minocycline and Pseudomonas-Infections

Acinetobacter baumannii and Pseudomonas aeruginosa are gram-negative pathogens that target immunocompromised patients. They express a variety of determinants that confer resistance to a broad array of antimicrobial agents. Mechanisms of resistance include impaired entry through the bacterial outer membrane, production of antibiotic-modifying enzymes, active efflux, and target mutations that reduce antimicrobial affinity. It has been a challenge to identify new agents that have activity against the more resistant variants of these species. Doripenem is a carbapenem in phase 3 trials that has excellent activity against P. aeruginosa and A. baumannii. However, it lacks activity against strains that express resistance to the currently available carbapenems. Tigecycline is a newly licensed glycylcycline that lacks activity against P. aeruginosa but has encouraging activity against many A. baumannii isolates. Resistance to tigecycline can emerge during therapy, however, and is due to expression of multidrug efflux pumps.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Infective Agents; Biofilms; Carbapenems; Clinical Trials as Topic; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Immunocompromised Host; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline

Topics: Acinetobacter baumannii; Acinetobacter Infections; Alginates; Animals; Anti-Bacterial Agents; Burns; Female; Gentamicins; Hydrogels; Microbial Sensitivity Tests; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus; Swine; Vancomycin; Wound Healing; Wound Infection

Pseudomonas aeruginosa has been detected in the lungs of ∼50% of patients with cystic fibrosis (CF), including 20% of adult CF patients. The majority of these adult patients harbor multi-drug resistant (MDR) strains, limiting the available treatment options. Silver has long been used as a broad-spectrum antimicrobial agent with a low incidence of resistance. Despite low toxicity, poor availability of silver cations mandates a high dosage to effectively eradicate infections. To address this shortcoming of silver, nanoparticles have been used as delivery devices to improve treatment outcomes. Furthermore, studies have demonstrated that synergistic combinations with careful dose calibrations and efficient delivery systems result in superior antimicrobial activity while avoiding potential side effects of both therapeutics. Here 4-epi-minocycline, a metabolite of minocycline, was identified as an active antimicrobial against P. aeruginosa using a high-throughput screen. The antimicrobial activities of 4-epi-minocycline, minocycline, and silver acetate against clinical isolates of P. aeruginosa obtained from CF patients were evaluated in vitro. Next, the synergistic activity of the silver/minocycline combination against P. aeruginosa isolates was investigated using checkerboard assays and identified with end-point colony forming unit determination assays. Finally, nanoparticles coloaded with minocycline and silver were evaluated in vitro for antimicrobial activity. The results demonstrated that both silver and minocycline are potent antimicrobials alone and that the combination allows a reduced dosage of both therapeutics to achieve the same antimicrobial effect. Furthermore, the proposed synergistic silver/minocycline combination can be coloaded into nanoparticles as a next-generation antibiotic to combat the threats presented by MDR pathogens.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Metal Nanoparticles; Minocycline; Polyphosphates; Pseudomonas aeruginosa; Pseudomonas Infections; Silver

Burn and blast injuries are frequently complicated by invasive infections, which lead to poor wound healing, delay in treatment, disability, or death. Traditional approach centers on early debridement, fluid resuscitation, and adjunct intravenous antibiotics. These modalities often prove inadequate in burns, where compromised local vasculature limits the tissue penetration of systemic antibiotics. Here, we demonstrate the treatment of infected burns with topical delivery of ultrahigh concentrations of antibiotics. Standardized burns were inoculated with Staphylococcus aureus or Pseudomonas aeruginosa. After debridement, burns were treated with either gentamicin (2 mg/mL) or minocycline (1 mg/mL) at concentrations greater than 1,000 times the minimum inhibitory concentration. Amount of bacteria was quantified in tissue biopsies and wound fluid following treatment. After six days of gentamicin or minocycline treatment, S. aureus counts decreased from 4.2 to 0.31 and 0.72 log CFU/g in tissue, respectively. Similarly, P. aeruginosa counts decreased from 2.5 to 0.0 and 1.5 log CFU/g in tissue, respectively. Counts of both S. aureus and P. aeruginosa remained at a baseline of 0.0 log CFU/mL in wound fluid for both treatment groups. The findings here demonstrate that super-therapeutic concentrations of antibiotics delivered topically can rapidly reduce bacterial counts in infected full-thickness porcine burns. This treatment approach may aid wound bed preparation and accelerate time to grafting.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Burns; Debridement; Disease Models, Animal; Female; Gentamicins; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus; Swine; Wound Healing; Wound Infection

