Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies.

INTRODUCTION: The emergence of carbapenemase resistant Gram-negative is designated as an 'urgent' priority of public health. Carbapenemase producing Klebsiella pneumoniae (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome. AREAS COVERED: This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel ß-lactam/ß-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed. EXPERT OPINION: Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing K. pneumoniae infections. However, are inactive against metallo-ß-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active in vitro against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant K. pneumoniae.

Emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in KPC-2-producing Klebsiella pneumoniae of sequence type 39 during treatment.

Three ceftazidime-avibactam-resistant KPC-2-producing Klebsiella pneumoniae strains of ST39 were isolated in Greece, from rectal swabs of three patients after 10-15 days of treatment. The patients were treated with ceftazidime-avibactam as monotherapy or in combination with colistin. Two of these strains harbored a D179Y or a D179V substitution in the Ω loop of KPC-2, corresponding to KPC-33, or to the novel KPC-57, respectively. The third strain had a 15 amino acid insertion after position 259 in the KPC-2, corresponding to KPC-44.

Lipid A profiling and metabolomics analysis of paired polymyxin-susceptible and -resistant MDR Klebsiella pneumoniae clinical isolates from the same patients before and after colistin treatment.

BACKGROUND: The increased incidence of polymyxin-resistant MDR Klebsiella pneumoniae has become a major global health concern. OBJECTIVES: To characterize the lipid A profiles and metabolome differences between paired polymyxin-susceptible and -resistant MDR K. pneumoniae clinical isolates. METHODS: Three pairs of K. pneumoniae clinical isolates from the same patients were examined [ATH 7 (polymyxin B MIC 0.25 mg/L) versus ATH 8 (64 mg/L); ATH 15 (0.5 mg/L) versus ATH 16 (32 mg/L); and ATH 17 (0.5 mg/L) versus ATH 18 (64 mg/L)]. Lipid A and metabolomes were analysed using LC-MS and bioinformatic analysis was conducted. RESULTS: The predominant species of lipid A in all three paired isolates were hexa-acylated and 4-amino-4-deoxy-l-arabinose-modified lipid A species were detected in the three polymyxin-resistant isolates. Significant metabolic differences were evident between the paired isolates. Compared with their corresponding polymyxin-susceptible isolates, the levels of metabolites in amino sugar metabolism (UDP-N-acetyl-α-d-glucosamine and UDP-N-α-acetyl-d-mannosaminuronate) and central carbon metabolism (e.g. pentose phosphate pathway and tricarboxylic acid cycle) were significantly reduced in all polymyxin-resistant isolates [fold change (FC) > 1.5, P < 0.05]. Similarly, nucleotides, amino acids and key metabolites in glycerophospholipid metabolism, namely sn-glycerol-3-phosphate and sn-glycero-3-phosphoethanolamine, were significantly reduced across all polymyxin-resistant isolates (FC > 1.5, P < 0.05) compared with polymyxin-susceptible isolates. However, higher glycerophospholipid levels were evident in polymyxin-resistant ATH 8 and ATH 16 (FC > 1.5, P < 0.05) compared with their corresponding susceptible isolates. CONCLUSIONS: To our knowledge, this study is the first to reveal significant metabolic perturbations associated with polymyxin resistance in K. pneumoniae.

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment.

OBJECTIVES: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. METHODS: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. RESULTS: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). CONCLUSIONS: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.

Efficacy of tigecycline alone and in combination with gentamicin in the treatment of experimental endocarditis due to linezolid-resistant Enterococcus faecium.

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.

Cefditoren: Comparative efficacy with other antimicrobials and risk factors for resistance in clinical isolates causing UTIs in outpatients.

