Comparison of six generic vancomycin products for treatment of methicillin-resistant Staphylococcus aureus experimental endocarditis in rabbits.

Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics in vivo and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10(7) CFU of methicillin-resistant Staphylococcus aureus (MRSA) strain COL (VAN MIC, 1.5 µg/ml). In vitro, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 µg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) µg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (P < 0.02 for each comparison) and in the spleen (P < 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.

Use of daptomycin in a pregnant patient with Staphylococcus aureus endocarditis.

OBJECTIVE: To report on 6 weeks of daptomycin treatment for tricuspid valve endocarditis caused by Staphylococcus aureus in a pregnant female in her second trimester. CASE SUMMARY: A 24-year-old, 14-week pregnant patient with no significant medical history, but with a history of intravenous drug abuse presented with tricuspid valve endocarditis caused by methicillin-sensitive S. aureus. After initial treatment with vancomycin, the patient continued to have fever and bacteremia and was initiated on daptomycin 6 mg/kg for 6 weeks of therapy. The treatment resulted in the resolution of the endocarditis, and no adverse sequelae were identified in the mother or baby. DISCUSSION: Infective endocarditis is a common infection encountered in the hospital setting and represents an increased cost burden to institutions due to prolonged lengths of treatment. Antimicrobial resistance, antimicrobial failure, inadequate attainment of effective drug concentrations, drug allergies, and adverse reactions may be factors that limit the use of commonly utilized antimicrobial agents. Therefore, newer therapies like daptomycin may need to be employed in these situations. Although daptomycin is pregnancy category B, limited case reports with neonatal outcomes are reported. CONCLUSIONS: This case provides further support for the safety of daptomycin in pregnancy with the dose of 6 mg/kg, the extended duration of therapy (6 weeks), and the primary exposure in the second trimester.

Daptomycin for methicillin-resistant Staphylococcus epidermidis native-valve endocarditis: a case report.

Coagulase-negative staphylococci (CoNS) have been increasing in importance as a cause of native valve endocarditis (NVE). Most cases of NVE caused by CoNS are attributable to Staphylococcus epidermidis. NVE caused by CoNS acquired in a nosocomial setting may differ from cases acquired in the community in several ways. It may be associated with hemodialysis, the presence of a long-term indwelling central catheter or pacemaker, or a recent invasive procedure; nosocomial cases may have a higher rate of methicillin resistance among CoNS isolates, and so be more likely to be treated with vancomycin. Unfortunately, NVE caused by methicillin-resistant CoNS has been associated with significantly higher rates of persistent bacteremia and in-hospital mortality than methicillin-susceptible isolates. The poor outcomes in these cases point to the need for alternative therapies with potent activity against methicillin-resistant CoNS. In our medical center, a 76-year-old man presented with native-valve endocarditis and positive blood cultures for methicillin-resistant Staphylococcus epidermidis (MRSE). During each of three 6-week courses of treatment with vancomycin, blood cultures were negative, but they once again became positive for MRSE when vancomycin was discontinued. The minimum inhibitory concentration of the MRSE isolates for vancomycin remained stable at 2 microg/mL. Eventually, treatment with daptomycin was initiated (500 mg [7 mg/kg]) 3 times/week for 6 weeks. Over the following year, no positive cultures for MRSE were detected.

Clinical presentation of rheumatic fever in an endemic area.

This study documented whether patients diagnosed with acute rheumatic fever (ARF) in North Queensland, Australia, conformed to the 1992 Revised Jones Criteria (RJC). The authors aimed to determine whether inclusion of subclinical carditis (SCC) and monarthritis as major manifestations and a low-grade temperature as a minor manifestation in the RJC are justified in this population. A retrospective review of patients in whom the diagnosis of ARF relied on the experience of clinicians and who were admitted to the Townsville and Cairns Base Hospitals between 1997 and 2007 was undertaken. Of the 98 cases reviewed, 71.4% satisfied the RJC. Modification of the RJC increased the rate of criteria satisfaction to 91.8%. On presentation, 27 patients had SCC. Of the patients with SCC followed up, 70.5% had long-term valvular consequences. In populations endemic for ARF, monarthritis, SCC and a low-grade temperature should be included in the RJC.

