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Biomedical subjects

G C Schito

Publications and source records attributed to G C Schito.

At least 19 recordsLinked to original sources

The importance of the development of antibiotic resistance in Staphylococcus aureus.

Hospital- and community-acquired Staphylococcus aureus infections pose a substantial burden in terms of morbidity, mortality and health care costs. The introduction of new antibiotics to counter this pathogen has frequently been closely followed by the emergence of resistant strains. Most significantly, S. aureus isolates resistant to beta-lactams have become common, and many of these are also resistant to beta-lactamase-resistant penicillins. The rapid spread of methicillin-resistant S. aureus (MRSA) clones across the world often results in hospital outbreaks, but implementation of appropriate control measures usually reduces prevalence to sporadic levels. However, the recent emergence of MRSA infections in the community, affecting patients with no established risk factors for MRSA acquisition, is likely to impact significantly on future strategies for control of nosocomial MRSA. In contrast to other antibiotic classes, S. aureus resistance to glycopeptides did not emerge until nearly 40 years after their clinical introduction, and as a result this drug class has remained the mainstay of treatment for MRSA infections. However, a number of vancomycin-intermediate S. aureus isolates have emerged worldwide and four fully resistant S. aureus isolates have been reported in the USA. This raises the concern that the current first-line treatment for MRSA infection may become ineffective in an increasing proportion of cases in the near future. New classes of antibiotic are urgently needed to treat infections with this growing population of multidrug-resistant S. aureus, and the recently introduced oxazolidinone linezolid and the cyclic lipopeptide daptomycin are welcome additions to the ever-narrowing range of therapies effective against this pathogen.

Aminoglycosides↗

Efficacy of N-acetyl-cysteine in combination with thiamphenicol in sequential (intramuscular/aerosol) therapy of upper respiratory tract infections even when sustained by bacterial biofilms.

A total of 102 patients with recurrent upper respiratory tract infections underwent microbiological exploration with appropriate sampling and direct biopsies of the infected sites. Therapy was then started and on day 1 each patient received two intramuscular injections of thiamphenicol glycinate acetylcysteinate (TGA). From day 2 to 10 sequential therapy with the same drug was continued employing TGA administered by aerosol. All putative etiologic agents recovered were susceptible to thiamphenicol and only 24 demonstrated the ability to produce in vitro biofilms. The organisms comprised 10 Staphylococcus aureus, 6 Streptococcus pyogenes, 4 Streptococcus pneumoniae and 3 Haemophilus influenzae. Of the 24 subjects in whom biofilms were demonstrated to be present in vivo by Scanning Electron Microscopy, clinical and bacteriological cure was obtained in 21 cases (87.5%) following sequential therapy with TGA. Failures were considered to be persistent signs and symptoms at day 15 after initiation of treatment and lack of eradication of 3 S. aureus strains, despite their in vitro susceptibility to thiamphenicol. Very few adverse events attributable to TGA were reported in this cohort of patients. In no case was discontinuation of treatment deemed necessary by the attending physician.

Acetylcysteine↗

Susceptibility of Streptococcus pneumoniae to penicillin, azithromycin and telithromycin (PROTEKT 1999-2003).

Isolates of Streptococcus pneumoniae collected over the first 4 years of the PROTEKT study were tested for susceptibility to penicillin, azithromycin and telithromycin. A total of 20,750 isolates were collected from 39 countries. Penicillin non-susceptibility rates were stable over the study period; overall, 21.8% of isolates were resistant. Azithromycin resistance increased from 31.0% in Year 1 to 36.3% in Year 4. Resistance rates for penicillin and azithromycin varied between countries and were highest in France, Spain, South Africa, USA and the Far East. Multidrug resistance in S. pneumoniae did not change significantly over the 4 years, with an overall rate of 38.6%. Telithromycin retained good activity against S. pneumoniae (0.1% of isolates resistant), including multidrug-resistant isolates.

Anti-Bacterial Agents↗

The Sentinel Project: an update on the prevalence of antimicrobial resistance in community-acquired respiratory Streptococcus pneumoniae and Haemophilus spp. in Italy.

