistic or antagonistic inhibitory activity of DNA gyrase-A and DNA gyrase-B inhibitors in vitro.

The utility of non-beta-lactam antimicrobial MICs as markers to distinguish oxacillin-resistant from oxacillin-susceptible strains of Staphylococcus epidermidis.

Among 6,068 strains of Staphylococcus epidermidis, 75.5% were oxacillin-resistant. Oxacillin-susceptible strains were more frequently susceptible to erythromycin, clindamycin, ciprofloxacin, trimethoprim/sulfamethoxazole, gentamicin, and tetracycline than oxacillin-resistant strains. With the exception of erythromycin, non-beta-lactam MICs were less discriminatory for identifying oxacillin-resistant strains with oxacillin MICs < or = 2 micrograms/ml than for those with oxacillin MICs > or = 4 micrograms/ml.

Minimal inhibitory concentrations of broad spectrum beta-lactam antibiotics for bacterial control strains.

The minimal inhibitory concentrations of 21 broad spectrum beta-lactam antibiotics for five bacterial control strains, as determined by a microtube method in cation-supplemented Mueller-Hinton broth, are reported.