Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial

BACKGROUND: It is often difficult to administer extended antibiotic therapy in the hospital for right-sided Staphylococcus aureus endocarditis. Although the effectiveness of single-drug therapy given for 4 to 6 weeks and that of two-drug therapy given for 2 weeks have been shown, no data are available on the effectiveness of short-course single-drug therapy. OBJECTIVE: To compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin for the 2-week treatment of right-sided S. aureus endocarditis in intravenous drug users. DESIGN: Open, randomized study. SETTING: An academic tertiary care hospital in Barcelona, Spain. PATIENTS: 90 consecutive intravenous drug users who had isolated tricuspid valve endocarditis caused by methicillin-susceptible S. aureus, had no allergy to study medications, and had no systemic infectious complications that required prolonged therapy. An efficacy subset consisted of 74 of these patients who did not meet an exclusion criterion. INTERVENTION: Cloxacillin (2 g intravenously every 4 hours for 14 days) alone or combined with gentamicin (1 mg/kg of body weight intravenously every 8 hours for 7 days). MEASUREMENTS: Clinical or microbiological evidence of active infection after 2 weeks of therapy, relapse of staphylococcal infection, or death. RESULTS: In an analysis of the efficacy subset, treatment was successful in 34 of the 38 patients who received cloxacillin alone (89% [95% CI, 75% to 97%]) and 31 of the 36 patients who received cloxacillin plus gentamicin (86% [CI, 71% to 95%]). Three patients died: one in the cloxacillin group and two in the combination therapy group. Of the 37 patients who completed 2-week treatment with cloxacillin, 34 (92%) were cured, and 3 (8%) needed prolonged treatment to cure the infection. Of the 34 patients who completed 2-week treatment with cloxacillin plus gentamicin, 32 (94%) were cured and 2 (6%) required treatment for 4 weeks. One patient in the combination group had relapse. CONCLUSIONS: A penicillinase-resistant penicillin used as single-agent therapy for 2 weeks was effective for most patients with isolated tricuspid endocarditis caused by methicillin-susceptible S. aureus. Adding gentamicin did not appear to provide any therapeutic advantages. Additional studies to confirm the therapeutic equivalence of short-course therapy with penicillinase-resistant penicillin alone and therapy with combined regimens are warranted.     

Reconsideration of the role of fibronectin binding in endocarditis caused by Staphylococcus aureus

The adherence characteristics in vivo and virulence of two isogenic strains of Staphylococcus aureus differing in fibronectin binding were compared in a rat model of catheter-induced infective endocarditis. No differences were found between the two strains. The results strongly point to the multifactorial nature of bacterial adherence to damaged heart valves and suggest that other binding functions can compensate for the lack of fibronectin binding in S. aureus.     

Staphylococcus aureus nasal colonization in HIV-seropositive and HIV-seronegative drug users

Five cases of adenoid basal carcinoma (ABC) of the uterine cervix were examined for the presence of p53 tumor suppressor gene, K-ras-2 oncogene, and human papillomavirus (HPV). A topographic genotyping approach was used to search for point mutations in K-ras-2 (exon 1 and 2) and p53 (exons 5 to 8) in archival formalin-fixed tissue blocks. Minute target sites were selected from polymerase chain reaction (PCR) amplified and directly sequenced tissue sections. Tissue sections were additionally subjected to immunohistochemical staining for p53 and WAF-1 protein. Because wild type p53 induces WAF-1 gene expression, immunohistochemical staining for WAF-1 protein using monoclonal antibodies may serve as an indirect means to test for p53 mutational damage. Mutational genotype was compared to histopathologic features and immunohistochemical staining. To study the role of HPV, L1 region consensus primers were used to amplify topographic samples, followed by HPV genotyping by direct sequencing and comparison to known viral strains. ABC was found to contain HPV in all cases, proven by genotyping to be HPV type 16 in each case. The virus showed no evidence of genomic variation from prototype HPV type 16 in the L1 segment examined. No K-ras-2 point mutations were identified. p53 immunopositivity was present in all tumors, being weak and focal in 4 and strong and diffuse in 1. WAF-1 immunostaining was positive in two tumors showing weak focal p53 immunopositivity. The single strong and diffuse p53 immunopositive tumor was negative for WAF-1 and was shown to contain a missense p53 point mutation (exon 7-codon 248 tryptophan). In conclusion, ABC is characterized by the presence of HPV type 16. K-ras-2 point mutation appears to play no role in the development of this tumor. p53 gene alterations are common including wild type hyperexpression (weak focal p53 immunopositivity, WAF-1 positivity, no mutational change) and p53 point mutational damage.     

