minocycline and Endocarditis--Bacterial

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.

Topics: Acetamides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Endocarditis, Bacterial; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Pneumonia, Bacterial; Staphylococcal Infections; Teicoplanin; Tigecycline; Treatment Outcome; Vancomycin

The tetracyclines are a family of related natural products that were originally discovered by virtue of their antibacterial activities. As one of the earliest antibiotics to be marketed after penicillin and streptomycin, and because of their convenient oral dosing, tetracyclines have achieved wide clinical usage. However, this widespread clinical use, in addition to their use in animal feed, and even as an antibiotic spray for fruit and other crops, has produced widespread resistance that ultimately has limited the clinical utility of the entire family of tetracycline antibiotics. More recently, however, there has been renewed interest in this antibiotic class, with attempts being made to identify compounds capable of evading common bacterial resistance mechanisms and to search for potential uses beyond antibacterial therapy. This review will discuss the identification of 9-glycylamido-tetracyclines (glycylcyclines) and related compounds that have successfully evaded most bacterial resistance mechanisms, resulting in the approval of the first glycylcycline, tigecycline, for clinical use.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Endocarditis, Bacterial; Humans; Minocycline; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Tetracyclines; Tigecycline

Tigecycline is the first commercially available member of the glycylcyclines, a new class of antimicrobial agents. The glycylcyclines are derivatives of the tetracycline antibiotics, with structural modifications that allow for potent gram-positive, gram-negative, and anaerobic activity, including certain multidrug-resistant strains. The enhanced activity can be attributed to stronger binding affinity and enhanced protection against several mechanisms of resistance that affect other antibiotic classes such as tetracyclines. Tigecycline exhibits generally bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation. In vitro activity has been demonstrated against multidrug-resistant gram-positive pathogens including methicillin-resistant and glycopeptide-intermediate and -resistant Staphylococcus aureus, as well as vancomycin-resistant enterococci. Multidrug-resistant gram-negative pathogens, such as Acinetobacter baumannii and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli, are typically highly susceptible to tigecycline. The drug also has displayed significant activity against many clinically important anaerobic organisms. This agent demonstrates a predictable pharmacokinetic profile and minimal drug interactions, and is generally well tolerated, with nausea being the most common adverse event. It was approved in June 2005 for the treatment of complicated skin and skin structure infections (SSSIs) and complicated intraabdominal infections. Currently, a limited number of broad-spectrum antimicrobials are available to combat multidrug-resistant organisms. The addition of new agents is essential to limiting the spread of these pathogens and improving outcomes in patients with these types of infections. Tigecycline has demonstrated promising results in initial in vitro and clinical studies for SSSIs and complicated intraabdominal infections; however, further clinical experience will clarify its role as a broad-spectrum agent.

Topics: Animals; Anti-Infective Agents; Bacteria, Anaerobic; Bacterial Infections; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple, Bacterial; Endocarditis, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Minocycline; Osteomyelitis; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Tigecycline

We retrospectively assessed the initial clinical impact of the locally administered bacteriostatic antibiotic, powder minocycline, during surgery for active infective endocarditis (AIE).. Among 38 surgical AIE patients, 36 patients who underwent surgical intervention for AIE using local administration of powder minocycline between January 2008 and August 2017 in our institute were enrolled. During surgery, the local administration and dispersion of powder minocycline at not only the valvular annulus and perivalvular cavity, but also the prosthetic cuff and ring were performed following the complete resection and aggressive debridement of infectious tissues. Early clinical outcomes, including survival, postoperative co-morbidities, and freedom from re-intervention or significant paravalvular leakage (PVL), were assessed.. Early mortality within 30 days was 5.6% and hospital death was 13.9%. There was no reoperation within 30 days and only one patient (3.8%) developed recurrent infection, which improved with additional antibiotic treatments. More than moderate PVL within 30 days was detected in one patient only (3.8%). Over a median follow-up period of 38.3 ± 35.5 months, a Kaplan-Meier analysis revealed that 1- and 5-year survival rates were 75.7 and 66.8%, respectively, and freedom from reoperation was 100% at 5 years. Freedom from significant PVL at 5 years was 91.0%.. The local administration of powder minocycline may be a simple and effective manipulation during surgical intervention for AIE without extensive reconstruction; however, the surgical management of AIE remains challenging.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Debridement; Endocarditis, Bacterial; Female; Hospital Mortality; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Minocycline; Powders; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; Endocarditis, Bacterial; Eye Color; Female; Humans; Hyperpigmentation; Minocycline; Skin Pigmentation

We evaluated the efficacy of tigecycline in a rabbit model of experimental endocarditis caused by a linezolid-resistant clinical strain of Enterococcus faecium. Tigecycline-treated animals had a 2.8-log10-CFU/g reduction in microbial counts in excised vegetations compared with controls. Addition of gentamicin caused a further arithmetical reduction in colony counts. The therapeutic effect was sustained 5 days after completion of treatment, as shown by relapse studies performed in treatment groups.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gentamicins; Gram-Positive Bacterial Infections; Linezolid; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Rabbits; Tigecycline