A total of 460 Streptococcus pneumoniae and Haemophilus spp. collected from respiratory infections during 2000 was tested for their susceptibility to 15 selected antibiotics. Overall, penicillin resistance among pneumococci was 10.5%, while lack of susceptibility to macrolides, co-trimoxazole, tetracycline and chloramphenicol reached 35.2%, 26.2%, 22.6% and 6.0%, respectively. Amoxicillin/clavulanic acid and levofloxacin were the most potent compounds (100% and 99.9% susceptible strains, respectively). Among isolates of Haemophilus influenzae and Haemophilus parainfluenzae, beta-lactamase production (12.5% and 10%, respectively), and co-trimoxazole (19.9% and 40.0%) and clarithromycin (11.2% and 40.0%) resistance were the prevalent threats. This study confirms the trend observed in Italy since 1992: macrolide resistance among respiratory microorganisms is increasing, while several drugs including amoxicillin/clavulanic acid, third generation injectable cephalosporins and fluoroquinolones remain active on the great majority of these pathogens.

Community-Acquired Infections↗

Antibiotic susceptibility and serotype distribution in Streptococcus pneumoniae circulating in Italy: results of the SEMPRE surveillance study (2000-2002).

During 2000-2002, 20 clinical microbiology centres collected 1623 Streptococcus pneumoniae isolates. Susceptibility to penicillin, amoxicillin, amoxicillin/clavulanic acid, cefaclor, cefuroxime, cefotaxime, clarithromycin, ciprofloxacin, levofloxacin, rifampicin and teicoplanin was determined locally by the Etest and/or by the microdilution method by three co-ordinating centres. Total resistance to penicillin increased from 15.2% to 16.1% and macrolide resistance increased from 37.9% to 43.7%. Overall, the most effective drugs (>99% susceptible strains) were amoxicillin, amoxicillin/clavulanic acid, levofloxacin and rifampicin. The most frequent serotypes were: 23F (15.8%), 3 (10.8%) 14 (9.1%), 19F (9.1%), 6B (7.2%), 19A (6.9%) and 6A (4.8%). In conclusion, penicillin and macrolide resistance is increasing in Italy, whilst fluoroquinolone currently remains active. The most common serotypes circulating are included in the heptavalent conjugate vaccine, with the exception of type 3.

Anti-Bacterial Agents↗

Antimicrobial susceptibility patterns of contemporary pathogens from uncomplicated urinary tract infections isolated in a multicenter Italian survey: possible impact on guidelines.

During 2004 four Italian Laboratories assessed the prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in female out-patients. A total of 600 urine samples from individuals aged 18-65 were studied. The overall prevalence of Escherichia coli was 85.3%. Klebsiella pneumoniae, Staphylococcus saprophyticus, Proteus mirabilis, Enterococcus faecalis and other rarer species were far less represented. Determination of the antibiotic susceptibility pattern of the entire collection of E. coli (512 organisms) revealed that among the drugs analyzed ampicillin was the least active molecule with only 62.5% of the strains being inhibited. Amoxicillin-clavulanate and cefuroxime displayed a higher potency (87.7% and 89.2% respectively). Cotrimoxazole inhibited only 70.1% of the uropathogens. The three fluoquinolones tested had comparable activity ranging from 83.0% for ciprofloxacin, to 83.6% for levofloxacin and 84.9% for prulifloxacin, indicating an identical spectrum of cross resistance. Nitrofurantoin (96.7%) and fosfomycin (98.6%) were the most potent drugs. Against the whole collection of uropathogens, only cefuroxime, nitrofurantoin and fosfomycin overcame the threshold of 90% activity, with the fluoroquinolones and amoxicillin-clavulanate suffering from about 15% resistance. The results of this survey strongly support the conclusions of recent Italian guidelines concerning the best empiric treatment of UTI in this country today.

Adolescent↗

Predicting the clinical efficacy of generic formulations of ceftriaxone.

