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PubMed2001

Multidrug-resistant bacteria: overcoming antibiotic permeability barriers of gram-negative bacteria.

Because of the permeability barrier provided by the outer membrane (OM), gram-negative bacteria are inherently resistant to many hydrophobic antibiotics. This resistance limits the arsenal of antibiotics that are effective in treating gram-negative bacterial infections. Compounding this problem, strains of gram-negative bacteria have emerged that display specific resistance mechanisms for effective antibiotics. As a means of expanding the arsenal of effective antibiotics for gram-negative bacteria, compounds that permeabilize the OM to hydrophobic substances have been developed. These compounds are typically cationic, amphiphilic molecules that can be prepared from peptides or steroids. Effective OM permeabilizers sensitize gram-negative bacteria to hydrophobic antibiotics, including erythromycin, fusidic acid, novobiocin and rifampin. These antibiotics are generally not useful in treating gram-negative bacterial infections because they traverse the OM ineffectively. The use of OM permeabilizers, in combination with hydrophobic antibiotics, may provide additional means of controlling growth of gram-negative bacteria. This review describes classes of permeabilizers, including those derived from peptides, and recently reported examples based on steroids.

Animals↗
PubMed2001

Antimicrobial resistance surveillance of bacteria in 1999 in Korea with a special reference to resistance of enterococci to vancomycin and gram-negative bacilli to third generation cephalosporin, imipenem, and fluoroquinolone.

The trend of antimicrobial resistance of bacteria isolated from patients in 30 Korean hospitals in 1999 was analyzed with a particular attention to cefotaxime- or fluoroquinolone-resistant gram-negative bacilli, imipenem-resistant Pseudomonas aeruginosa, and vancomycin-resistant enterococci. Adequacy of susceptibility testing, and any change in the frequencies of isolated species were also analyzed. The results showed that only 20% and 30% of hospitals tested the piperacillin-tazobactam and cefoxitin susceptibility of Enterobacteriaceae, respectively, only 24% of hospitals the piperacillin-tazobactam susceptibility of P. aeruginosa, and 17% of hospitals the fusidic acid susceptibility of staphylococci. Among the isolates 26.3% were glucose-nonfermenting gram-negative bacilli, and 34.7% of Enterococcus were Enterococcus faecium. Slight decline of cefotaxime-resistance rate to 20% was noted in Klebsiella pneumoniae, while fluoroquinolone-resistance rate was 68% in Acinetobacter baumannii. The ceftazidime- and imipenem-resistance rates were 17% and 18%, respectively in P. aeruginosa. The vancomycin-resistance rate of E. faecium rose significantly to 15.1%, but the rates varied significantly depending on hospitals suggesting presence of different degree of selective pressure or nosocomial spread. In conclusion, the prevalence of imipenem-resistant P. aeruginosa and the increase of vancomycin-resistant E. faecium were the particularly worrisome phenomena observed in this study.

Anti-Bacterial Agents↗
PubMed1988

Late-onset neonatal sepsis due to multiply-resistant coagulase-negative staphylococci.

A cluster of septic episodes that were caused by coagulase-negative staphylococci occurred in eight patients, over a six-month period from August 1, 1984 to January 31, 1985, in a Brisbane neonatal intensive-care unit where sepsis which was due to these organisms previously was uncommon. The organisms were universally-resistant to tobramycin (the aminoglycoside agent that was used at that time) and were variably-resistant to gentamicin, flucloxacillin and cephalothin. All organisms were sensitive to netilmicin, vancomycin, fusidic acid and rifampicin. The affected infants were all of 32 weeks' or less gestation and most of them weighed less than 1500 g at birth. All neonates had been ventilated artificially and had had long intravascular lines. Two infants had ventriculoperitoneal shunts that had been infected with coagulase-negative staphylococci--a potentially-important problem that has not been noted in premature infants in previous reports. Our experience demonstrates that it is important to consider the patterns of resistance to aminoglycoside as well as to beta-lactam antibiotic agents for the empirical therapy of septic episodes and for neurosurgical prophylaxis in nurseries where coagulase-negative staphylococci are emerging as common nosocomial pathogens.