BACKGROUND: To investigate a possible role of Cefditoren, a recently marketed in Greece third-generation oral cephalosporin in urinary infections of outpatients. METHODS: During a multicenter survey of Enterobacteriaceae causing UTIs in outpatients during 2005-2007, Cefditoren MICs were determined by agar dilution method in a randomly selected sample of uropathogens. Susceptibility against 18 other oral/parenteral antimicrobials was determined according to Clinical and Laboratory Standards Institute methodology. RESULTS: A total of 563 isolates (330 Escherichia coli, 142 Proteus mirabilis and 91 Klebsiella spp) was studied; MIC50/MIC90 of Cefditoren was 0.25/0.5 mg/L respectively, with 97.1% of the isolates being inhibited at 1 mg/L. All 12 strains producing ESBLs or AmpC enzymes were resistant to cefditoren. Susceptibility rates (%) for amoxicillin/clavulanic acid, cefuroxime axetil, cefotaxime, ciprofloxacin, trimethoprim/sulfamethoxazole and fosfomycin were 93.1- 94.1- 96.8-93.1-71.9 and 92.8% respectively. Cefditoren MIC was significantly higher in nalidixic/ciprofloxacin non-susceptible strains; resistance to cefditoren was not associated with resistance to mecillinam, fosfomycin nitrofurantoin and aminoglycosides. Multivariate analysis demonstrated history of urinary infection in the last two weeks or three months as risk factors for cefditoren resistance. CONCLUSIONS: Cefditoren exhibited enhanced in vitro activity against the most common uropathogens in the outpatient setting, representing an alternative oral treatment option in patients with risk factors for resistance to first-line antibiotics.

Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

BACKGROUND: Extended-spectrum ß-lactamases (ESBLs) have emerged as an important mechanism of ß-lactam resistance among community uropathogens. We characterized the ESBLs of a collection of Escherichia coli isolates recovered from outpatients with urinary tract infection during nationwide surveillance conducted from 2005 to 2006 in Greece, and evaluated the in vitro activity of mecillinam and mecillinam/clavulanate against them. MATERIALS AND METHODS: ESBLs were characterized with PCR and sequencing. In vitro interactions were evaluated with agar dilution with and without clavulanate (4 mg/L) using an inoculum of 10(4) or 10(6) cfu/spot as well as with time-kill methodology. RESULTS: Among 48 ESBL producers, 47 (97.9%) were susceptible to mecillinam. CTX-M-type enzymes were produced by 87.2%, with CTX-M-3 being the most prevalent. SHV enzymes were found in 10.6%, VEB enzymes in 2.1%, TEM enzymes in 19.2% and OXA-type enzymes in 12.8%. Synergy with clavulanate was detected in 60.4% using the agar dilution method and in 43.8% using the time-kill methodology. An inoculum effect was detected in 64.6% of isolates, but this phenomenon was inverted and synergy was evidenced for 85.4% with clavulanate. When a high inoculum was used, 60.4% (29/48) were resistant to mecillinam, but 97.9% (47/48) were susceptible in the presence of clavulanate. CONCLUSIONS: CTX-M-type enzymes were the most prevalent among ESBL-producing E. coli uropathogens in Greece. Mecillinam may be useful in uncomplicated cystitis caused by ESBL producers with low MICs. The addition of the inhibitor could improve and extend the activity of mecillinam, even in the setting of infection with a high bacterial inoculum, and merits clinical evaluation.

The value of successive Infecton scans in assessing the presence of chronic bone and joint infection and in predicting its evolution after treatment and after a prolonged follow-up.

OBJECTIVE: Our objective was to monitor the evolution of bone and/or joint infections with the aid of successive radiolabelled ciprofloxacin (Infecton) scans during antimicrobial treatment and to compare the results of an Infecton scan at the end of therapy with the respective results of clinical evaluation, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in predicting resolution or recurrence of infection after a long period of posttreatment follow-up. METHODS: Thirty-three patients with documented bone and/or joint infection were subjected to successive Infecton scans on two or three visits. Infecton scans were evaluated visually and scored accordingly. Clinical evaluation was scored by the referring clinicians. ESR and CRP values were evaluated independently. A minimum of 2-year free-of-infection follow-up after discontinuation of the antibiotic treatment served as a measure of successful antimicrobial therapy and nonrecurrence of infection. Statistics included survival analysis (Cox regression). RESULTS: During follow-up, five patients in the study presented with recurrence, and three died as a result of an irrelevant cause. The remaining patients were followed up for a median of 108 months (range 97-132 months) without any signs of recurrence of infection. Recurrence of infection was 4.2 times more likely to occur in patients with positive Infecton scans [hazard ratio (HR): 4.2, confidence intervals 95%: 1.39-12.67, P=0.011]. Infecton had the highest sensitivity (83.3%), accuracy (69.69%) and negative predictive value (94.74%), whereas CRP had the highest specificity (76.92%). CONCLUSION: Infecton scintigraphy proved to be more sensitive and accurate and had a higher negative predictive value compared with clinical evaluation, ESR and CRP in predicting infection resolution or recurrence in patients with chronic bone and joint infections.