Time above MIC (T>MIC) is regarded as the best pharmacokinetic/pharmacodynamic (PK/PD) parameter for predicting the clinical efficacy of cephalosporins. The concentration of non-protein-bound proprietary ceftriaxone (Rocephin, Roche) in body fluids exceeds this PK/PD criterion for the treatment of Streptococcus pneumoniae respiratory infections. However, the pharmaceutical quality of several generic products may be inferior to Rocephin. We have calculated the variations in fluid concentrations of 34 generic formulations of ceftriaxone and, by mathematical modelling, the implications for attainment of recommended PK/PD criteria, specifically: Treatment of S. pneumoniae infections based on the time that non-protein-bound ceftriaxone concentration in pleural fluid exceeds the CLSI (NCCLS) breakpoint of 4 mg/L for identification of resistant isolates. Impact upon Monte Carlo simulations in plasma for the treatment of S. pneumoniae infections based on T>MIC for 50% dosing interval. Rocephin exceeded the required PK/PD parameters at the mean and two standard deviation levels in both investigations. In contrast, most generic products failed to achieve required PK/PD levels in both investigations. As a consequence, some generic formulations of ceftriaxone may increase risks of clinical failure and/or emergence of resistant isolates.

Anti-Bacterial Agents↗

In vitro activity of ertapenem against selected respiratory pathogens.

OBJECTIVES: The in vitro activity of ertapenem was evaluated in comparison to 21 selected agents against a large collection of recently isolated respiratory tract pathogens including: 180 Streptococcus pneumoniae, 100 Streptococcus pyogenes, 70 Haemophilus influenzae, 70 Moraxella catarrhalis, 100 methicillin-susceptible Staphylococcus aureus and 30 Klebsiella pneumoniae. Additional in vitro tests (time-kill curves with ertapenem alone and in combination with four other agents) for S. pneumoniae were carried out. METHODS: MIC determinations and time-kill curves were carried out following the procedures suggested by the NCCLS. RESULTS: According to NCCLS susceptibility breakpoints, ertapenem was comparable to the most potent compounds tested for all pathogens studied. Ertapenem was 100% active against penicillin-susceptible and -intermediate S. pneumoniae and against 60% of penicillin-resistant strains. Time-kill tests at 4x MIC confirmed a pronounced bactericidal potency of ertapenem against these organisms. Interactions of ertapenem with several other agents against pneumococci resulted in clear synergic interactions (98.4%). Indifference was extremely rare and antagonism was not observed. All S. pyogenes strains tested were inhibited by ertapenem, irrespective of their macrolide resistance phenotypes. Ertapenem was also fully active against H. influenzae (100% susceptible) and M. catarrhalis (MIC90 0.015-0.03 mg/L) even when capable of synthesizing beta-lactamases. Methicillin-susceptible S. aureus and K. pneumoniae, including extended-spectrum beta-lactamase-producing strains, were 100% susceptible to ertapenem. CONCLUSIONS: Our results indicate that ertapenem has a suitable spectrum of activity against organisms encountered in community-acquired bacterial respiratory tract infections.

Bacteria↗

Antimicrobial susceptibility profiles of Pseudomonas aeruginosa and Staphylococcus aureus isolated in Italy from patients with hospital-acquired infections.

Here we report the results of the Sentinel Project 2000 and give the susceptibility to selected antibiotics of 108 Pseudomonas aeruginosa and 108 Staphylococcus aureus strains isolated from patients with hospital-acquired lower respiratory tract infections. In P. aeruginosa, susceptibility to aztreonam and ciprofloxacin was lower than 50%. The resistance rate to beta-lactams was up to 25% and to amikacin 15.7%. Blood isolates showed 80-90% susceptibility to all antibiotics tested except for aztreonam and tobramycin. Overall, oxacillin resistance in S. aureus was 45%, reaching 64.3% among the bronchoalveolar lavage isolates, and 42.9% among the blood isolates. These worrying results confirm the need for continuous monitoring of bacterial resistance trends in the hospitals, mainly in ICUs.

Anti-Bacterial Agents↗

Comparative activity of telithromycin against macrolide-resistant isolates of Streptococcus pneumoniae: results of two years of the PROTEKT surveillance study.