The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis.. The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed.. Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log(10) cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals.. The novel β-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Daptomycin; Disease Models, Animal; Drug Resistance, Bacterial; Endocarditis, Bacterial; Female; Methicillin-Resistant Staphylococcus aureus; Microbial Viability; Minocycline; Rabbits; Rodent Diseases; Staphylococcal Infections; Tigecycline; Treatment Outcome

Topics: Aged, 80 and over; Bacteremia; Daptomycin; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Male; Minocycline; Tigecycline; Vancomycin Resistance

A 22-year-old man was diagnosed with active mitral endocarditis 14 months after mitral valve repair. The responsible organism was methicillin-resistant Staphylococcus epidermidis. Transthoracic echocardiography showed an 8-mm patch of vegetation adhering to the anterior part of the artificial ring. Although antibiotics (piperacillin, minocycline, imipenem/cilastatin, and ampicillin) were administered, the vegetation grew to 30 mm. Reoperation was performed 35 days after the diagnosis. Before surgery, there was mild mitral regurgitation without congestive heart failure. Re-repair was performed by removing the vegetation and the artificial ring, and mattress sutures repaired the circumferential sulcus formed by the artificial ring. Teicoplanin and minocycline were administered for 6 weeks. At 20 months, infective endocarditis was absent. Residual mitral regurgitation has been consistently mild. Although active mitral endocarditis after mitral valve repair is rare, prompt reoperation should be considered if the responsible organism is drug-resistant and infection spreads to the artificial ring.

Topics: Anti-Bacterial Agents; Combined Modality Therapy; Device Removal; Drug Therapy, Combination; Endocarditis, Bacterial; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Male; Methicillin Resistance; Minocycline; Mitral Valve Prolapse; Prosthesis Design; Prosthesis Failure; Prosthesis-Related Infections; Reoperation; Staphylococcus epidermidis; Teicoplanin; Young Adult

To report a case of multidrug-resistant Enterococcus faecium requiring combination antibacterial therapy.. A 39-year-old female presented with chest pain and a history of endocarditis 3 years prior to admission. Blood cultures were positive for E. faecium. She was treated initially with daptomycin 6 mg/kg daily, which was later increased to 8 mg/kg daily despite poor gentamicin clearance. A variety of antibiotics were used in combination with daptomycin, but the patient remained febrile, with positive blood cultures revealing vancomycin minimum inhibitory concentration (MIC) greater than 256 microg/mL and daptomycin MIC 3 microg/mL (and later, 4 microg/mL). Following the addition of tigecycline, the patient experienced rapid clinical and microbiologic improvement, and blood cultures remained negative 9 weeks after discharge.. Limited clinical data support the use of daptomycin for the treatment of E. faecium endocarditis, and information regarding the effects of escalating doses and combination therapy is scant. After failing multiple combination regimens, this patient responded to a combination of tigecycline and daptomycin. Daptomycin 8 mg/kg daily did not result in creatine kinase elevation in the face of evidence of possible renal dysfunction.. Increasing doses of daptomycin may enhance efficacy without compromising safety, even in patients with some renal dysfunction. The combination of daptomycin and tigecycline may be useful for the treatment of multidrug-resistant E. faecium.

Topics: Adult; Anti-Bacterial Agents; Daptomycin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Female; Humans; Microbial Sensitivity Tests; Minocycline; Tigecycline

Endocarditis, and prosthetic valve endocarditis in particular, is a serious disease with high morbidity and mortality. We investigate the effects of tigecycline, linezolid and vancomycin on biofilms of viridans group streptococci (VGS) isolated from patients with definite native or prosthetic valve endocarditis.. Ten of 20 VGS blood stream isolates from patients with endocarditis formed biofilms in the microtiter plate biofilm model. The minimal inhibitory concentrations (MIC) for tigecycline, linezolid and vancomycin were determined using the microdilution broth method. Biofilms were grown for 24 hours and were incubated with tigecycline, linezolid and vancomycin at increasing concentrations from 1-128x MIC of the isolate being tested. Biofilm thickness was quantified by measuring the optical density (OD) after dyeing it with crystal violet. The incubation of the biofilms with tigecycline, linezolid or vancomycin resulted in a significant reduction of OD compared to the control biofilm without antibiotic (p<0.05). The optical density ratio (Odr) decreased significantly at 2x MIC for tigecycline, and at 8x MIC for linezolid and vancomycin (p<0.05). Although biofilms persisted even at the highest antibiotic concentrations of 128x MIC, bacterial growth was eradicated starting at concentrations of 16x MIC for vancomycin and of 32x MIC for linezolid, but not for tigecycline, up to a concentration of 128x MIC.. In the present study on viridans streptococci isolated from patients with endocarditis, tigecycline and linezolid reduced the density of the biofilms as effectively as vancomycin. However, linezolid and vancomycin were bactericidal at higher concentrations. Linezolid and vancomycin at very high doses may be useful in the treatment of biofilm-associated diseases caused by VGS infections.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biofilms; Dose-Response Relationship, Drug; Endocarditis, Bacterial; Female; Heart Valve Prosthesis; Humans; Linezolid; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Oxazolidinones; Prosthesis-Related Infections; Streptococcal Infections; Tigecycline; Treatment Outcome; Vancomycin; Viridans Streptococci