Anti-Bacterial Agents↗
PubMed1989

A national survey of antimicrobial resistance in Staphylococcus aureus in Australian teaching hospitals.

An extensive survey of the in-vitro susceptibility of clinical isolates of Staphylococcus aureus to 18 antimicrobial agents was conducted over three separate periods during 1986-1987 in 14 teaching hospitals in major Australian cities. The survey aimed to document the prevalence of resistance to a wide variety of drugs that are important as antistaphylococcal agents or as epidemiological markers. More than 7500 isolates were examined. Nationally, the prevalence of resistance was 85.3% to penicillin G, 14.4% to methicillin, 14.0% to amoxycillin/clavulanate, 9% to cephalothin, 5.4% to cephamandole, 9.9% to cefotaxime, 25.0% to erythromycin, 11.2% to clindamycin, 21.7% to tetracycline, 13.0% to gentamicin, 1.9% to amikacin, 5.8% to chloramphenicol, 18.3% to trimethoprim, 0.6% to rifampicin, 3.0% to fusidic acid and 1.2% to novobiocin. For none of the strains was resistance to vancomycin confirmed by minimal-inhibitory-concentration determination. A high proportion of the resistances was harboured in methicillin-resistant Staph. aureus, except for resistance to penicillin G, erythromycin and tetracycline. The prevalence of methicillin resistance varied widely among the states: 25.2% in Queensland, 23.5% in Victoria, 12.6% in New South Wales/the Australian Capital Territory, 11.3% in South Australia and 0.4% in Western Australia. Isolates from blood cultures were slightly-more susceptible to antimicrobial agents than were isolates from other body sites. Six common profiles of resistance to penicillin G, methicillin, erythromycin, clindamycin and tetracycline accounted for more than 95% of the isolates that were tested against all five agents. Vancomycin remains the most important antistaphylococcal drug in areas where resistance to methicillin is common.

Anti-Bacterial Agents↗
PubMed1991

The outer membrane permeability-increasing action of deacylpolymyxins.

The outer membrane permeability-increasing action of deacylpolymyxins was compared to the well-known potent action of polymyxin B nonapeptide (PMBN). Deacylpolymyxin B (DAPB), prepared by treating polymyxin B with polymyxin acylase, was found to be a slightly more effective permeabilizer than PMBN. As low a DAPB concentration as 1 microgram/ml sensitized Escherichia coli to the probe antibiotics (rifampin, fusidic acid, erythromycin, clindamycin, novobiocin) by factors 30-100 and Salmonella typhimurium by factors 10-100. A higher concentration (3 micrograms/ml) of DAPB elicited further sensitization. Also deacylcolistin (DAC) was found to be an effective permeabilizer.

Amino Acid Sequence↗
PubMed1992

Polymyxin B octapeptide and polymyxin B heptapeptide are potent outer membrane permeability-increasing agents.

Polymyxin B octapeptide (PBOP) and polymyxin B heptapeptide (PBHP) were found to be effective permeabilizers of the outer membrane of Escherichia coli and Salmonella typhimurium. PBOP was as effective as polymyxin B nonapeptide (PMBN), the known very potent permeabilizer. As low a PBOP concentration as 1 microgram/ml sensitized E. coli to rifampicin by a factor of 100. Three micrograms of PBOP per ml was sufficient to sensitize this target to all the other tested hydrophobic antibiotics (erythromycin, fusidic acid, clindamycin, and novobiocin) by a factor of 30. Only a slightly higher (3-fold) concentration of PBHP was required for a similar sensitizing effect.

Amino Acid Sequence↗
PubMed1999

[Use and adverse reactions of local antibiotics and disinfectants on the skin].