UNLABELLED: The increase in resistance to macrolides has been linked with increasing use of these agents as empirical therapy for community-acquired respiratory tract infections (CARTIs). As part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance program, over 7600 Streptococcus pneumoniae isolates were collected worldwide from 1999-2001 and evaluated for macrolide resistance. Globally, macrolide resistance was 31-33%, with considerable inter-country variation (<10-88%) and particularly high prevalence in the Far East (>71%). In Europe, France had the most resistant isolates (>53%). The highest rates of macrolide resistance were seen in 0-2 year olds. Co-resistance to clindamycin (64%) and all beta-lactams (14-79%) was seen among macrolide-resistant isolates, but >99% of these isolates were susceptible to telithromycin, vancomycin and linezolid. There was considerable variation in the prevalence of erm(B) (56-64%) and mef(A) (30-35%): erm(B) was prevalent in Europe and mef(A) in North America. Globally, 5-7% isolates carried both mechanisms (erm(B)+mef(A)); of these, 47-65% were from South Korea. These double resistance isolates were >90% resistant to the beta-lactams, except amoxicillin-clavulanate. Clindamycin was active against >98% mef(A) but poorly active against erm(B) and erm(B)+mef(A) isolates. Telithromycin, vancomycin and linezolid were highly active (>99.5%) across all three genotypes. CONCLUSIONS: In vitro, telithromycin, vancomycin and linezolid are highly active against antibiotic-resistant strains of S. pneumoniae. Telithromycin may be a useful therapeutic alternative to macrolides for the treatment of CARTIs.

Acetamides↗

Why fosfomycin trometamol as first line therapy for uncomplicated UTI?

Uncomplicated urinary tract infection (UTI) is one of the most common conditions requiring diagnostic and therapeutic intervention. The aetiology and the treatment of these infectious diseases have changed little during last years of the 'antibiotic era'. Escherichia coli is the most prevalent uropathogen (85->90%) and treatment is aimed at eradicating the infection using shorter regimes that typically may employ a 3-day course with once-a-day dosing of a selected drug or a single dose of a particular efficacious antibiotic. Antibiotic resistance to commonly used agents, such as trimethoprim and ampicillin, often now exceeds 30-50%, while fosfomycin trometamol, despite many years of usage, continues to be characterized by an extremely low incidence of E. coli resistant strains (about 1%) worldwide. Many factors may have contributed to preserve fosfomycin trometamol antibacterial activity including single dose usage limited to urinary infections, very high and sustained urinary concentrations that rapidly kill bacteria reducing the opportunity for mutant selection. In addition there is no animal feed that contains the drug, resistance is most commonly acquired by chromosomal mutations that do not spread easily and the biological cost of these genetic modifications is high. To these parameters fosfomycin trometamol adds excellent tolerability and safety. Although nowadays, microbial resistance limits available resources and some drugs can no longer be recommended as reliable agents, fosfomycin trometamol, because of its properties, remains a drug of choice for the eradication of uncomplicated UTI.

Animals↗

Antibacterial resistance in Streptococcus pneumoniae and Haemophilus influenzae from Italy and Spain: data from the PROTEKT surveillance study, 1999-2000.

Antibacterial resistance was evaluated among Streptococcus pneumoniae (n=252) and Haemophilus influenzae (n=202) from two centres in Spain (Barcelona and Madrid) and two centres in Italy (Genoa and Catania) collected during 1999-2000 as part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) international surveillance program. Pneumococcal nonsusceptibility to penicillin G was found to be considerably higher in Spain (53.4%) than in Italy (15.1%), whereas erythromycin A resistance was higher in Italy (42.9%) than in Spain (28.6%). Among macrolide-resistant isolates investigated for resistance genes, the prevalence of mefA was higher among isolates from Italy (20/51, 39.2%) than among Spanish isolates (2/38, 5.3%). All other macrolide-resistant isolates possessed ermB. Telithromycin possessed good anti-pneumococcal activity against isolates from both countries (MIC90 0.03 mg/L [Spain]; 0.25 mg/L [Italy]), irrespective of resistance to other antibacterials. Beta-lactamase production among H. influenzae was low: Spain, 10.9%; Italy, 1.8%. With the exception of ampicillin and co-trimoxazole, all H. influenzae isolates were highly susceptible to the antibacterials tested, and all were inhibited by telithromycin at a concentration of < or = 2 mg/L. The findings of PROTEKT 1999-2000 highlight the importance of local resistance patterns in guiding the choice of empirical antibacterials for community-acquired respiratory tract infections.

Anti-Bacterial Agents↗

A human placental polydeoxyribonucleotide (PDRN) may promote the growth of human corneal fibroblasts and iris pigment epithelial cells in primary culture.