The widespread use of tigecycline raises the question of increasing infection rates of Pseudomonas aeruginosa (PA) in ICUs which are not affected by this antibiotic.. The aim of this study was to determine if treatment with tigecycline is a risk factor for PA infection in ICU patients.. A retrospective and observational study was conducted at Erciyes University Hospital, Turkey, between 2008 and 2010. The Erciyes University Hospital is a 1300-bed tertiary care facility. The patients included in this study were hospitalized in four adult ICUs. Patients with PA infections (case group) were compared with patients with nosocomial infection other than PA (control group).. A total of 1,167 patients with any nosocomial infections were included in the study. Two hundred and seventy eight (23.8%) of the patients had PA infection during their ICU stay. Fifty nine patients (21.2%) in the case group received tigecycline before developing PA infections, which were found to be significantly more frequent than in the controls (p < 0.01). Multivariate analysis showed that risk factors for PA infection were previous tigecycline use (4 times), external ventricular shunt (4.2 times), thoracic drainage catheter (2.5 times) and tracheostomy (1.6 times).. Our results contribute to the need for new studies to determine the safety of tigecycline use, especially for the treatment of critically ill patients. Since tigecycline seems to be an alternative for the treatment of multidrug resistant (MDR) microorganisms, rational use of this antibiotic in ICU patients is essential.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Child; Child, Preschool; Female; Hospitals, University; Humans; Infant; Male; Middle Aged; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Assessment; Tertiary Care Centers; Tigecycline; Turkey; Young Adult

Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Treatment Outcome

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that is refractory to a variety of current antimicrobial therapeutic regimens. Complicating treatment for such infections is the ability of P. aeruginosa to form biofilms, as well as several innate and acquired resistance mechanisms. Previous studies suggest iron plays a role in resistance to antimicrobial therapy, including the efficacy of an FDA-approved iron chelator, deferasirox (DSX), or Gallium, an iron analog, in potentiating antibiotic-dependent killing of P. aeruginosa biofilms. Here, we show that iron-replete conditions enhance resistance of P. aeruginosa nonbiofilm growth against tobramycin and tigecycline. Interestingly, the mechanism of iron-enhanced resistance to each of these antibiotics is distinct. Whereas pyoverdine-mediated iron uptake is important for optimal resistance to tigecycline, it does not enhance tobramycin resistance. In contrast, heme supplementation results in increased tobramycin resistance, while having no significant effect on tigecycline resistance. Thus, nonsiderophore bound iron plays an important role in resistance to tobramycin, while pyoverdine increases the ability of P. aeruginosa to resist tigecycline treatment. Lastly, we show that iron increases the minimal concentration of tobramycin, but not tigecycline, required to eradicate P. aeruginosa biofilms. Moreover, iron depletion blocks the previous observed induction of biofilm formation by subinhibitory concentrations of tobramycin, suggesting iron and tobramycin signal through overlapping regulatory pathways to affect biofilm formation. These data further support the role of iron in P. aeruginosa antibiotic resistance, providing yet another compelling case for targeting iron acquisition for future antimicrobial drug development.

Topics: Anaerobiosis; Anti-Bacterial Agents; Biofilms; Cation Transport Proteins; Drug Resistance, Bacterial; Heme; Iron; Iron Chelating Agents; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Siderophores; Tigecycline; Tobramycin

Tigecycline has broad spectrum antimicrobial activity and is approved for complicated intra-abdominal infections, complicated skin and soft tissue infections, and community-acquired pneumonia. There are few data on clinical experience of tigecycline in hospital-acquired pneumonia (HAP) and Acinetobacter spp. infection.. A retrospective study was performed at eight hospitals in Korea from May 2009 to January 2010. Adult patients treated with tigecycline regardless of their source of infection or pathogens were enrolled.. Tigecycline was administered in 108 patients. Pneumonia was the most common infection (43.5%), followed by skin and soft tissue infections (20.4%). Acinetobacter baumannii was isolated from 83 patients (76.9%) accounting for 50.3% of isolated pathogens, showing a resistance rate of 67.5% to carbapenems. Superinfection was identified in 32 patients (29.6%). Pseudomonas aeruginosa was most common microorganism causing superinfection (46.9%). Overall 30-day mortality rate was 52.9%. Thirty-day mortality rate of HAP and Acinetobacter spp. infection was 60.5% and 59.4%, respectively.. Tigecycline can be considered as an alternative therapy in patients with HAP or infections caused by Acinetobacter spp., especially extensively drug-resistant A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Coinfection; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Minocycline; Pseudomonas aeruginosa; Pseudomonas Infections; Republic of Korea; Retrospective Studies; Survival Rate; Tigecycline