The local antibiotics are an important addition to the treatment of moderately severe skin infections. Development of contact allergy and bacterial resistance, however, are some of the adverse reactions that may occur. Fusidic acid and tetracycline are the most suitable products for the treatment of superficial primary infections of the skin caused by Gram-positive cocci and secondary infected dermatoses. In case of insufficient effect mupirocin may be tried. Mupirocin is an effective antibiotic in the treatment of nasal carriage of Staphylococcus aureus in cases of increased risk of infection (haemodialysis, continuous peritoneal dialysis, after thoracic surgery). Besides it is an important local antibiotic in the treatment of meticillin-resistant staphylococci in the nose. In order to prevent development of bacterial resistance its further use has to be restricted. Silver sulfadiazine is a good option for the local treatment of infections by Pseudomonas aeruginosa and other Gram-negative bacteria. Erythromycin and clindamycin are useful local antibiotics for the treatment of mild acne vulgaris. Disinfectants are mainly suitable for the use on the intact skin.

Acne Vulgaris↗
PubMed1999

In-vitro disk diffusion sensitivity of meropenem against bacterial pathogens in Harare.

OBJECTIVE: To compare the in-vitro sensitivity of meropenem with imipenem and other antibiotics against clinically significant bacteria. DESIGN: A longitudinal survey. SETTING: Department of Medical Microbiology, in a tertiary care university hospital. SUBJECTS: Specimens obtained from patients attending various clinics at tertiary care and teaching hospital in Harare. Those submitted to the Public Health Bacteriology Laboratory were analysed. MAIN OUTCOME MEASURES: Rates of resistance or susceptibility of the various bacteria to the antibiotics employed in the study. RESULTS: There was excellent in-vitro bacterial activity of meropenem against virtually all clinically significant Gram positive and Gram negative isolates when compared with other antibiotics such as imipenem, ciprofloxacin, gentamicin, penicillin, ampicillin, fusidic acid, tetracyclines, erythromycin and clindamycin (p < 0.5). All isolates of Streptococcus pyogenes, Pseudomonas aeruginosa, Enterobacteriaceae, Neisseria meningitidis were susceptible to meropenem. Meropenem showed 99% overall in-vitro sensitivity against Gram positive and Gram negative bacteria. About 80% of staphylococci were resistant to penicillin whereas at least 20-25% of S. aureus, coagulase negative staphylococci, S. pyogenes showed resistance to ampicillin, erythromycin, gentamicin, tetracycline and clindamycin. CONCLUSION: Meropenem is not included in the list of routinely tested antibiotics in our laboratory, a major tertiary laboratory in the country. As a result of the ultra-broad spectrum of activity, we recommend its inclusion in our routine antibiotic sensitivity testing and observe that there is a great potential for meropenem in the treatment of infections caused by several genera of bacteria in our environment.

Drug Resistance, Microbial↗
PubMed1999

[Susceptibility to selected chemotherapeutics of Staphylococcus aureus strains resistant to methycyline isolated from clinical materials in the years 1991-1992 and 1997].

The susceptibility to selected chemotherapeutic agents was determined in 100 strains of Staphylococcus aureus methicillin-resistant (MRSA) isolated from clinical materials in 1991-1992 (50 strains) and in 1997 (50 strains). Two methods were used for the determination: disc method and antibiotic dilution in agar. The minimal inhibitory concentration (MIC) was determined for vancomycin, teicoplanin, furazolidone, nitrofurantoin, ofloxacin, gentamicin, netilmicin and trimethoprim. The concentrations of the chemotherapeutics in the substrate ranged from 0.125 to 512 mg/l. The obtained results served for drawing of the following conclusions: all studied MRSA strains isolated in 1991-1992 and in 1997 were sensitive to glycopeptide antibiotics: vancomycin and teicoplanin, to nitrofurans: nitrofurantoin and furazolidone, and to fusidic acid. MRSA strains isolated in 1991-1992 were sensitive to ofloxacin, but in 1997 about 80% of the strains were resistant to that antibiotic, and this resistance was noted in S. aureus strains with homogeneous resistance to methicillin. Increasing frequency of resistance to mupirocin was found, in 1991-1992 4% of the strains were resistant, and in 1997 the resistance of MRSA to that antibiotic was found in 12%. No changes occurred in the sensitivity of staphylococci to trimethoprim/sulfamethoxazole (cotrimoxazole). About 94% of strains in 1991-1992 and 1997 were sensitive to that drug. The sensitivity to cotrimoxazole is connected with one of its components (trimethoprim), with 94% of MRSA strains sensitive to it.

Anti-Bacterial Agents↗
PubMed2000

[Bioavailability of antibiotics].