The optimal concentration of a human placental polydeoxyribonucleotide (PDRN) preparation (100 microg/ml) enhances the growth of human corneal fibroblasts in primary culture depending upon the donor age. In particular, this effect is very consistently reproducible with donors over 60 years of age (p = 0.0028), suggesting a selective benefit of PDRN in the tissue culture of senescent cells. Moreover, this drug may promote the development of human iris pigment epithelium (IPE) cells with much lower concentrations of fetal bovine serum than those suitable for the culture of IPE. Lastly, the use of a 'gauze disk' on the pieces of the corneal explants improves the efficiency of growth of the control fibroblast primary cultures.

Adolescent↗

Is antimicrobial resistance also subject to globalization?

In recent years one of the more alarming aspects of clinical microbiology has been the dramatic increase in the incidence of resistance to antibacterial agents among pathogens causing nosocomial as well as community-acquired infections. There are profound geographic differences in the incidence of resistance among pathogens of the respiratory tract, only some of which can be explained by the local use of antibiotics. A high percentage of Moraxella catarrhalis strains produce beta-lactamase and are thus resistant to many beta-lactam antibiotics. In contrast, beta-lactamase production among strains of Haemophilus influenzae rarely reaches more than 30% around the world. Methicillin-resistance in Staphylococcus aureus is a common and increasing problem in hospitals but its extent varies both locally and nationally. Resistance is usually associated with the local spread of resistant strains. High standards of hygiene in hospitals can prevent the spread of such strains but once established they can be difficult to eradicate. Although Streptococcus pyogenes remains highly susceptible to penicillins, even after many decades of their use, resistance to macrolides has occurred. This resistance can rise and fall. Although the increase of macrolide resistance in S. pyogenes can often be associated with an increase in the use of these drugs, this is not always so. In some cases it has been shown to be caused by the spread of one or more resistant clones. Eradication of these clones can reduce the level of resistance markedly. Resistance to both macrolides and penicillins among strains of Streptococcus pneumoniae is seen world-wide but is highly variable from country to country. Local habits of drug usage may play a part. In Italy, for example, there is preference for the use of parenteral third-generation cephalosporins for some severe infections and there is a corresponding low level of penicillin-resistance among pneumococci.

Anti-Bacterial Agents↗

Multicentre evaluation of the VITEK 2 Advanced Expert System for interpretive reading of antimicrobial resistance tests.

Interpretive reading analyses the complete resistance profiles of bacteria to multiple antibiotics and infers the resistance mechanisms present; it aids therapeutic choice and enhances surveillance data. We evaluated the Advanced Expert System (AES), which interprets MICs generated by the VITEK 2. Ten European laboratories tested 42 reference strains and 76-106 of their own strains, representing important resistance genotypes. Interpretive reading by the VITEK 2 AES achieved full agreement with genotype data for 88-89% of strains, with the correct mechanism identified as one of two possibilities for a further 5-6%. Mechanisms inferred with 90% agreement with reference data included methicillin resistance in staphylococci, glycopeptide resistance in enterococci, quinolone resistance in staphylococci and Enterobacteriaceae, AAC(6')-APH(2")-mediated aminoglycoside resistance in Gram-positive cocci, erm-mediated macrolide resistance in pneumococci, extended-spectrum beta-lactamases (ESBLs) in Enterobacteriaceae and Pseudomonas aeruginosa, and acquired penicillinases in Enterobacteriaceae. VanA, VanB and VanC phenotypes of enterococci were distinguished reliably, and ESBL production was accurately inferred in AmpC-inducible species as well as Escherichia coli and Klebsiella spp. Mechanisms identified, but only as possibilities among several, included IRT-type beta-lactamases and individual aminoglycoside-modifying enzymes in Enterobacteriaceae. Most disagreements with reference data concerned pneumococci found to have high-level penicillin resistance by the VITEK 2 AES but previously determined, phenotypically, to have intermediate resistance. When ESBL production was inferred in E. coli and klebsiellae, the VITEK 2 AES edited susceptible results for cephalosporins (except cefoxitin) to resistant; when an acquired penicillinase was inferred in Enterobacteriaceae, piperacillin results were edited to resistant; and when staphylococci were found methicillin resistant, resistance was reported for all beta-lactams. Further editing may be desirable (e.g. of cephalosporin results for salmonellas inferred to have ESBLs).

Data Interpretation, Statistical↗