Our aim was to determine the prevalence of multidrug resistance of Acinetobacter baumannii and other pathogens at a tertiary-care teaching hospital in Mexico over a 3-year period. Clinical isolates of A. baumannii (n = 550), Pseudomonas aeruginosa (n = 250), some Enterobacteriaceae species (n = 500) and Staphylococcus aureus (n = 250) collected over a 3-year period were included. Susceptibility tests were performed by the broth microdilution method. 74% of A. baumannii, 40% of Escherichia coli, 34% of P. aeruginosa, 22% of Klebsiella pneumoniae, 9% of Enterobacter cloacae, and 7% of Serratia sp. were multidrug resistant. 59% of A. baumannii clinical isolates were meropenem-resistant. A. baumannii isolates from the lower respiratory tract were the most susceptible, followed by urine clinical isolates. Species from Enterobacteriaceae showed susceptibility rates higher than 90% to meropenem and tigecycline and Serratia sp. showed the highest susceptibility to the drugs evaluated. For P. aeruginosa, the most potent drug was levofloxacin, followed by meropenem and piperacillin-tazobactam. With regard to S. aureus, 96% of the isolates were susceptible to vancomycin, followed by tigecycline and minocycline (91% of strains susceptible). The high multidrug resistance observed underscores the need for surveillance of bacterial drug resistance.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Hospitals, Teaching; Humans; Klebsiella pneumoniae; Meropenem; Mexico; Microbial Sensitivity Tests; Minocycline; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcus aureus; Thienamycins; Tigecycline

A case of osteomyelitis caused by multidrug-resistant Pseudomonas aeruginosa is reported in a patient who underwent allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. The patient was successfully treated by prolonged administration of a full dose of colistin and tigecycline, and surgical curettage with the positioning of resorbable calcium sulfate pellets loaded with colistin.

Topics: Adult; Anti-Bacterial Agents; Bone Marrow Transplantation; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Minocycline; Osteomyelitis; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Transplantation, Homologous

Prosthetic valve endocarditis (PVE) is a relatively uncommon but very serious condition. As bacterial colonization of the prosthetic heart valve sewing cuff can be a prelude to the clinical occurrence of PVE, antimicrobial coating of the sewing cuff may be beneficial. The study aims were to examine the antimicrobial activity in vitro and anti-infective efficacy in vivo of prosthetic heart valve sewing cuffs coated with minocycline and rifampin.. Zones of inhibition by antimicrobial-coated sewing cuffs were assessed in vitro against Staphylococcus epidermidis, S. aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans. The ability of subcutaneously implanted devices coated with minocycline and rifampin to resist colonization and infection by P. aeruginosa was also examined in a rabbit model.. Antimicrobial-coated sewing cuffs produced zones of inhibition against all tested organisms. Coated devices were significantly less likely than uncoated devices to become colonized (2/24; 8% versus 20/24; 83%; p <0.001) or to cause device-related infection (0/24; 0% versus 18/24; 75%; p <0.001) and device-related abscess (0/24; 0% versus 10/24; 42%; p <0.001) due to P. aeruginosa.. Prosthetic heart valve sewing cuffs coated with minocycline and rifampin provide broad-spectrum antimicrobial activity in vitro, and are anti-infective in vivo against P. aeruginosa. These results encourage the clinical evaluation of these sewing cuffs.

Topics: Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antibiotics, Antitubercular; Coated Materials, Biocompatible; Drug Therapy, Combination; Heart Valve Prosthesis; In Vitro Techniques; Minocycline; Prosthesis Design; Prosthesis-Related Infections; Pseudomonas Infections; Rabbits; Rifampin