First case of Pasteurella multocida endocarditis of the tricuspid valve: a favorable outcome following medical treatment.

We describe a rare case of tricuspid valve endocarditis caused by Pasteurella multocida in an elderly woman with no previous history of valvular heart disease. Risk factors included contact with animals and old age. The patient was treated successfully with five days of intravenous ampicillin followed by four weeks of oral ciprofloxacin.

Successful treatment with moxifloxacin of experimental aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA).

Moxifloxacin (MXF) is an 8-methoxyquinolone with high activity against Gram-positive bacteria. In an experimental model of aortic valve endocarditis (EAVE), the efficacy of MXF was evaluated against a strain of methicillin-resistant Staphylococcus aureus (MRSA). Rabbits with catheter-induced aortic valve vegetations were randomly assigned to a control group or to groups receiving MXF 20 mg/kg intravenous (i.v.) twice a day (bid) or vancomycin (VAN) 30 mg/kg i.v. bid for a total of eight doses (4 days). Rabbits were sacrificed 15 h after the last dose of antibiotics. In another group, treatment with MXF was extended to 5 days and rabbits were sacrificed 5 days after the last dose (10th dose) of MXF in order to detect possible relapses of endocarditis after the end of treatment (test-of-cure (TOC) study). Both MXF and VAN significantly reduced the bacterial load in vegetations (P < 0.001 vs. controls). All animals in the MXF-TOC group had sterile vegetations. MXF given at a dose of 20 mg/kg i.v. bid for 4 days was equally effective as VAN in the treatment of EAVE due to MRSA. When treatment with MXF was extended to 5 days, the cure rate reached 100% and no relapses of endocarditis were observed.

Daptomycin is effective in treatment of experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus.

Daptomycin is a lipopeptide antibiotic with potent in vitro activity against gram-positive cocci, including Staphylococcus aureus. This study evaluated the in vitro and in vivo efficacies of daptomycin against two clinical isolates: methicillin-resistant S. aureus (MRSA) 277 (vancomycin MIC, 2 microg/ml) and glycopeptide-intermediate S. aureus (GISA) ATCC 700788 (vancomycin MIC, 8 microg/ml). Time-kill experiments demonstrated that daptomycin was bactericidal in vitro against these two strains. The in vivo activity of daptomycin (6 mg/kg of body weight every 24 h) was evaluated by using a rabbit model of infective endocarditis and was compared with the activities of a high-dose (HD) vancomycin regimen (1 g intravenously every 6 h), the recommended dose (RD) of vancomycin regimen (1 g intravenously every 12 h) for 48 h, and no treatment (as a control). Daptomycin was significantly more effective than the vancomycin RD in reducing the density of bacteria in the vegetations for the MRSA strains (0 [interquartile range, 0 to 1.5] versus 2 [interquartile range, 0 to 5.6] log CFU/g vegetation; P = 0.02) and GISA strains (2 [interquartile range, 0 to 2] versus 6.6 [interquartile range, 2.0 to 6.9] log CFU/g vegetation; P < 0.01) studied. In addition, daptomycin sterilized more MRSA vegetations than the vancomycin RD (13/18 [72%] versus 7/20 [35%]; P = 0.02) and sterilized more GISA vegetations than either vancomycin regimen (12/19 [63%] versus 4/20 [20%]; P < 0.01). No statistically significant difference between the vancomycin HD and the vancomycin RD for MRSA treatment was noted. These results support the use of daptomycin for the treatment of aortic valve endocarditis caused by GISA and MRSA.