An outbreak of infection due to beta-Lactamase Klebsiella pneumoniae Carbapenemase 2-producing K. pneumoniae in a Greek University Hospital: molecular characterization, epidemiology, and outcomes.

BACKGROUND: We describe the emergence and spread of Klebsiella pneumoniae carbapenemase 2 (KPC-2)-producing K. pneumoniae at a Greek University hospital. METHODS: Isolates with a carbapenem minimum inhibitory concentration >1 microg/mL and a negative EDTA-imipenem disk synergy test result were submitted to boronic acid disk test and to polymerase chain reaction (PCR) for KPC gene and sequencing. Records from patients who had KPC-2-producing K. pneumoniae isolated were retrospectively reviewed. Clinical isolates were submitted to molecular typing using pulsed-field gel electrophoresis, and the beta-lactamase content was studied using isoelectric focusing and PCR. RESULTS: From January 2007 through December 2008, 50 patients (34 in the intensive care unit [ICU]) were colonized (n = 32) or infected (n = 18) by KPC-2-producing K. pneumoniae. Increasing prevalence of KPC-2-producing K. pneumoniae coincided with decreasing prevalence of metallo-beta lactamase-producing isolates in our ICU. Multidrug resistance characterized the studied isolates, with colistin, gentamicin, and fosfomycin being the most active agents. Besides KPC-2, clinical isolates encoded TEM-1-like, SHV-11, SHV-12, CTX-M-15, and LEN-19 enzymes. Four different clonal types were detected; the predominant one comprised 41 single patient isolates (82%). Sporadic multiclonal cases of KPC-2-producing K. pneumoniae infection were identified from September 2007 through May 2008. The outbreak strain was introduced in February 2008 and disseminated rapidly by cross-transmission; 38 patients (76%) were identified after August 2008. Fourteen cases of bacteremia, 2 surgical site infections, 2 lower respiratory tract infections (1 bacteremic), and 1 urinary tract infection were identified. Most patients received a colistin-containing combination treatment. Crude mortality was 58.8% among ICU patients and 37.5% among non-ICU patients, but attributable mortality was 22.2% and 33.3%, respectively. CONCLUSIONS: The emergence of KPC-2-producing K. pneumoniae in Greek hospitals creates an important challenge for clinicians and hospital epidemiologists, because it is added to the already high burden of antimicrobial resistance.

Acute uncomplicated cystitis: from surveillance data to a rationale for empirical treatment.

The objectives of this study were to explore the epidemiological features and resistance rates in uropathogens isolated from cases of acute uncomplicated cystitis (AUC) in Greece, and subsequently to guide empirical treatment. Urine samples from outpatients aged >16 years were cultured and for each uropathogen isolated non-susceptibility to orally administered antimicrobial agents was defined. Demographic and clinical data were provided in questionnaire form. From January 2005 to March 2006 a total of 1936 non-duplicate positive urinary cultures were collected and 889 AUC cases were evaluated. Escherichia coli was the main aetiological agent (83%). In the AUC group, non-susceptibility rates for E. coli isolates were as follows: amoxicillin 25.8%; co-trimoxazole 19.2%; cefalothin 14.9%; nitrofurantoin 10.7%; amoxicillin/clavulanic acid 5.2%; nalidixic acid 6%; mecillinam 3.4%; ciprofloxacin 2.2%; cefuroxime 1.7%, and fosfomycin 1.6%. Amoxicillin and/or co-trimoxazole use in the previous 3 months was significantly associated with isolation of a co-trimoxazole-resistant E. coli isolate. The same applied for previous use of a fluoroquinolone agent and isolation of a ciprofloxacin-resistant E. coli isolate. In conclusion, increased co-trimoxazole non-susceptibility rates undermine its use as a first-line agent in empirical treatment, especially in cases of recent use of co-trimoxazole and/or amoxicillin. Fluoroquinolones display potent in vitro activity against community uropathogens, but prudent use is warranted for uncomplicated infections. Mecillinam and nitrofurantoin could serve as effective front-line agents in an effort to design fluoroquinolones-sparing regimens.