Outpatient intravenous antibiotic therapy for endocarditis

The clinical spectrum of endocarditis continues to evolve, as does its diagnosis and management. Outpatient parenteral antimicrobial therapy has been demonstrated to be safe and effective for medically stable patients with viridans streptococcal endocarditis. Other carefully selected and monitored patients with infective endocarditis may also be considered for completion of therapy outside the hospital setting.     

Postoperative enteritis caused by methicillin-resistant Staphylococcus aureus

We examined the clinical features of 14 men (mean age 72 years) with postoperative enteritis caused by methicillin-resistant Staphylococcus aureus (MRSA). The patients had all undergone surgery for the treatment of digestive diseases and had received antibiotic prophylaxis consisting of an extended-spectrum cephem. Diarrhea appeared a mean of 3.3 days postoperatively and lasted for 5 days on average. In severe cases organ insufficiency was involved. Coagulate-positive staphylococci were the predominant organisms isolated from watery diarrhea. In 13 of 14 patients, coagulase type II isolates producing enterotoxins A, C and toxic shock syndrome toxin-1 (TSST-1) with enterotoxin A, C, and 1st genes were isolated. These strains were sensitive to vancomycin and arbekacin; however, they were highly resistant to many other antibiotics. We also investigated the effects of a glucocorticoid hormone and gamma globulin on production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) obtained from healthy volunteers. TNF-alpha and IL-2 production was enhanced by TSST-1 and the supernatant of Iscove-modified dulbecco medium, in which coagulase type II isolates producing enterotoxins A, C and TSST-1 with enterotoxin A, C were cultured for 24 h. Both glucocorticoid hormone and gamma globulin suppressed TNF-alpha and IL-2 production, thus suggesting that these drugs may be effective in treating postoperative MRSA enteritis.     

Spondylitis and medullary transverse syndrome caused by Staphylococcus aureus

Three cases of haematogenous osteomyelitis in the vertebral column caused by Staphylococcus aureus are reported. The cases, which were associated with severe neurological symptoms and/or death, were initially characterized by a long period with no or discrete local signs of infection and by values of temperature and leucocyte counts within or close to normal values. In this period measurements of the sedimentation reaction and C-reactive protein were elevated, and were markers of persistent infection. At the Department of Clinical Microbiology in the county of Copenhagen blood cultures from a total of 49 patients were found to be positive for S. aureus during the period January to March 1996. Six patients were found to have osteomyelitis (12%, including four cases of spondylitis) and nine patients were suspected of having osteomyelitis. This frequency of patients with S. aureus bacteraemia having osteomyelitis was significantly higher than reported in another Danish study (10), which together with the severe outcome of the infection emphasizes the need for attentiveness to these serious complications of S. aureus bacteraemia.     

Increased overall antibiotic susceptibility in Staphylococcus aureus femAB null mutants

The staphylococcal pentaglycine side chain of the peptidoglycan is reduced to one glycine in femAB null mutants. This is associated with increased susceptibility to methicillin and to a whole range of unrelated antibiotics as well. Genetic evidence suggests that femAB null mutants are only viable because of a compensatory mutation in an unlinked site.     

Native valve infective endocarditis caused by Streptococcus bovis. Efficacy of short-term antibiotic therapy and usefulness of serial echocardiographic evaluation

We report a case of infective endocarditis on native valve, due to Streptococcus bovis, treated successfully with short time antibiotic therapy (10 days versus minimum suggested treatment of two weeks) by using penicillin G together with streptomycin (six days), followed, by treatment with imipenem (four days) because of allergic reactions. Diagnosis was simpler thanks to Durack's new criteria that include positive echocardiographic findings (valvular vegetations) within major clinical criteria for definite diagnosis of infective endocarditis, different from preceding Von Reyn's criteria which did not provide diagnostic weight for echocardiographic data. Serial echocardiograms have also been useful to evaluate the early response to the treatment and its persistent efficacy in the follow-up.     

