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Biomedical subjects

P C Appelbaum

Publications and source records attributed to P C Appelbaum.

At least 19 recordsLinked to original sources

The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is well-recognised as a major cause of infection in the health care setting but, even more worryingly, is now emerging in the community. The glycopeptides-notably vancomycin-have traditionally been the mainstay of treatment of MRSA but overuse has led to the emergence of vancomycin-intermediate and vancomycin-resistant MRSA (VISA and VRSA, respectively). Although the mechanisms underlying vancomycin resistance are not yet fully understood, changes to the bacterial cell wall-the site of action of the glycopeptides-are believed to be key. Recent evidence also supports the transfer of genetic material among bacteria as contributing to the development of VRSA. Based on the cases identified to date, risk factors for the development of VRSA may include older age, compromised blood flow to the lower limbs, and the presence of chronic ulcers. The true extent of the problem, however, remains to be determined-it is likely that many cases of VISA and VRSA infection go undetected because of suboptimal screening programmes and possible limitations of automated and non-automated detection methods. Effective screening directed at those patients considered to be most at risk should therefore be a priority. Not surprisingly, the spread of MRSA from the hospital to the community setting, coupled with the emergence of VISA and VRSA, has become a major cause of concern among clinicians and microbiologists. The treatment options available for these infections are now severely compromised and thus new classes of antimicrobial agents effective against MRSA, VISA and VRSA are urgently required.

Anti-Bacterial Agents↗

MRSA--the tip of the iceberg.

Methicillin-resistant Staphylococcus aureus (MRSA) strains cause serious nosocomial infections all over the world. Overall, approximately 20% of S. aureus isolates in Europe are reported as methicillin-resistant, whereas in US hospitals the prevalence ranges from 33% to 55%. The past few years have also witnessed an increase in life-threatening community-acquired infections caused by Panton-Valentine leukocidin-producing MRSA in the USA. Increasing use of glycopeptides for treatment of community-acquired MRSA infections may result in higher rates of glycopeptide resistance. Since 1996, five vancomycin-intermediate S. aureus (VISA; vancomycin MIC = 8-16 mg/L) strains have been identified in Europe, Asia and the USA, and vancomycin-resistant S. aureus (VRSA) strains (vancomycin MIC > or = 32 mg/L) have also been reported in the USA between 2002 and 2005. Most infections with VISA and VRSA have occurred in a setting of heavy prior use of glycopeptides and other antimicrobial agents. Emergence of reduced vancomycin susceptibility in S. aureus increases the possibility that currently available antimicrobial agents may become ineffective for treating systemic infections, especially bacteraemia, endocarditis and osteomyelitis. Ceftobiprole is a novel broad-spectrum cephalosporin with expanded activity against Gram-positive bacteria, including MRSA. Ceftobiprole is refractory to the development of endogenous resistance both in vitro and in vivo. The additional activity of ceftobiprole against MRSA strains makes it a potentially important addition to currently available agents.

Anti-Bacterial Agents↗

Antimicrobial resistance of nasopharyngeal pneumococci from children from day-care centres and orphanages in Russia: results of a unique prospective multicentre study.

This study assessed the antimicrobial resistance of nasopharyngeal pneumococci isolated from children aged < 5 years in day-care centres and orphanages throughout Russia during 2001-2002. Swabs were collected from 2484 children in 43 day-care centres and eight orphanages in 11 cities of European Russia, and from 1669 children in 37 day-care centres and three orphanages in eight cities of Asian Russia, with a total of 1144 and 912 Streptococcus pneumoniae isolates being recovered in European and Asian Russia, respectively. All macrolide-non-susceptible (MICs 0.5-128 mg/L) and fluoroquinolone-non-susceptible (ciprofloxacin MICs > or = 4 mg/L) isolates were tested for resistance mechanisms and clonal relatedness. Non-susceptibility rates, by CLSI criteria, were 19.3%, 0.9% and 0.4% for penicillin G, cefotaxime and amoxycillin-clavulanate, respectively. Resistance to macrolides and lincosamides was also relatively low, i.e., < 7% for clindamycin and 14- and 15-membered macrolides. The highest rates of non-susceptibility were for tetracycline and co-trimoxazole (52.0% and 64.5%, respectively). No clones resistant to ciprofloxacin (MICs > or = 8 mg/L) were found, but 1.7% of isolates were non-susceptible (MIC 4 mg/L). No resistance was found to levofloxacin, gemifloxacin, telithromycin or vancomycin. Pulsed-field gel electrophoresis analysis showed no relationship between ciprofloxacin- and macrolide-non-susceptible isolates in European and Asian Russia. Resistance among macrolide-resistant isolates resulted mostly from the presence of erm(B) and mef(A), and from changes in L4; additionally, L22 mutations were common in isolates from Asian Russia. Non-susceptibility to quinolones was associated with mutations in parC and parE among European isolates. Asian Russian isolates had mutations in parC and gyrA, and alterations in parE were more common. There were substantial differences in non-susceptibility and mechanisms of resistance between pneumococci from Asian and European Russia, with orphanages appearing to be 'hot-spots' of resistance.