Tigecycline in the treatment of infections from multi-drug resistant gram-negative pathogens.

OBJECTIVE: This observational retrospective study aims to present early experience with tigecycline (TIG) in the treatment of infections due to multi-drug resistant (MDR) microorganisms. METHODS: Adult patients included, received TIG for >5 days either as monotherapy (M group) or as presumed active monotherapy (PAM group). In the PAM group, all co-administered antimicrobial(s) were resistant in vitro against the targeted pathogen(s) or had been clinically and microbiologically failing after >or=5 days of therapy despite in vitro susceptibility. RESULTS: Forty-five patients (35 in ICU) were treated for 28 Acinetobacter baumannii and 23 Klebsiella pneumoniae infections [21 ventilator-associated and healthcare-acquired pneumonia (VAP/HCAP), 10 bloodstream infections (BSI) and 14 surgical infections (SI)]. Successful overall clinical outcome was 80%, i.e. 81.8% in M group, 78.3% in PAM group, 90.5% in VAP/HCAP, 80% in BSI, 64.3% in SI and 85% in the cases with septic shock. Superinfections from Enterobacteriaceae inherently resistant to tigecycline occurred in 31.8% of M and 13% of PAM group (p<0.001). CONCLUSION: TIG represents a promising option in infections from MDR pathogens, however, further clinical experience is required.

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.

Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a synthetic carrier of calcium sulphate (Stimulan) releasing moxifloxacin.

The objectives of this study were to assess the efficacy of a synthetic semihydrate form of calcium sulphate (Stimulan) in experimental bone infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Osteomyelitis was induced after inoculation of the test pathogen in the left tibia of 72 New Zealand rabbits assigned to the following groups: 18 control rabbits (Group A); 18 rabbits with Stimulan implanted (Group B); and 36 rabbits with moxifloxacin-impregnated Stimulan implanted (Group C). Rabbits were sacrificed at weekly intervals and cancellous bone was harvested for histopathology and for estimation of bacterial growth and concentrations of moxifloxacin. Bacterial growth from cancellous bone of Group C was significantly lower than the respective growth of Groups A and B on all days of sacrifice. The main histological finding of animals in all three groups was a moderate to intense inflammatory reaction accompanied by fibrosis. The degree of fibrosis was higher in Group C compared with both other groups. Infiltration by giant cells was also observed, which was greater in Group C on Day 42. Antibiotic levels in bone were higher for bone samples closer to the site of implantation. In conclusion, Stimulan admixed with 10% moxifloxacin was very effective in achieving complete eradication of the causative pathogen in experimental osteomyelitis caused by MRSA.

Screening for resistant gram-negative microorganisms to guide empiric therapy of subsequent infection.

