Postantibiotic effect and postantibiotic sub-MIC effect of LTX-109 and mupirocin on Staphylococcus aureus blood isolates.

The development of new synthetic antimicrobial peptides like LTX-109 provides a new class of drugs for the treatment of Staphylococcus aureus infections. We evaluated LTX-109 and mupirocin for pharmacodynamic parameters against 10 methicillin-resistant S. aureus isolates. The postantibiotic effect (PAE) is defined as the length of time that bacterial growth is suppressed following a brief exposure to an antibiotic. We also determined the sub-MIC effect (SME) which measures the direct effect of subinhibitory levels on strains that have not previously been exposed to antibiotics. The postantibiotic sub-MIC effect (PA-SME) is a combination of the PAE and SME. LTX-109 had an average PAE of 5·51 h vs 1·04 h for mupirocin. The PA-SME of LTX-109 ranged from 2·51 to 9·33 h as the concentration increased from 0·2 to 0·4 times the minimal inhibitory concentration (MIC). The PA-SME range for mupirocin was 0·93-2·58 h. LTX-109, as compared to mupirocin, demonstrated prolonged time of effect for these pharmacodynamic parameters, which supports persistent activity for several hours after the drug is no longer present or is below the MIC. The pharmacodynamic parameters studied here suggest that LTX-109 is less likely than mupirocin to generate resistance to S. aureus. SIGNIFICANCE AND IMPACT OF THE STUDY: Resistant bacterial infections continue to be a challenge for clinicians. Identification of antibiotics with pharmacodynamic advantages may be beneficial in the treatment of these infections. An antibiotic with a longer postantibiotic effect may be able to be administered less frequently resulting in improved adherence. In this study, a new synthetic antimicrobial peptide, LTX-109, demonstrated a more prolonged time for LTX-109 than mupirocin against methicillin-resistant Staphylococcus aureus.

Detection of Streptococcus pneumoniae colonisation in respiratory tract secretions of military personnel.

Respiratory tract infections with Streptococcus pneumoniae are an important cause of morbidity and mortality among military personnel. A sensitive method is needed to determine the prevalence of S. pneumoniae colonisation in respiratory secretions, as well as its role in pneumonia without an established aetiology. This study investigated the efficacy of two PCR assays in screening military personnel for S. pneumoniae colonisation. Nasopharyngeal swabs were obtained from 200 military personnel and tested for S. pneumoniae by culture and PCR. S. pneumoniae was cultured from three (1.5%) of the 200 samples. PCR for the lytA gene detected S. pneumoniae in 11% of the samples, while PCR for the pneumolysin gene detected S. pneumoniae in 3% of the samples. The sensitivity and negative predictive values were 100% for both PCR assays when compared to culture; the specificity and positive predictive values for the lytA PCR were 90.4% and 13.6%, respectively, compared with 98.5% and 50%, respectively, for the pneumolysin gene PCR. It was concluded that respiratory tract colonisation of military personnel with S. pneumoniae can be identified rapidly and reliably by PCR assays. The use of this technique may greatly enhance the ability to identify a microbial aetiology for pneumonia when compared with conventional culture methods.

Persistently positive culture results in a patient with community-acquired pneumonia due to Legionella pneumophila.

We describe a patient with community-acquired pneumonia due to Legionella pneumophila serogroup 6. This patient was found to have bronchoalveolar carcinoma of the lung by means of cytologic testing in 1 of 2 bronchoalveolar lavage samples, but no lesions were visible on bronchoscopy. Despite intravenous administration of azithromycin to the patient, repeat culture and polymerase chain reaction showed persistence of Legionella; the isolates remained susceptible to azithromycin. The patient did not respond to 14 doses of daily intravenously administered azithromycin. The poor outcome may have been partially due to the suspected underlying lung malignancy, as shown by cytologic examination, and by a delay in seeking medical attention.

Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease.

We collected human immunodeficiency virus (HIV) disease progression, survival, most recent CD4 cell count, and plasma HIV RNA levels from patients (n=157) who participated in randomized clinical trials of interleukin (IL)-2 that commenced before 1995. Data were available for 155 (99%) patients. Statistical analyses were based on the intention-to-treat principle. Median follow-up was 28 months and 30 months for control and IL-2 patients, respectively. Twenty-five (16%) patients developed AIDS or died during follow-up (16 control patients vs. 9 IL-2 patients; R2=0.57; P=.22). Mean change from baseline CD4 cell count was significantly higher in patients randomized to receive IL-2 (368 vs. 153 cells/microL; P=.003). Mean change from baseline plasma HIV RNA was significantly lower in patients randomized to receive IL-2 (-0.98 vs. -0.63 log copies/mL; P=.004). Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 relative to control patients were associated with a nonsignificant trend toward improved clinical outcome.