Our objective was to determine the in vitro activity of minocycline against isolates of Burkholderia cepacia (BC), Stenotrophomonas maltophilia (SM), and Pseudomonas aeruginosa (PA) cultured from the respiratory tract of patients with cystic fibrosis (CF). Cultures of BC, SM, and PA were isolated in a hospital bacteriology laboratory from the sputum or oropharyngeal cultures obtained from patients attending a Cystic Fibrosis Center, and were prospectively tested for in vitro sensitivity to minocycline by Kirby-Bauer disk diffusion. From January 1994 to July 1995, 116 cultures from 61 patients had at least one of the three pathogens; 9/61 (15%) patients had an isolate of BC, and 7/9 (78%) had an initial isolate sensitive to minocycline, of which 3 were sensitive only to minocycline; 2 cultures were resistant to all antibiotics. Four of 7 patients with BC were treated with minocycline; 3 patients developed resistant isolates 3-13 months after therapy. Five of 61 patients (8%) had an isolate of SM: 4/5 (80%) of these isolates were sensitive to minocycline, of which 1 was sensitive only to minocycline. Fifty-five of 61 patients (90%) had at least one PA isolate, with 112 morphotypes recovered from 90 cultures: 40/112 morphotypes (36%) were sensitive to minocycline, 65 (58%) were resistant, and 7 (6%) were intermediate in sensitivity. We conclude that the marked in vitro activity of minocycline against BC and SM isolated from patients with CF suggests that minocycline may have an adjunct role in the antimicrobial therapy of multidrug resistant, respiratory pathogens in CF.

Topics: Adolescent; Anti-Bacterial Agents; Burkholderia cepacia; Burkholderia Infections; Child; Child, Preschool; Cystic Fibrosis; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Male; Minocycline; Oropharynx; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Stenotrophomonas maltophilia; Tetracycline Resistance

A big problem of nosocomial infections is some refractory infections, so that present important nosocomial infections are deep infections by MRSA and weakly virulent gram-negative bacilli such as Pseudomonas aeruginosa, which are not susceptible to many antimicrobial agents. It is also noteworthy that MRSA can infect to both immunonormal and immunocompromised patients, although clinical signs of that infection are much more severe in the latters. On the other hand, weakly virulent bacilli can infect to only immunocompromised patients. Immunocompromised states are divided into two categories, namely general and local deficiencies. The mechanism of general immunodeficiency is mainly depend upon leukopenia or diminishment of phagocytic activity of them, and that of local immunodeficiency is bases on formation of biofilms which protect bacteria from phagocytosis and killing effect of antimicrobial agents. In this paper, it is emphasized that both countermeasure for nosocomial infections and adequate use of antimicrobial agents or immunomodulators are necessary to decrease number of patients with hospital infections.

Topics: Cross Infection; Disinfection; Granulocyte Colony-Stimulating Factor; Humans; Methicillin Resistance; Minocycline; Premedication; Pseudomonas Infections; Staphylococcal Infections; Vancomycin

Pseudomonas cepacia, considered a phytopathogenic organism for many years, has been shown recently to be widely distributed geographically. The hospital environment has become an important source of this organism but the resistance of Ps. cepacia to most antibiotics has made the treatment of infections a problem. One hundred per cent of the strains tested have proved to be sensitive to the sulphonamides and to novobiocin, 93.0% to the combination of trimethoprim and sulfamethoxazole (co-trimoxazole); 85.2% to minocycline; 77.8% to chloramphenicol and dibekacin and 44.4% to nalidixic acid. One hundred per cent of the strains exhibit resistance to ampicillin, cephalothin, cefamandole, cefoxitin, colistin, cefuroxime, tetracycline and cefazolin; 88.9% to amikacin, tobramycin and sisomycin; 85.2% to carbenicillin. The new beta-lactams, apalcillin, ceftazidime, N-formimidoyl-thienamycin, piperacillin, cefotaxime and azlocillin proved to be the most potent of the molecules tested, inhibiting 90% of the strains, at concentrations of 4, 8, 8, 8, 32 and 16 mg/l and 100% of the strains at 8, 16, 16, 32, 32 and 64 mg/l, respectively. In contrast to the usual sensitivity patterns of Pseudomonas spp, Ps. cepacia has been shown to be resistant to colistin, cefsulodin and the aminoglycosides. However, unlike Ps. aeruginosa, Ps. cepacia has been shown, by the dilution method, to be sensitive to co-trimoxazole, 92.3% of the strains being inhibited by 16 mg/l.

Topics: Anti-Bacterial Agents; Ceftazidime; Cross Infection; Drug Combinations; Drug Resistance, Microbial; Humans; Microbial Sensitivity Tests; Minocycline; Novobiocin; Pseudomonas; Pseudomonas Infections; Species Specificity; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Amino Sugars; Anti-Bacterial Agents; Bacteria; Candidiasis; Carbenicillin; Cephalosporins; Cryptococcosis; Drug Synergism; Flucytosine; Glycosides; Gonorrhea; Humans; Meningococcal Infections; Minocycline; Pseudomonas Infections; Spectinomycin; Sulfonamides; Tetracycline; Trimethoprim