OBJECTIVE: To define the potential of resistant gram-negative colonization surveillance to predict etiology of subsequent infection and improve adequacy of empiric antimicrobial treatment. DESIGN: Retrospective cohort study. SETTING: A mixed medical-surgical six-bed intensive care unit (ICU), from November 2003 to December 2006. PATIENTS: All patients having at least one episode of ventilator-associated pneumonia (VAP) or bloodstream infection (BSI) caused by a resistant gram-negative pathogen during the study period. INTERVENTIONS: Colonization surveillance of the respiratory tract and gastrointestinal tract was systematically performed in all ICU patients. Tracheal aspirates were obtained twice weekly and rectal swabs once weekly. Both tracheal and rectal samples were cultured in antibiotic-enriched media (containing ceftazidime, ciprofloxacin, imipenem or piperacillin/tazobactam), to focus on resistant gram-negative pathogen isolation. MEASUREMENTS AND RESULTS: Colonization concordance between resistant, gram-negative pathogens of infectious episodes and previous, recent (

Efficacy and pharmacodynamics of linezolid, alone and in combination with rifampicin, in an experimental model of methicillin-resistant Staphylococcus aureus endocarditis.

OBJECTIVES: To evaluate the efficacy of oral linezolid, with or without rifampicin, on valve vegetations and secondary foci of infection compared with vancomycin, in the absence or presence of rifampicin, in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. METHODS: Treatment groups were controls (n = 16), linezolid (n = 15), vancomycin (n = 15), linezolid and rifampicin (n = 15), vancomycin and rifampicin (n = 13), linezolid relapse (n = 11) and vancomycin relapse (n = 9). Therapy lasted 5 days in all groups, with survival of animals in the linezolid relapse and vancomycin relapse groups being recorded for an additional 5 days. Blood was drawn to determine the linezolid concentration, and valve vegetations, and kidney, liver, lung and spleen segments were collected for culture. RESULTS: Survival in each individual group was higher than that in the control group; bacterial load in valve vegetations was reduced by all treatment regimens, with linezolid exhibiting bactericidal effects. Bactericidal activity of linezolid was noted in all secondary foci of infection except the lung, where only the combination of rifampicin with linezolid was bactericidal. CONCLUSIONS: Orally administered linezolid is effective in limiting bacterial growth in the secondary foci of endocarditis. Co-administration of rifampicin favoured the suppression of bacterial growth in the lung.

Doripenem: an expected arrival in the treatment of infections caused by multidrug-resistant Gram-negative pathogens.

BACKGROUND: Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing medical threat, are almost absent from the future pharmaceutical pipeline. OBJECTIVE: This drug evaluation focuses on the position of doripenem, a novel forthcoming carbapenem. Mechanisms of resistance and new drugs with anti-Gram-negative activity are also briefly reviewed. METHODS: Literature search was performed for new carbapenems, new antibiotics, doripenem, metallo-beta-lactamase inhibitors, multidrug-resistant pathogens, antipseudomonal antibiotics and multidrug-resistant epidemiology. RESULTS: Doripenem possesses a broad spectrum of activity against Gram-negative bacteria, similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem exhibits rapid bactericidal activity with 2 - 4-fold lower MIC values, compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic applications could offer a treatment opportunity against strains exhibiting borderline resistance to doripenem. Stability against numerous beta-lactamases, low adverse event potential and more potent in vitro antibacterial activity against P. aeruginosa and A. baumanni compared to the existing carbapenems, are its principal features.

Local treatment of experimental Pseudomonas aeruginosa osteomyelitis with a biodegradable dilactide polymer releasing ciprofloxacin.

A biodegradable system of poly-D,L-dilactide releasing ciprofloxacin was assessed in a Pseudomonas aeruginosa osteomyelitis model after inoculation of the test pathogen into the left tibia of 76 New Zealand White rabbits; 31 were controls (group A), and 45 were implanted with the polymer at the infection site (group B). The rabbits were killed on a weekly basis, and cancellous bone was harvested for histopathology and for estimation of bacterial growth and the concentrations of ciprofloxacin. Tibial X ray was performed immediately before the animals were killed. The total number of fistulas with purulent discharge that developed after inoculation of the pathogen was counted, and fistulas with purulent discharge were found in 16 animals in group A (51.6%) and 3 animals in group B (6.7%) (P < 0.0001). The animals in group A had a profound loss of body weight compared to the animals in group B. The main radiological finding was the presence of sequestra in 25 animals (80.6%) in group A and 6 animals in group B (13.3%) (P < 0.0001). The bacterial load in group B was significantly reduced compared to that in group A, possibly due to the prolonged local antibiotic release at concentrations exceeding even 80 times the MIC for the test pathogen. The histology of animals killed after week 49 revealed a mild inflammatory reaction accompanied by diffuse fibrosis and new bone formation in group A animals and the presence of small polymer particles in group B animals. It is concluded that the system described achieved eradication of the pathogen, accompanied by clinical and radiologically confirmed benefits, so this treatment may be a candidate for the management of difficult orthopedic infections.