To be effective, an antibiotic must achieve therapeutic concentrations at the site of infection. This article is a review on the bioavailability of local and systemic antibiotics. Amongst topical antibiotics, fluoroquinolones and fusidic acid have the best intra-corneal and intra-cameral penetration. Chloramphenicol penetrates the anterior chamber but not always at therepeutic levels. Serum levels are low from topical administration, and haematological toxicity of chloramphenicol eyedrops is still not proven. Amongst systemic antibiotics, the molecules capable of penetrating the eye at therapeutic levels are fosfomycin, imipenem, some of third generation cephalosporins, fluoroquinolones and ureidopenicillins. Intra-ocular penetration of antibiotics is increased by infection, corneal epithelium abrasion, increasing dose frequency or delivery using a biomaterial reservoir (soft contact lenses or collagen schields). Antibiotic-antiinflammatory associations can make infected sites more accessible to antibiotics. The choice of a treatment must take in consideration molecules, dosing and route, and be adapted to the germ to kill and the infected site to treat.

Animals↗
PubMed2000

[Susceptibility to selected coagulase-negative chemotherapeutic agents of methicillin resistant staphylococci isolated from clinical materials in 1997-1998].

The study was aimed at assessment of the sensitivity of methicillin-resistant coagulase-negative staphylococci isolated from clinical material in 1997/1998 to selected chemotherapeutic agents. The investigated material comprised 96 methicillin-resistant coagulase-negative staphylococci from hospital and ambulatory infections isolated during the period from April 1997 to May 1998. Species affiliation was determined by classical identification methods and commercial diagnostic tests for identification of staphylococci. Methicillin resistance was determined by agar disk-diffusion method and screening. Sensitivity to chemotherapeutics was determined by agar disk-diffusion method and agar dilution methods. All the investigated strains were sensitive to nitrofurantoin, furazolidone and vancomycin. To teicoplanin--the second glycopeptide antibiotic--84% strains were sensitive, whereas the percentages of resistant and moderately sensitive strains amounted to 5.2% and 10.4%, respectively. 85% and 82% of coagulase-negative staphylococcal strains were sensitive to fusidic acid and mupirocin. Considerable differences were noted with respect to sensitivity to aminoglycoside group antibiotics. About 35% of strains were sensitive to gentamicin, and 90% sensitive to netilmicin. Ca. 40% of coagulase-negative staphylococci were resistant both to cotrimoxazole and trimethoprim, which, in view of 98% resistance to the second component of cotrimoxazole, may be associated with the activity of only one of the components of the drug--trimethoprim.

Coagulase↗
PubMed2001

Community-acquired, non-multiresistant oxacillin-resistant Staphylococcus aureus (NORSA) in South Western Sydney.

Community-acquired oxacillin-resistant Staphylococcus aureus (ORSA) infections are an emerging problem in the 1990s in Sydney, Australia. Laboratory data pertaining to all specimens that grew S. aureus between 1/1/1990 and 31/12/1999 were analysed. A total of 12,909 isolates of S. aureus were obtained. The proportions that were nonmultiresistant oxacillin-resistant S. aureus (NORSA) increased from 0.09% in 1990 to 5.5% in 1999. Resistance of NORSA strains to erythromycin was 8.5%, ciprofloxacin 8.4%, tetracycline 13%, rifampicin 0.7%, and fusidic acid 5.3%. A chart review was performed for cases of NORSA infection which occurred 1/1/1998-3/5/1998. Isolates from these cases underwent E-test oxacillin MIC testing, mecA determinant PCR, phage typing and pulsed-field gel electrophoresis. All nine of the patients with NORSA were Polynesians, and all had serious soft tissue infections. Bacteraemia was not seen. Only one patient received vancomycin yet all recovered. Isolates from all nine patients contained the mecA determinant. Oxacillin MICs were 1-8 mg/l. Strain differentiation with phage typing and pulsed-field gel electrophoresis showed isolates from eight patients were closely related and were similar to New Zealand WSPP1 and WSPP2 strains. Medical practitioners should take specimens for culture and sensitivity from lesions where infection with S. aureus is likely. Empirical treatment of staphylococcal infections in Polynesians needs to cover NORSA. Methods to detect oxacillin resistance need to be robust.