Hepatitis C virus transmission dynamics in injection drug users

Hepatitis C virus (HCV) presents several challenges to the development of prevention programs. HCV infection is persistent in up to 80% of cases, and viremic individuals may transmit infection to others. With 65-90% of injection drug users anti-HCV positive, a large reservoir of infection exists in most drug-injector populations. Studying the genetic variability of HCV infections could permit researchers to reconstruct chains of viral transmission in IDUs. However, the relationship of HCV to HIV epidemiology remains unclear and may depend on whether the proportions of infectious persons in the population are similar for both viruses.     

Antimicrobial drug resistance in Staphylococcus aureus isolated from cattle in Brazil

Isolates of Staphylococcus aureus obtained from apparently healthy cattle in the State of Paraiba, Brazil were characterized in relation to resistance to 21 antimicrobial agents. Among the 46 isolates obtained, resistance to penicillin was most frequent, followed by resistance to cadmium, streptomycin, arsenate, tetracycline, mercury, erythromycin and kanamycin/neomycin. All isolates were susceptible to fusidic acid, ethidium bromide, cetrimide, chloramphenicol, benzalkonium chloride, doxycycline, gentamicin, methicillin, minocycline, novobiocin, rifamycin, tylosin and vancomycin. Only six isolates were susceptible to all the drugs tested. With respect to the antibiotics, multi-resistant isolates were uncommon. These results are probably a consequence of the peculiarities of local drug usage pressures. In relation to metal ions, resistance to mercury was rare while resistance to arsenate was relatively frequent, which contrasts with the situation for human Staph. aureus strains. After treatment with ethidium bromide, elimination of resistance to penicillin, tetracycline, streptomycin, erythromycin and cadmium was observed, which was consistent with the genetic determinants being plasmid-borne.     

Incidence and risk factors for hepatitis C among injection drug users in Baltimore, Maryland

Between 1988 and 1996, the incidence of and risk factors for hepatitis C virus (HCV) infection were studied in a cohort of injection drug users in Baltimore, Maryland. By second-generation antibody testing of stored serum samples, 142 participants were found to be susceptible to HCV at the time they entered the study. After a median follow-up of 6.5 years, 43 participants (30.3%) developed antibodies to HCV (anti-HCV). The overall incidence was 6.4 cases per 100 person-years, but a substantial decline in the annual incidence rate was observed after the first 2 years (1988 to 1990, 13.4/100 person-years; 1991 to 1996, 2.3/100 person-years [P = 0.0001 for trend]). Participants who acknowledged active drug use, especially those who acknowledged frequent use and sharing of drug paraphernalia, were at increased risk of HCV infection. However, high-risk sexual practices were not associated with HCV seroconversion. Efforts to reduce HCV infection must be focused on curbing drug use and especially on the sharing of needles and drug paraphernalia.     

Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus

Staphylococcus aureus causes pathologies ranging from minor skin infections to life-threatening diseases. Pathogenic effects are largely due to production of bacterial toxin, which is regulated by an RNA molecule, RNAIII. The S. aureus protein called RAP (RNAIII activating protein) activates RNAIII, and a peptide called RIP (RNAIII inhibiting peptide), produced by a nonpathogenic bacteria, inhibits RNAIII. Mice vaccinated with RAP or treated with purified or synthetic RIP were protected from S. aureus pathology. Thus, these two molecules may provide useful approaches for the prevention and treatment of diseases caused by S. aureus.     

Tumor necrosis factor alpha and interleukin 6 release induced by antibiotic killing of Pseudomonas aeruginosa and Staphylococcus aureus

