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.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

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.

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.

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.

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.

A pseudoepidemic of Legionella infections.

During a six-month period, we observed an increase in the incidence of presumed Legionnaires' disease (LD) due to false-positive direct immunofluorescent antibody (DFA) staining. Contamination of the DFA staining reagents with Legionella appeared to account for our pseudoepidemic. Although a positive DFA stain has been regarded as highly specific for the diagnosis of LD, the clinician must interpret such results with caution.

Direct immunofluorescence in the diagnosis of Legionnaires' disease.

Over a 2 1/2 year period, 61 clinical specimens from 41 patients with pneumonia of uncertain etiology were evaluated for the presence of Legionella pneumophila (serogroups 1 to 4) by immunofluorescent antibody techniques. In 13 of 19 patients with Legionnaires' disease, the diagnosis was established by fluorescent antibody (FA) staining of lung biopsies, pleural fluids, or respiratory tract secretions. In the 19 patients with Legionnaires' disease, the diagnosis was confirmed by isolation of L pneumophila by in vitro culture techniques in five or by measurement of serum antibody titers in 17. Although the FA staining technique was of limited sensitivity (68 percent), it was highly specific: no patients with non-Legionnaires' pneumonia had a false-positive fluorescent stain. In addition, the FA staining of lung tissue was positive only when performed during the first nine days of antimicrobial therapy and when an acute bronchopneumonia was noted histologically. In cases of a nonspecific interstitial pneumonitis, FA stain was always negative, and the diagnosis could be confirmed only by serum antibody measurements. Tests for serogroups 1 to 4 with a polyvalent conjugate showed that L. pneumophila serogroup 1 was the predominant strain detected in pneumonia of uncertain etiology in the Detroit area.

Comparison of methicillin-resistant and methicillin-sensitive Staphylococcus aureus bacteremia.

Methicillin-resistant Staphylococcus aureus (MRSA) has become endemic in Detroit, accounting for 50% of bacteremias in heroin abusers. To identify the salient epidemiologic and clinical features of MRSA bacteremia, case-control studies were performed comparing 28 cases of MRSA bacteremia to 28 cases of methicillin-sensitive S. aureus (MSSA) bacteremia in intravenous drug abusers. Infective endocarditis was diagnosed in 46.4% (13 of 28). In endocarditis and nonendocarditis bacteremia alike, the duration of fever, length of hospitalization, need for surgery, and mortality rates were similar. A history of recent antimicrobial therapy, especially cephalosporins, was more common in the MRSA group (p = 0.006). Complications including neurologic, renal, vascular, and musculoskeletal manifestations were more common in the MSSA endocarditis patients than MRSA endocarditis patients, although this difference was not significant. Complications related to antibiotic therapy were similar for both groups. The case-control studies indicate that MRSA and MSSA are similar in their virulence as measured by duration of hospitalization, duration of fever, complications, and mortality.

Ophthalmology operating room standards and infection control concerns.

Postoperative infection is a rare complication of intraocular surgery. Although the incidence is low, the morbidity is high in terms of long-term sequelae. Because some ophthalmologists have requested separate operating rooms to reduce the risk of exogenous sources of infection, ophthalmology training program directors were surveyed to determine national standards of practice. Among the 100 centers responding, most were university affiliated (73%), had more than 500-bed hospitals (67%), and had fewer than 50 practicing ophthalmologists (92%). A single operating room was used in 50 centers and only 33 did not permit nonophthalmology cases in the ophthalmology operating rooms. Centers with a greater ophthalmology volume did not differ from low-volume centers in the scheduling of ophthalmology and nonopthalmology clean or infected cases. Program directors from larger centers, however, were more frequently of the opinion that a separate ophthalmology operating room was needed: 86.2% vs. 63.5% (p = 0.04).

Evaluation of the insulin jet injector as a potential source of infection.

In recent years jet injection of insulin has been widely used by patients with diabetes mellitus. Jet injectors may become contaminated by bacteria because of repeated use without cleaning; cleansing every 2 weeks is recommended. We investigated the occurrence of bacterial contamination by culturing jet injectors in everyday use by 19 patients with diabetes. Swabs from the interior chambers were cultured on blood agar plates. Only one of 20 cultures yielded bacterial growth, and the organism recovered was a presumed contaminant that could not be identified as any common pathogen. No study patient, nor any of more than 70 patients whom we instructed in jet injection, showed any clinical evidence of infection attributable to jet injector use. Jet injectors are unlikely to become colonized by bacteria or to cause infection in patients using them for insulin administration. The low rate of colonization may be due to the antibacterial preservatives added to commercial preparations of insulin. Additional data based on larger numbers of patients would be useful in further clarifying the risk of infection associated with jet injectors.

Infection surveillance in cardiac transplantation.