Adolescent↗
PubMed2001

DNA fingerprinting of methicillin-resistant Staphylococcus aureus by pulsed-field gel electrophoresis (PFGE): comparison of strains from 2 Malaysian hospitals.

AIM OF STUDY: To determine and compare the pulsed-field gel electrophoresis (PFGE) patterns of endemic MRSA strains in 2 major Malaysian hospitals and to compare the PFGE patterns with antibiotypes of the strains studied. METHODS: Fifty-six MRSA strains selected randomly between September 1997 and July 1998 from Hospital Queen Elizabeth (HQE) and Hospital Umum Sarawak (HUS) were tested for antimicrobial resistance and DNA fingerprinting was carried out by pulsed-field gel electrophoresis (PFGE) technique. RESULTS: Seven PFGE types were recognised (A, B, C, D, E and F). All 7 PFGE types were observed in HQE while only 2 PFGE types (B, C) were noted in HUS strains. There is a predominance of a single PFGE pattern (type B) in both hospitals, as seen in 46% of HQE strains and 89% of HUS strains. Subtype B2 was the commonest subtype in HQE while subtype B1 predominated in HUS. Strains resistant to fusidic acid and rifampicin exhibited PFGE type F that is unique to HQE. All strains were resistant to penicillin, erythromycin, cotrimoxazole, tetracycline and gentamicin. Strains with the same antibiotic susceptibility pattern can be different PFGE types. CONCLUSION: Molecular typing of the MRSA by PFGE is a useful tool in the study of endemic strains present in an institution. Strains in HQE were found to be more heterogeneous than HUS strains. Common PFGE types can also be seen in both hospitals suggesting that some of the strains was genetically related and has propagated within and between the 2 hospitals. Our findings also indicate that the relationship between antibiotic susceptibility and PFGE patterns was not close and antibiograms should not be relied upon for typing strains in epidemiological studies. By knowing the DNA fingerprints of the isolates endemic in each hospital, the spread of MRSA with a particular PFGE type can be monitored within and between hospitals.

DNA Fingerprinting↗
PubMedDate not supplied

[Structure and functions of the prokaryotic elongation factor G].

Structural and functional data on elongation factor G (EF-G) are reviewed with regard to nucleotide exchange, GTP hydrolysis, mechanism of action of fusidic acid, and functional roles of the EF-G structural domains in translocation. Biochemical data are correlated with structural dynamics of the EF-G molecule on interaction with various ligands. Data on EF-Tu are also considered, as EF-G and EF-Tu share certain structural and functional features.

Amino Acid Sequence↗
PubMed2001

Increased sensitivity to protein synthesis inhibitors in cells lacking tmRNA.

tmRNA (also known as SsrA or 10Sa RNA) is involved in a trans-translation reaction that contributes to the recycling of stalled ribosomes at the 3' end of an mRNA lacking a stop codon or at an internal mRNA cluster of rare codons. Inactivation of the ssrA gene in most bacteria results in viable cells bearing subtle phenotypes, such as temperature-sensitive growth. Herein, we report on the functional characterization of the ssrA gene in the cyanobacterium Synechocystis sp. strain PCC6803. Deletion of the ssrA gene in Synechocystis resulted in viable cells with a growth rate identical to wild-type cells. However, null ssrA cells (deltassrA) were not viable in the presence of the protein synthesis inhibitors chloramphenicol, lincomycin, spiramycin, tylosin, erythromycin, and spectinomycin at low doses that do not significantly affect the growth of wild-type cells. Sensitivity of deltassrA cells similar to wild-type cells was observed with kasugamycin, fusidic acid, thiostrepton, and puromycin. Antibiotics unrelated to protein synthesis, such as ampicillin or rifampicin, had no differential effect on the deltassrA strain. Furthermore, deletion of the ssrA gene is sufficient to impair global protein synthesis when chloramphenicol is added at sublethal concentrations for the wild-type strain. These results indicate that ribosomes stalled by some protein synthesis inhibitors can be recycled by tmRNA. In addition, this suggests that the first elongation cycle with tmRNA, which incorporates a noncoded alanine on the growing peptide chain, may have mechanistic differences with the normal elongation cycles that bypasses the block produced by these specific antibiotics. tmRNA inactivation could be an useful therapeutic target to increase the sensitivity of pathogenic bacteria against antibiotics.