Anti-Bacterial Agents↗

Postantibiotic effect of ceftobiprole against 12 Gram-positive organisms.

The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of ceftobiprole were determined for 12 gram-positive organisms. Pneumococcal, staphylococcal, and enterococcal PAEs were 1.4 to 3.1 h, 0 to 1.8 h, and 0 to 0.9 h, respectively. The PA-SMEs (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 4.8 to >10.3 h, 1.5 to 9.6 h, and 3.8 to >10.7 h, respectively.

Anti-Bacterial Agents↗

Activity of the new quinolone WCK 771 against pneumococci.

The activity of WCK 771, a new experimental quinolone being developed to overcome quinolone resistance in staphylococci, against quinolone-susceptible and -resistant pneumococci was determined. Comparative activities of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, clinafloxacin, vancomycin, linezolid, amoxycillin, cefuroxime, azithromycin and clarithromycin were determined with MIC and time-kill experiments. Animal experiments were also performed to test the in-vivo anti-pneumococcal activity of WCK 771 compared to levofloxacin. WCK 771 MIC50/90 values for 300 quinolone-susceptible Streptococcus pneumoniae isolates (108 penicillin-susceptible, 92 penicillin-intermediate and 100 penicillin-resistant) were 0.5/0.5 mg/L; the MICs of beta-lactams and macrolides rose with those of penicillin G, and all isolates were susceptible to vancomycin and linezolid. WCK 771 MIC50/90 values for 25 quinolone-resistant pneumococcal isolates were 4/8 mg/L, compared to 0.5/1 mg/L for clinafloxacin, 2/4 mg/L for gatifloxacin and moxifloxacin, 8/16 mg/L for levofloxacin, and 16/>32 mg/L for ciprofloxacin. Time-kill studies showed that WCK 771 was bactericidal against pneumococci after 24 h at 4 x MIC, as were the other quinolones tested. Animal model studies showed that WCK 771 had efficacy comparable to that of levofloxacin, by both the oral and subcutaneous routes, for systemic infection caused by three quinolone-susceptible isolates of pneumococci. Overall, WCK 771 was potent both in vivo and in vitro against quinolone-susceptible, but not quinolone-resistant, S. pneumoniae, regardless of penicillin susceptibility.

Animals↗

Activity of five quinolones, three macrolides and telithromycin against 12 Haemophilus influenzae strains with different resistance phenotypes.

Gemifloxacin MICs for 12 Haemophilus influenzae strains with different resistance phenotypes were 0.001-0.015 mg/L. Gemifloxacin was bactericidal against all 12 strains after 24 h at 2 x MIC. Ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin had MICs of 0.008-0.03 mg/L and similar kill kinetics. Macrolides and telithromycin had unimodal MICs (1.0-8.0 mg/L), except for two strains without efflux systems (0.0125-0.5 mg/L) and two with efflux systems and ribosomal protein mutations (> 64.0 mg/L), and were bactericidal against eight to ten strains tested at 2 x MIC after 24 h.

Anti-Bacterial Agents↗

Postantibiotic effect of DX-619 against 16 gram-positive organisms.

The in vitro postantibiotic effects (PAEs), the postantibiotic sub-MIC effects (PA-SMEs), and the sub-MIC effects (SMEs) of DX-619 were determined for 16 gram-positive organisms. DX-619 pneumococcal, staphylococcal, and enterococcal PAE ranges were 1.7 to 5.0 h, 0.7 to 1.8 h, and 1.2 to 6.5 h, respectively. The PA-SME ranges (0.4x MIC) for pneumococci, staphylococci, and enterococci were 5.2 to >8.6 h, 2.1 to 8.3 h, and 4.9 to >10.0 h, respectively.

Anti-Bacterial Agents↗

Antimicrobial selection for community-acquired lower respiratory tract infections in the 21st century: a review of gemifloxacin.

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

Anti-Bacterial Agents↗

Alterations of penicillin-binding proteins 1A, 2X, and 2B in Streptococcus pneumoniae isolates for which amoxicillin MICs are higher than penicillin MICs.

Penicillin-binding proteins (PBPs) of 15 selected penicillin- and amoxicillin-resistant Streptococcus pneumoniae isolates (MICs of 2 to 8 and 8 to 16 microg/ml, respectively) were studied. In addition to typical changes in PBPs 1A and 2X, these strains had 10 unique changes in PBP 2B, including a (618)A-G substitution, which may be the key alteration associated with amoxicillin resistance.

Amoxicillin↗

Activity of telithromycin and seven other agents against 1034 pediatric Streptococcus pneumoniae isolates from ten central and eastern European centers.