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Middle Aged; Minocycline; Oxazolidinones; Tigecycline; Treatment Outcome; Vancomycin

We report a case of prosthetic valve endocarditis and persistent bacteremia due to vancomycin-resistant Enterococcus faecium. The combination of parenteral chloramphenicol plus minocycline therapy was administered for 8 weeks and resulted in cure after treatment with quinupristin-dalfopristin had failed.

Topics: Aged; Chloramphenicol; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Heart Valve Prosthesis; Humans; Male; Minocycline; Prosthesis-Related Infections; Vancomycin Resistance

Clinical blood isolates from three sequential episodes of endocarditis occurring over a 6-month period in a child with a malformative cardiopathy were investigated. All isolates identified as Abiotrophia defectiva were resistant to erythromycin-clindamycin and to tetracycline-minocycline, due to the presence of sequences homologous to the erythromycin resistance gene ermB and to the tetracycline resistance gene tet(M), respectively. These resistance genes were located on a chromosomally borne composite Tn916-related transposon. These results demonstrate the involvement of conjugative transposons in the dissemination of antibiotic resistance in the genus Abiotrophia.

Topics: Anti-Bacterial Agents; Blotting, Southern; Child, Preschool; Clindamycin; DNA Transposable Elements; Drug Resistance, Microbial; Electrophoresis, Gel, Pulsed-Field; Endocarditis, Bacterial; Erythromycin; Humans; Male; Methyltransferases; Microbial Sensitivity Tests; Minocycline; Polymerase Chain Reaction; Streptococcal Infections; Streptococcus; Tetracycline Resistance

GAR-936, a novel glycylcycline, was investigated with a rat model of experimental endocarditis. It was compared with vancomycin against both vancomycin-susceptible and -resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus. GAR-936 exhibited the lowest MICs (2 log(10) CFU, compared to those in untreated controls, for both vancomycin-susceptible and -resistant (VanA and VanB) E. faecalis strains and >4 log(10) CFU for a methicillin-resistant S. aureus isolate. The glycylcycline was more efficacious at a lower administered dose in the rat model of endocarditis than was vancomycin. The efficacy of GAR-936 in this model was apparently not enhanced by a factor in rat serum, as was observed for vancomycin with a time-kill curve. The results of this study demonstrate the therapeutic potential of GAR-936 for the treatment of enterococcal and staphylococcal infections and warrant further investigation.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Endocarditis, Bacterial; Enterococcus faecalis; Male; Microbial Sensitivity Tests; Minocycline; Rats; Rats, Wistar; Tigecycline

The purpose of this study was to determine the penetration of minocycline and vancomycin into cardiac vegetations and to determine their efficacy in a rabbit model of endocarditis caused by oxacillin-resistant Staphylococcus aureus. Animals were randomized into three groups: control (no antibiotic), minocycline (6 mg/kg given intravenously every 8 h), and vancomycin (50 mg/kg given intravenously every 8 h). Penetration of the antibiotics into aortic valve vegetations was determined by using the tissue/serum area under the concentration-time curve ratio. The reductions in the bacterial density of the vegetations caused by both vancomycin (4.8 +/- 1.2 CFU/g) and minocycline (5.3 +/- 1.6 CFU/g) were significantly different from that of controls (8.7 +/- 1.8 CFU/g). Although the penetration of minocycline was twice that of vancomycin, they were equally effective in reducing the bacterial density of the vegetations, since the concentrations of both agents in tissue remained above their MICs for oxacillin-resistant S. aureus. For organisms for which the MICs are higher, however, these penetration differences may result in treatment differences.

Topics: Animals; Aortic Valve; Endocarditis, Bacterial; Female; Microbial Sensitivity Tests; Minocycline; Oxacillin; Penicillin Resistance; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tissue Distribution; Vancomycin

Topics: Endocarditis, Bacterial; Heart Valve Prosthesis; Humans; Male; Middle Aged; Minocycline; Staphylococcal Infections; Tetracyclines

Topics: Child, Preschool; Endocarditis, Bacterial; Heart Valve Prosthesis; Humans; Male; Methicillin; Minocycline; Mitral Valve; Mitral Valve Insufficiency; Penicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Tetracyclines

Topics: Adult; Aged; Ampicillin; Cephalosporins; Child; Chloramphenicol; Drug Therapy, Combination; Endocarditis, Bacterial; Erythromycin; Female; Gastrointestinal Diseases; Gentamicins; Humans; Kanamycin; Lincomycin; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Oxacillin; Penicillin G; Streptococcal Infections; Streptococcus; Streptomycin; Tetracycline; Urologic Diseases; Vancomycin