Recurrent pneumococcal bacteremia: 34 episodes in 15 patients.

Thirty-four episodes of pneumococcal bacteremia were identified in 15 patients over 5 years in 10 hospitals in Franklin County, Ohio. Twelve patients each had 2 episodes of pneumococcal bacteremia, 2 had 3, and 1 had 4. All patients had predisposing conditions, with lymphoma, multiple myeloma, and chronic obstructive pulmonary disease being the most frequent. The mean interval between the first and second episode was 268 days. Serotyping and genotyping were performed on 29 isolates. The same serotypic and genotypic patterns were found for sequential isolates from four patients; three of these patients had a recurrence between 22 and 90 days after a previous episode. Seven (24%) of the 29 isolates were serotype 23F; four isolates (14%) were not susceptible to penicillin. All of our patients received appropriate antimicrobial therapy and appeared to be clinically cured of their initial infection. For patients with recurrent pneumococcal disease, alternate preventive measures such as immunization with conjugate pneumococcal vaccine and/or prophylactic antibiotic therapy should be considered.

Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. Investigators for the Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. METHODS: A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. RESULTS: After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine only (P=0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone. CONCLUSIONS: In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

A study of HIV RNA viral load in AIDS patients with bacterial pneumonia.

We examined the effect of bacterial pneumonia on the magnitude of circulating plasma HIV RNA in HIV-infected patients. Serum samples from 13 adult HIV-infected patients (median CD4 count = 83 cells/microl) were assayed for HIV RNA using the reverse transcriptase polymerase chain reaction assay (a) before bacterial pneumonia, (b) during the acute phase, and (c) after the recovery from the disease. Patients remained on constant antiretroviral therapy: HIV RNA was detected in all samples tested. The medians before, during, and after bacterial pneumonia were 60,000 copies per ml, 245,000 copies per ml, and 84,000 copies per ml, respectively. All 13 patients had increased HIV RNA levels on developing pneumonia. There was a decline in the level of HIV RNA with recovery from pneumonia in 12 of 13 patients. The difference between the HIV RNA levels before and after pneumonia was not significant, nor was there significant difference in the CD4 counts before and after pneumonia. In conclusion, bacterial pneumonia is associated with a consistent, transient increase in HIV RNA of variable magnitude in AIDS patients. Interpretation of HIV RNA changes for clinical management of AIDS patients must take into account this reversible elevation during infections.

Changes in virus load markers during AIDS-associated opportunistic diseases in human immunodeficiency virus-infected persons.

Human immunodeficiency virus (HIV) load markers are being used increasingly to monitor disease progression and evaluate antiretroviral therapy. This study examined plasma HIV RNA and p24 antigen levels before, during, and after 15 AIDS-associated opportunistic disease events in patients with AIDS (median CD4 cell count = 65/microL). Plasma HIV RNA was detected during 13 of the 15 events (median level before an event = 21,000 copies/mL). There was an increase in the level of plasma HIV RNA with the onset of an AIDS-associated opportunistic disease during 11 of 13 events for which HIV RNA was detectable (median level during an event = 145,000 copies/mL). There was a decline in the level of HIV RNA with the recovery from disease (median level after an event = 29,700 copies/mL). In contrast, there was no consistent or significant change in p24 antigen levels or CD4 cell counts with either the onset of or recovery from an event. Clinical interpretation of plasma HIV RNA changes must take into account this reversible elevation during AIDS-associated opportunistic disease.

Gender is not a factor in serum human immunodeficiency virus type 1 RNA levels in patients with viremia.

We investigated gender as a factor in viral load measurements for human immunodeficiency virus-infected patients. Forty antiretroviral-therapy-naive, age- and CD4-matched women and men were tested for serum RNA and p24 antigen levels prior to antiretroviral therapy and at approximately 12 weeks after therapy. No gender differences were observed for these two markers of viral load.

Comparison of HIV type 1 RNA plasma viremia, p24 antigenemia, and unintegrated DNA as viral load markers in pediatric patients.

Better surrogate markers need to be developed to evaluate therapy in HIV-infected children. This study evaluated plasma RNA, immune complex-dissociated p24 antigenemia, and unintegrated DNA (uDNA) in HIV-infected pediatric patients. Ten children were followed from initiation of nucleoside antiretroviral therapy at intervals up to 24 months. Prior to initiation of therapy, HIV RNA was detected in 10 of 10 patients (median, 76,000 Eq/ml), p24 antigen was detected in 8 of 10 patients (median, 193 pg/ml), and uDNA was detected in 6 of 7 patients (median, 10% uDNA). After 12 months the RNA decreased in all patients and became undetectable in six. In contrast, p24 antigenemia decreased in 6 of 10 patients, remained undetectable in 1, and increased in 3. HIV uDNA decreased in six of six patients and became undetectable in three. There was no overall change in CD4 cell count. Plasma RNA and uDNA levels are both sensitive markers of nucleoside therapy in children; however, they do not covary strongly.