Infections are a major cause of morbidity and mortality in cardiac transplantation. There is little information describing screening and prospective surveillance of heart recipients. We describe a surveillance program that was used for 35 patients, which screens and follows recipients through serologic, virologic, and immunologic parameters. Pretransplantation surveillance identified four (11.4%) patients whose skin tests with purified protein derivative (PPD) were positive, one patient with giardiasis, and seven (20%) recipients who were susceptible to cytomegalovirus (CMV). Twelve (34.3%) patients had CMV infections, only one of which was primary and involved a seropositive donor. The low rate of primary infection (14%) may result from our use of CMV-negative blood products. Seven (20%) recipients who were seronegative for toxoplasmosis received seropositive hearts, and disseminated toxoplasmosis developed in one of them. Eight (22.8%) patients had asymptomatic significant increases in Epstein-Barr virus antibody titers, without evidence of lymphoma. Fifteen (42.8%) recipients had at least one herpes simplex virus reactivation. Preventive, diagnostic, and early therapeutic interventions should occur as a result of infection surveillance, thus leading to a reduced risk of infection during the period after cardiac transplantation.

Comparison of intravenous administration with intrauterine irrigation with ceforanide for nonelective cesarean section.

A randomized, prospective, double-blind study was designed to compare intravenous administration with intrauterine irrigation using an extended half-life (t1/2 = three hours) cephalosporin, ceforanide. Patients included in the study had a nonelective cesarean section with rupture of membranes for three hours or longer. Sixty-four patients received a single dose of ceforanide immediately after clamping the umbilical cord. Patients were similar in both groups in age, weight, length of labor, and duration of ruptured membranes. The group receiving the intravenous ceforanide had a significantly shorter duration of surgery than the patients receiving the intrauterine ceforanide. Endometritis infection rates were similar, 11.8% (intravenous) versus 11.1% (intrauterine), P greater than .1. Serum levels were as much as tenfold higher in the intravenous group versus the intrauterine group. Intrauterine irrigation with an antimicrobial agent provided no advantage over systemic administration.

Dengue with hemorrhagic manifestations: an imported case from the Middle East.

We report a case of imported dengue with hemorrhagic manifestations seen in a patient who had recently returned from South Yemen. Conspicuous laboratory findings were marked thrombocytopenia and increase in the number of "transformed" lymphocytes. Hemagglutination-inhibition and complement-fixation antibody titers suggest a secondary heterotypic type of infection. Further studies should be done to establish the endemic nature of dengue throughout Yemen and adjacent countries on the Arabian peninsula.

Medical management of osteomyelitis: considerations for home antibiotic chemotherapy.

Osteomyelitis can result from hematogenous seeding or contiguous infection, especially in association with impaired vascularity. Appropriate antibiotic therapy requires identification of the pathogen or pathogens and confirmation that the pathogens are susceptible to the antibiotic selected. Because of the long duration of parenteral antibiotic therapy required, treatment of osteomyelitis is expensive when patients are kept in the hospital for this reason alone. The development of long-half-life antibiotics that can be administered intramuscularly once a day and that are well tolerated has made outpatient parenteral therapy possible for many such patients. Cefonicid is a long-acting second-generation cephalosporin with activity against many of the microorganisms involved in osteomyelitis. Clinical studies have shown that cefonicid is effective and safe when used in an outpatient treatment program. Such programs have realized considerable savings over the cost of inpatient therapy.

Filtration of dialysate using an on-line dialysate filter.

UNLABELLED: Increased concerns about pyrogenic contamination of dialysate have led to the development of an on-line dialysate filtration system. Bacteriological testing of the system was performed (n = 6) by introducing bicarbonate concentrate contaminated with E. coli 026:B 6 (3 x 10(9) cfu/ml) into a dialysis machine equipped with a two-stage polysulfone filtration system. The bacterial concentration of the dialysate entering the filtration system was maintained above 10(6) cfu/ml and endotoxin levels ranged from 30-300 ng/ml during the 3-hour test period. Bacterial and endotoxin levels on the input side of the first-stage filter reached minimum concentrations of 5.4 x 10(9) cfu/ml and 30,000 ng/ml respectively. All output samples of filtered dialysate showed no bacterial growth and endotoxin levels were below the sensitivity (0.003 ng/ml) of the LAL assay. A dialysis machine (QD = 500), equipped with a single stage filtration system, was used for 18 months of clinical testing. In order to evaluate the system's reliability with regard to membrane failures and reduced dialysate flow, filter membrane integrity was verified weekly using a pressure holding test and dialysate flow was measured under routine clinical conditions. No membrane failures occurred, and dialysate flow was maintained at 511 +/- 17 ml/min (n = 70) during the test period. IN CONCLUSION: dialysate filtration is an effective and practical method for prevention of pyrogenic reactions due to high levels of bacteria and endotoxins.