Current therapies for pseudomonas aeruginosa.

Based on the worldwide prevalence of multidrug-resistant strains of Pseudomas aeruginosa and the fact that no newer antipseudomonal agents are available, this article aims to investigate therapeutic solutions for combating infections caused by P aeruginosa, including multidrug-resistant strains. The article focuses mainly on colistin, the re-emerging old antibiotic that possesses prominent antipseudomonal activity in vitro and on doripenem, a newer carbapenem that seems to be close to its global marketing. Regarding older antipseudomonal antibiotics that have been reviewed extensively, only newer aspects on their use are considered in this article.

Impact of an antibiotic restriction policy on the antibiotic resistance patterns of Gram-negative microorganisms in an Intensive Care Unit in Greece.

The purpose of this study was to investigate the influence of an antibiotic policy programme based on restriction of the empirical use of fluoroquinolones and ceftazidime on the susceptibilities of Gram-negative microorganisms in a general Intensive Care Unit (ICU). The epidemiology of infections caused by the predominant ICU pathogens, i.e. Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, and their resistance patterns as well as antibiotic consumption were recorded for a 6-month period. An antibiotic restriction policy including ceftazidime and quinolones was applied. After an 18-month period of protocol application, the same parameters were recorded for another 6-month period. Consumption of restricted and overall antibiotics was reduced by 92.5% and 55.4%, respectively. Susceptibilities to ciprofloxacin of the three predominant infection-causing Gram-negative bacilli were significantly increased. Ceftazidime showed an increase in susceptibility only for P. aeruginosa. Similar rates of infectious episodes were recorded in the two periods and no differences were observed either in overall mortality or in ICU ecology as expressed by the type of microorganisms implicated in colonisation and/or infection. The reported data suggest that an antibiotic restriction policy can significantly reduce antimicrobial consumption and antimicrobial resistance rates, although the latter effect can be also influenced by the prevalent resistance mechanisms and the prevalence of imported resistance.

Dexamethasone as adjuvant therapy to moxifloxacin attenuates valve destruction in experimental aortic valve endocarditis due to Staphylococcus aureus.

Although the beneficial effects of dexamethasone have frequently been investigated in various serious-infection settings, insufficient data on valve histology and cardiac function for infective endocarditis are available. The efficacy of moxifloxacin for the treatment of experimental aortic valve endocarditis due to methicillin-susceptible Staphylococcus aureus and the long-term effects of dexamethasone were evaluated in the current study. Sixty-eight rabbits were randomly assigned to four groups: A, B, C, and D. Group A consisted of 18 animals and functioned as a control group. Groups B and C consisted of 11 and 23 subjects, respectively, which received moxifloxacin for 5 days in a human-like pharmacokinetic simulation. Group D consisted of 16 animals that were administered moxifloxacin plus dexamethasone (0.25 mg/kg of body weight twice a day intravenously). The group B animals were sacrificed a day after the completion of treatment, and group C and D animals were sacrificed after 12 days in order to monitor any possible relapse and allow microbiological, histopathological, and echocardiographic evaluation of the long-term effects of glucocorticoids. No differences in survival, sterilization rates, or inflammatory infiltration and calcification of valve tissue were observed among the treated groups. However, the degrees of valve damage and collagenization were significantly worse, the fibroblast content was higher, and fractional shortening of the left ventricle fluctuated significantly in group C compared to group D (all groups, P < 0.05). We concluded that dexamethasone treatment for experimental S. aureus endocarditis attenuates valve destruction and preserves overall cardiac function without impeding the efficacy of moxifloxacin.