OBJECTIVE: The purpose of this study was to determine the depth that implants may be safely placed into the distal femoral epiphysis (DFE) for the repair of distal femoral physeal fractures. STUDY DESIGN: The depth of the DFE was related to the radiographic thickness of the patella in this experimental study. ANIMALS OR SAMPLE POPULATION: Twenty immature canine cadavers. METHODS: Patella thicknesses were measured from lateral radiographs. Actual DFE depths were determined for pins driven in normograde fashion and for pins driven retrograde from the central depression between the metaphyseal pegs and from the cranial pegs. The association of DFE depth and patella thickness was evaluated using linear regression analysis. Using 95% confidence intervals, rules for estimating the safe depth of implant placement into the DFE were determined. RESULTS: DFE depth had significant correlation with patella thickness for pins placed in retrograde fashion from the central depression between the metaphyseal pegs (r2 = .83) and from the cranial pegs (r2 = .82) and for pins placed in normograde fashion (r2 = .65). CONCLUSIONS: Based on 95% confidence intervals, pins placed in retrograde fashion from the central depression between the metaphyseal pegs may be safely driven into the DFE a distance equal to 140% of patella thickness. Pins placed from the cranial metaphyseal pegs may be driven to a depth equal to 80% of patella thickness, and pins placed in normograde fashion may be driven to a depth equal to 30% of patella thickness. CLINICAL RELEVANCE: Measurement of patella thickness assists the surgeon in determining the approximate depth that pins may be driven into the DFE without penetrating the articular surface of the stifle joint.     

Prevalence of serologic markers of HBV, HDV, HCV and HIV in non-injection drug users compared to injection drug users in Gran Canaria, Spain

Von Hippel-Lindau disease (VHL) is an autosomal dominant tumour syndrome caused by germline mutations of the VHL tumour suppressor gene located on chromosome 3p25-26. In VHL tumours may occur in 14 different target organs, including the eye. Retinal angiomas are considered the first manifestation of VHL disease in 43% of cases, and the cumulative probability of developing a retinal angioma in one or both eyes rises during each decade of life, reaching 80% for patients over 80 years old. Since 1976 patients with VHL at the University Hospital of Utrecht and their at-risk relatives have been screened periodically by a multidisciplinary team. Long-term follow-up ophthalmological data were analysed with special attention to natural course and results of treatment. In addition, we looked for a genotype-phenotype correlation. Retinal angiomas were found in all families. In one large family with a missense mutation (V170D) of the VHL gene, in which the complete spectrum of visceral- and central nervous system (CNS) features of VHL is present, macular, parapapillary, optic disc and ora serrata angiomas were also found. In general, however, a clear-cut genotype-phenotype correlation could not be found. Only early detection and treatment of peripheral retinal angiomas can be expected to decrease the percentage of patients with decreased visual acuity. Therefore, early detection and treatment of these tumours is of paramount importance. Ophthalmological screening of patients and persons at risk should start as early as possible. In patients with apparently sporadic retinal angiomas it is advisable to perform germline DNA analysis, since the risk of developing VHL is high, especially if the angiomas are bilateral, or unilateral and multifocal, if the patient is young, or if there is a family history suggestive of VHL.     

Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus

Levofloxacin is the L isomer of ofloxacin, a racemic mixture in which the L stereochemical form carries the antimicrobial activity. Levofloxacin is more active than former quinolones against gram-positive bacteria, making it potentially useful against such pathogens. In this study, levofloxacin was compared to ciprofloxacin, flucloxacillin, and vancomycin for the treatment of experimental endocarditis due to two methicillin-susceptible Staphylococcus aureus (MSSA) and two methicillin-resistant S. aureus (MRSA) isolates. The four test organisms were susceptible to ciprofloxacin, the levofloxacin MICs for the organisms were low (0.12 to 0.25 mg/liter), and the organisms were killed in vitro by drug concentrations simulating both the peak and trough levels achieved in human serum (5 and 0.5 mg/liter, respectively) during levofloxacin therapy. Rats with aortic endocarditis were treated for 3 days. Antibiotics were injected with a programmable pump to simulate the kinetics of either levofloxacin (350 mg orally once a day), ciprofloxacin (750 mg orally twice a day), flucloxacillin (2 g intravenously four times a day), or vancomycin (1 g intravenously twice a day). Levofloxacin tended to be superior to ciprofloxacin in therapeutic experiments (P = 0.08). More importantly, levofloxacin did not select for resistance in the animals, in contrast to ciprofloxacin. The lower propensity of levofloxacin than ciprofloxacin to select for quinolone resistance was also clearly demonstrated in vitro. Finally, the effectiveness of this simulation of oral levofloxacin therapy was at least equivalent to that of standard treatment for MSSA or MRSA endocarditis with either flucloxacillin or vancomycin. This is noteworthy, because oral antibiotics are not expected to succeed in the treatment of severe staphylococcal infections. These good results obtained with animals suggest that levofloxacin might deserve consideration for further study in the treatment of infections due to ciprofloxacin-susceptible staphylococci in humans.