Frequencies of opportunistic diseases prior to death among HIV-infected persons. Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the complete history of major opportunistic events experienced by 1883 HIV-infected persons prior to and specifically within 6 months of death, and to determine whether the frequency of specific events varies according to demographic characteristics, risk behaviors or geographic location. DESIGN: Descriptive case series. METHODS: Of 6682 HIV-infected individuals enrolled in studies sponsored by the Community Programs for Clinical Research on AIDS between September 1990 and June 1994, 1883 died during follow-up. A complete history of AIDS-defining events was determined for these patients by combining medical history data obtained at the time of enrollment, new events that occurred during follow-up, and causes of death. RESULTS: The most common opportunistic AIDS-defining events these 1883 patients experienced before death were Pneumocystis carinii pneumonia (PCP; 45%), Mycobacterium avium complex (MAC; 25%), wasting syndrome (25%), bacterial pneumonia (24%), cytomegalovirus (CMV) disease (23%) and candidiasis (esophageal or pulmonary; 22%). In addition, 47% of patients experienced two or three AIDS-defining events before death, and 22% experienced four or more events. In the 6 months prior to death, 22% of patients had PCP, 21% had MAC, and 20% had CMV disease. Significant sex and ethnic differences were found: bacterial pneumonia occurred more often before death in women compared with men; fewer blacks and Latinos than whites experienced Kaposi's sarcoma (KS); and fewer blacks than whites had CMV disease before death. The percentage of patients with KS and CMV also varied by risk behavior. The frequency of 10 opportunistic diseases varied by geographic region after adjustment for demographic characteristics and risk behavior. Of note, many more patients in northeastern USA had tuberculosis and fewer had MAC. CONCLUSION: A large percentage of individuals with HIV infection experienced multiple AIDS-defining opportunistic diseases before death. PCP, MAC, wasting syndrome, bacterial pneumonia, CMV disease, and candidiasis (esophageal or pulmonary) account for a substantial proportion of morbidity associated with HIV infection. More diseases varied by geographic location than by demographic characteristics or risk behavior of patients. Continued research on the etiology and prevention of these diseases and how they relate to one another should be a high priority.

Selective inhibitory effects of stress hormones on natural killer (NK) cell activity of lymphocytes from AIDS patients.

To examine the potential role of stress hormones in the progression of HIV infections, we developed an in vitro model system that investigates the effects of cortisol, adrenocorticotropin-releasing hormone (ACTH) and beta-endorphin on the natural killer cell activity of lymphocytes from normal subjects and AIDS patients. The system employs a 4 hr 51Cr release assay and K562 target cells. Direct addition of cortisol (0.05, 0.1, and 0.2 microgram/ml) or ACTH (10(-6) to 10(-8) M) to the mixture of effector and prelabeled target cells did not produce any significant immunoregulatory effects on the NK cell activity of normal lymphocytes. Direct addition of beta-endorphin (10(-13) to 10(-17) M) to the mixture of effector and prelabeled target cells did not produce any significant immunoregulatory effects on the NK cell activity of lymphocytes from normal or AIDS subjects. However, cortisol and ACTH significantly inhibited the NK activity of lymphocytes from AIDS patients. The selective inhibitory effects of cortisol and ACTH in patients with HIV infections are consistent with a model which proposes that stress related neurohormones and/or neuropeptides may be involved in the progression of HIV infections.

Treatment of Legionella pneumophila lung abscess with clindamycin.

Clindamycin was used to successfully treat a lung abscess caused by Legionella pneumophila. The activity of clindamycin, erythromycin, and rifampin against cell-associated growth of L. pneumophila in human monocytes was determined by broth time-kill methodology. More killing of cell-associated growth of L. pneumophila was achieved with clindamycin than with erythromycin. Synergy with rifampin was demonstrated with both erythromycin and clindamycin.

Antiretroviral therapy is associated with a decrease in unintegrated HIV-1 DNA in pediatric patients.

Good markers for monitoring the efficacy of antiretroviral therapy in children do not currently exist. This study examined the effect of antiretroviral therapy on human immunodeficiency virus (HIV-1) unintegrated DNA (uDNA), integrated DNA (iDNA), percent uDNA, immune complex dissociated (ICD) p24 antigenemia, and plasma viral titer. Seven children were followed at therapy initiation and at approximately 3- and 10-month intervals. HIV-1 uDNA was detected in all children prior to start of therapy (average percent uDNA, 43%). At 3 months, the percent HIV uDNA decreased in all patients to an average of 18% (p = 0.01) and at 10 months decreased to an average of 1%. In contrast, the amount of HIV iDNA was relatively constant after initiation of therapy. ICD HIV p24 antigen was detected in all patients prior to therapy (average, 538 pg/ml). Over the study period, the ICD p24 antigen level decreased in three patients and remained relatively unchanged in four patients. Plasma cultures of HIV-1 were positive in only one of the seven patients prior to therapy. Among the methods evaluated, measurement of uDNA was the only parameter which reliable decreased after initiation of nucleoside therapy.