Efficacy of telavancin in the treatment of experimental endocarditis due to glycopeptide-intermediate Staphylococcus aureus.

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate Staphylococcus aureus: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 microg/ml and 6 microg/ml, respectively, for telavancin and 46 microg/ml and 6 microg/ml, respectively, for vancomycin. In glycopeptide-intermediate S. aureus ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (P = 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (P = 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation; P = 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation; P = 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate S. aureus.

Efficacy of Telavancin in a rabbit model of aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus or vancomycin-intermediate Staphylococcus aureus.

The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 microg/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 microg/ml and bactericidal at 10 microg/ml against COL and was bacteriostatic at 10 microg/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log(10) CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log(10) CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log(10) CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.

Culture results of heart valves resected because of streptococcal endocarditis: insights into duration of treatment to achieve valve sterilization.

OBJECTIVES: To analyse the culture results of heart valves removed following streptococcal endocarditis in order to gain insight into the duration of treatment required for valve sterilization. PATIENTS AND METHODS: Retrospective review of 131 episodes of streptococcal endocarditis: 94 due to alpha-haemolytic streptococci; 15 due to beta-haemolytic streptococci; 10 due to nutritionally deficient streptococci; eight due to the Streptococcus anginosus group and four due to Streptococcus pneumoniae. Patients had their valves removed during antimicrobial treatment. Culture results were analysed with respect to duration of treatment before surgery. RESULTS: For alpha-haemolytic streptococci, 17 (18%) valves were culture-positive and 77 (82%) culture-negative after a median (range) of 4 (1-20) and 16 (4-58) days of treatment, respectively, P < 0.001. For beta-haemolytic streptococci, two valves (13%) were culture-positive; both patients had received < or = 4 days of treatment. Four patients (40%) with nutritionally deficient streptococci were culture-positive, and had received < or = 8 days of treatment. For the S. anginosus group, two valves (25%) were culture-positive; both patients had received < or = 4 days of treatment before operation. Overall, only one of 131 (0.8%) valves was culture-positive after 14 days of treatment. All valves infected with beta-haemolytic streptococci, nutritionally deficient streptococci and the S. anginosus group, who were treated for more than 8 days before surgery, were culture-negative. CONCLUSIONS: Our findings support current treatment guidelines for endocarditis caused by alpha-haemolytic streptococci. We suggest that the recommended duration of treatment for endocarditis resulting from other streptococci may be excessive and treatment trials evaluating 2 and 4 week regimens are justified.

[Primary acute rheumatic fever in juveniles from an organized community]. / Pervichnaia ostraia revmaticheskaia likhoradka u iunoshei, prebyvaiushchikh v usloviiakh organizovannogo kollektiva.

A closed population of juveniles was studied to follow-up manifestations of primary rheumatic fever. In line with other unfavourable factors, the onset of the disease within the first 6 months of the observation was due to cross streptococcal infection (foci of chronic nasopharyngeal infection were detected in 68.6% examinees, rheumatism debut after acute nasopharyngeal infection was in 91.0% patients). Persistence of streptococci was established in many blood counts in immunofluorescence reaction in 88.2% patients in acute disease, in more patients with lingering rheumatic process. Clinical manifestations include, aside from arthritis and rheumocarditis, frequent thyroid and gastrointestinal lesions. It is thought valid to raise the dose and duration of administration of penicillin in patients with primary rheumatic fever as it eradicates chronic infection foci, prevents recurrences, reduces the number of patients with a lingering course of the disease, with recurrences and valvular defects of the heart.

Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

Successful trovafloxacin prophylaxis against experimental streptococcal aortic valve endocarditis.

Single-dose trovafloxacin (15 mg/kg given intravenously [i.v.]) and ampicillin (40 mg/kg given i.v.) protected 38 and 33% of animals challenged with an ampicillin-tolerant strain of Streptococcus oralis, respectively. As a double-dose regimen, trovafloxacin afforded total protection (100%; P < 0.001 versus controls). Trovafloxacin is the first fluoroquinolone effective in preventing experimental streptococcal endocarditis.