Chloramphenicol↗
PubMed1991

Antibiotics and expression of microbial virulence factors: implications for host defense.

The discovery that antibiotics are capable of modifying both the structural appearance and physiology of pathogenic bacteria when they are incorporated in the culture medium at sub-growth inhibitory concentrations, has led to numerous examples in which the expression of one or more virulence factors (both structural and soluble) is inhibited or potentiated--some of these bacterial products are recognized in their own right as substances which can interfere with one or more stages of the normal process of phagocytosis viz, chemotaxis and Staphylococcus aureus alpha-toxin; opsonization and M protein of Streptococcus pyogenes; phagocytic ingestion and capsule of Bacteroides fragilis; phagocytic killing and streptolysin O of Streptococcus pyogenes. Exposure to these bacteria to low concentrations of various chemotherapeutic drugs can alter the efficacy of the phagocytic process. However, many examples exist in which no specific biochemical lesion induced by exposure to the antibiotic has been recognized. By way of contrast some recent experimental studies using genetically defined variants of S. aureus expressing protein A, alpha-toxin, beta-toxin or coagulase have allowed some discrimination as to the specifity of the drug action and the relative role of each virulence factor in bacterial pathogenicity. In particular it can be recognized that the presence or absence of protein A either through drug treatment (clindamycin or fusidic acid) or through gene delation is critical in determining bacterial susceptibility to opson-ophagocytosis. Extension of these studies to in vivo models will shed light on possible antibiotic-host defence interaction during chemotherapy.

Anti-Bacterial Agents↗
PubMed2002

[Staphylococcus aureus infections--the clinical picture and treatment].

Infections caused by Staphylococcus aureus comprise relatively benign local skin infections, as well as serious generalised conditions. In Denmark, more than 85% of all S. aureus isolates are found resistant to penicillin, whereas resistance to methicillin is rare (< 1%) and therefore one of the penicillinase-stable penicillins is still the drug of choice. Dicloxacillin is usually chosen, because of its superior penicillinase stability. Infections caused by methicillin resistant strains may be treated with different combinations of macrolides, fusidic acid, aminoglycosides, fluoroquinolones, and rifampicin, but vancomycin is generally used. Newer drugs like the oxazolidinones and streptogramins are effective against methicillin-resistant strains and will be available in Denmark within a short time. Antibiotic treatment, however, is most often only a supplement to surgical intervention. This paper deals with the clinical picture and treatment of some common S. aureus infections.

Anti-Bacterial Agents↗
PubMed2002

[Methicillin-resistant Staphylococcus aureus (MRSA) with high resistance to mupirocin in hospitals of the Gdańsk region].

Occurrence of high-level mupirocin resistance in methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from 18 hospitals in Gdańsk area was determined. The study was carried out on 190 MRSA isolated in 1997-2000 from various clinical samples. The strains were tested for high-level mupirocin resistance by 200 micrograms mupirocin disc. The minimum inhibitory concentrations (MIC) for methicillin were estimated by agar dilution. Sensitivity to other antibiotics was determined in disc-diffusion method and to vancomycin in agar dilution method additionally. The strains were typed by set of 10 experimental phages and compared by the method of PCR-RFLP analysis of coagulase gen restriction fragment length polymorphism. There were low frequency of high-level mupirocin resistance in MRSA strains (4.7%) that were found only in 3 hospitals, in 6 patients. All of them were high-resistant also to methicillin and resistant to doxycyclin, gentamycin, erytromycin, klindamycin, ciprofloksacin, rifampicin, resistant or intermediate sensitive to fusidic acid but sensitive to vancomycin, teikoplanin and bacitracin. The origin all of the MRSA strains high-resistant to mupirocin probably was the same, except one strain, because they were belonged to one genetic type and possessed the same phage pattern.

Bacteriophage Typing↗