Rapid decrease in unintegrated human immunodeficiency virus DNA after the initiation of nucleoside therapy.

Better markers for determining therapeutic efficacy of antiretroviral drugs are needed for human immunodeficiency virus (HIV) infection. The amounts of unintegrated HIV DNA (uDNA) were sequentially determined in peripheral blood mononuclear cells (PBMC) from 20 HIV-infected patients starting nucleoside therapy. HIV copy number was determined using a quantitative polymerase chain reaction assay. Before therapy, 19 of 20 patients had detectable HIV uDNA. The average percentage of uDNA was 42%. After 1, 4, and 8 weeks of nucleoside therapy the average decreased to 23% (P < .001), 7%, and 3%, respectively. The amount of HIV uDNA decreased in all 19 patients during the first week and was undetectable in 14 by 8 weeks. Thus, measurement of HIV uDNA has many characteristics needed for a good marker of therapeutic efficacy of antiretroviral drugs, including detectability in a high proportion of patients, large and rapid response to initiation of therapy, and a biologically plausible mechanism.

Clinical safety, tolerability, and pharmacokinetics of murine monoclonal antibody to human tumor necrosis factor-alpha.

The safety, tolerability, and pharmacokinetic profile of murine monoclonal antibody to human tumor necrosis factor-alpha (TNF alpha MAb) were evaluated in 20 uninfected patients at risk of sepsis and 16 septic patients. TNF alpha MAb was well tolerated in all patients, with no immediate or delayed signs of allergic reaction. During the 28-day evaluation, side effects included thrombocytosis (11), hepatic enzyme elevations (8), cardiac arrhythmias (3), and deaths (5). Each was attributed to the patient's severe underlying disease and not to TNF alpha MAb; however, a relationship between TNF alpha MAb and these events cannot be ruled out. The half-life was 52 h for a single infusion of TNF alpha MAb. Human antibody against TNF alpha MAb was observed in 13 (76.5%) of 17 phase IA patients and 10 of 10 phase IB patients and anti-idiotype antibodies in 11 (91.7%) of 12 phase IA patients and 2 (33.3%) of 6 phase IB patients. TNF alpha MAb should be evaluated as adjunctive therapy for patients with sepsis.

Increased detection of human immunodeficiency virus antigenemia after dissociation of immune complexes at low pH.

This study compared the number of patients with detectable human immunodeficiency virus (HIV) antigenemia after immune complex (IC) dissociation by established methods using either 0.5 NCl or 1.5 M glycine buffer. Without IC dissociation, HIV antigen was detected in 43% of patients. After dissociation, the HCl method detected only an additional 7% of patients (P = 0.09), while the glycine method detected an additional 34% (P < 0.001). However, care must be taken in setting the threshold of the standards, and confirmatory neutralization assays should be performed to ensure specificity of HIV antigen enzyme immunoassay after IC dissociation.

Quantitation of unintegrated HIV-1 DNA in asymptomatic patients in the presence or absence of antiretroviral therapy.

The objective of this work was to determine the amount of unintegrated human immunodeficiency virus (HIV) DNA (HIV uDNA) in asymptomatic individuals in the presence or absence of antiretroviral therapy. Twenty-one healthy seropositive individuals with no history of any opportunistic infection or previous use of nucleoside antiretrovirals, and 9 similarly asymptomatic individuals who had initiated nucleoside antiretroviral therapy within the last 24 months were studied. All patients had CD4 lymphocyte counts above 400/microliters. All subjects administered antiretrovirals received 400-600 mg of zidovudine daily for 2-24 months. Two individuals additionally received 400 mg of dideoxyinosine (ddI) daily for 4 and 5 months. Patient peripheral blood mononuclear cells (PBMCs) were examined for integrated and unintegrated HIV DNA by a quantitative PCR assay. In addition, CD4 counts were measured, and free and immune complex dissociated p24 antigen was detected in plasma by ELISA. The mean percentage of HIV uDNA in asymptomatic individuals not on therapy was 59%, with 95% confidence limits from 50 to 69%. In contrast, patients on therapy had a mean of only 13% HIV uDNA, with confidence limits from 2 to 25% (p < 0.001). These findings indicate that a significant amount of HIV DNA in infected, healthy patients not on therapy is in the unintegrated form, and that the amount of HIV uDNA in asymptomatic patients on nucleoside therapy is much less. The amount of HIV uDNA in PBMCs deserves further study as a new marker of the efficacy of antiretroviral therapy.