Efficacy of levofloxacin for experimental aortic-valve endocarditis in rabbits infected with viridans group streptococcus or Staphylococcus aureus.

Levofloxacin is among the more active fluoroquinolones against streptococci and staphylococci. It is effective against moderately severe infections caused by these organisms, but its efficacy in the treatment of bacteremia and serious infections such as endocarditis is not well defined. We compared the efficacy of levofloxacin to those of standard agents in the rabbit model of aortic-valve endocarditis caused by fluoroquinolone-susceptible strains including a penicillin-susceptible strain of Streptococcus sanguis, a penicillin-resistant strain of Streptococcus mitis, a methicillin-resistant strain of Staphylococcus aureus, and a methicillin-susceptible strain of S. aureus. Levofloxacin administered intramuscularly at dosages of 20 to 40 mg/kg of body weight twice daily (b.i.d.) was completely ineffective against the penicillin-susceptible strain, with mean vegetation titers after 3 days of therapy not statistically significantly different from those for controls. Levofloxacin was no more effective than penicillin against the penicillin-resistant strain. Levofloxacin administered for 4 days at a dosage of 20 mg/kg b.i.d. was at least as effective as vancomycin administered intravenously at a dosage of 25 mg/kg b.i. d. against the methicillin-resistant S. aureus strain and was as effective as nafcillin administered intramuscularly at 100 mg three times daily against the methicillin-susceptible strain. Emergence of resistance to levofloxacin in vitro was less likely to occur than resistance to ciprofloxacin, and resistance to levofloxacin was not observed in vivo. Levofloxacin-rifampin combinations were antagonistic in vitro and in vivo. Levofloxacin was highly effective as a single agent against experimental staphylococcal endocarditis but was surprisingly ineffective against streptococcal endocarditis, suggesting that it has a potential role as treatment for serious S. aureus but not viridans group streptococcal infections in humans.

[The current course and treatment of infectious endocarditis]. / Sovremennoe techenie i lechenie infektsionnogo éndokardita.

Clinical study of 172 patients treated in the Burdenko Military Hospital for subacute infectious endocarditis in 1980-1996 compared with 192 cases in 1950-1979. Contemporary course of the disease is attended by a few symptoms, primordiality and single-valve affection. On the grounds of antibiotics sensitivity of the most prevalent infection agents discovered in 1996, the article develops some schemes of antibacterial therapy for Streptococcus, Enterococcus and staphylococcal etiology of disease. Rational antibiotic therapy together with surgery measures reduced lethality to 14.3% for Streptococcus endocarditis, to 16.7%--for Enterococcus and to 34.4%--for Staphylococcus.

Tricuspid valve endocarditis due to a moderately susceptible Streptococcus constellatus: persistent bacteremia and fatal outcome despite penicillin plus gentamicin therapy.

An intravenous drug-user developed tricuspid valve endocarditis caused by a moderately susceptible strain of Streptococcus constellatus. Bacteremia and fever persisted despite penicillin and gentamicin therapy. Eventually, he developed massive hemoptysis and expired. We believe that the propensity of this group of organisms for suppurative complications and the suboptimal antibiotic susceptibility may have contributed to the failure of medical therapy and the fatal outcome. Similar cases may benefit from a higher dose of penicillin or early surgical intervention.

Evaluation of cilofungin (LY121019) for treatment of experimental Candida albicans endocarditis in rabbits.

The efficacy of cilofungin (LY121019) for aortic valve endocarditis caused by Candida albicans in rabbits was studied. Vegetation titers were similar for cilofungin-treated and untreated rabbits. No rabbit survived beyond 5 days in either group. All rabbits given amphotericin B survived, and titers were reduced. Cilofungin was ineffective in this model.