OBJECTIVE: To test the activity of telithromycin against 1034 Streptococcus pneumoniae isolates from pediatric patients in ten centers from ten central and eastern European countries during 2000-2001, and to compare it with the activities of erythromycin A, azithromycin, clarithromycin, clindamycin, and quinupristin-dalfopristin. METHODS: The minimum inhibitory concentrations (MICs) of telithromycin, erythromycin A, azithromycin, clarithromycin, clindamycin, levofloxacin, quinupristin-dalfopristin and penicillin G were tested by the agar dilution method with incubation in air, and mechanisms of resistance to macrolides and quinolones were investigated. RESULTS: Strains were isolated from sputum, tracheal aspirates, ear, eye, blood, and cerebrospinal fluid. Among S. pneumoniae strains tested, 36% had raised penicillin G MICs (>/= 0.12 mg/L). Susceptibilities were as follows: telithromycin, quinupristin-dalfopristin and levofloxacin, >/= 99%; clindamycin, 83%; and erythromycin A, azithromycin and clarithromycin, 78%. Of 230 (22.3%) erythromycin A-resistant S. pneumoniae strains, 176 (79.6%) had erm(B), 38 (16.1%) had mef(A), and 10 (4.3%) had mutations in 23S ribosomal RNA or in ribosomal protein L4. The rates of drug-resistant S. pneumoniae are high in all centers except Kaunas, Riga, and Prague. CONCLUSION: Telithromycin had low MICs against all strains, irrespective of macrolide, azalide or clindamycin resistance. Ribosomal methylation was the most prevalent resistance mechanism among all resistant strains, except in Sofia, where the prevalence of the efflux mechanism was higher.

Adolescent↗

Activity of telithromycin compared with seven other agents against 1039 Streptococcus pyogenes pediatric isolates from ten centers in central and eastern Europe.

In total, 1039 pediatric Streptococcus pyogenes isolates from Bulgaria, Croatia, the Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia were studied. All strains were susceptible to penicillin G, levofloxacin, and quinupristin-dalfopristin, 91-100% to telithromycin, and 82-100% to erythromycin, azithromycin, and clarithromycin, and 90-100% to clindamycin. Macrolide resistance occurred mainly in Slovakia (25%), the Czech Republic (17.3%), and Croatia (15.8%). Overall, 9.7% of S. pyogenes isolates were erythromycin resistant due to erm(B)- or erm(A)-encoded methylases (72.3%) or to a mef(A)-encoded efflux pump (25.7%). One strain had alterations of both 23S rRNA (A2058G Escherichia coli numbering) and ribosomal protein L22 (G95D).

Adolescent↗

Development of macrolide resistance by ribosomal protein L4 mutation in Streptococcus pyogenes during miocamycin treatment of an eight-year-old Greek child with tonsillopharyngitis.

Streptococcus pyogenes isolates with the same pulsed-field patterns were recovered from the throat cultures of a child with tonsillopharyngitis before and after treatment with miocamycin, a 16-membered macrolide. The initial isolate was macrolide-susceptible, but the isolates after the treatment were resistant to 14 and 15-membered macrolides and had two amino acid (65WR66) deletions in ribosomal protein L4.

Amino Acid Sequence↗

Postantibiotic effects of garenoxacin (BMS-284756) against 12 gram-positive or -negative organisms.

Conventional in vitro methods were used to determine the postantibiotic effects (PAEs), sub-MIC effects (SMEs), and postantibiotic sub-MIC effects (PA-SMEs) of garenoxacin for a range of organisms. The mean PAEs of garenoxacin for pneumococci, staphylococci, and enterococci were 0.3 to 2.2 h. For Escherichia coli and Pseudomonas aeruginosa, the PAEs were 0.9 to 1.6 h. The mean PA-SMEs (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 3.0 to >10 h, 1.8 to >10.7 h, and 5.8 h, respectively, while those for E. coli and P. aeruginosa were 7.6 and 4.4 h, respectively.

Anti-Bacterial Agents↗

Antianaerobe activity of RBX 7644 (ranbezolid), a new oxazolidinone, compared with those of eight other agents.

The activity of ranbezolid (RBX 7644), a new oxazolidinone, against 306 anaerobes was compared with those of 11 other agents. The MICs at which 50% of the isolates tested are inhibited and those at which 90% of the isolates tested are inhibited (in micrograms per milliliter) were as follows: ranbezolid, 0.03 and 0.5; linezolid, 2 and 4; vancomycin, >16 and >16; teicoplanin, 1 and >16; quinupristin-dalfopristin, 1 and >8; amoxicillin-clavulanate, 0.5 and 2; imipenem, 0.125 and 1; clindamycin, 0.25 and 8; metronidazole, 1 and 4; gatifloxacin, 0.5 and 4; and moxifloxacin, 0.5 and 2, respectively. Ranbezolid had very good in vitro activity against both gram-negative and -positive anaerobes.

Anti-Bacterial Agents↗

Macrolide resistance phenotypes in Streptococcus pneumoniae in Santiago, Chile.

The mechanism of resistance was investigated in 39 macrolide-resistant clinical isolates of Streptococcus pneumoniae isolated from January 1997 to July 1999 in Santiago, Chile. Our results showed that 22 (56.5%) were macrolide-resistant, clindamycin-susceptible isolates (M phenotype) and 17 (43.5%) were macrolide and clindamycin resistant (MLS(B) phenotype). mefE gene was detected in all M phenotype, while ermB gene was detected in all MLS(B)-phenotype strains. Serotype 14 was the most frequent serotype among M-phenotype strains, and serotypes 19 and 23F were the most frequent serotypes in MLS(B) strains. These results demonstrate that both phenotypes of macrolide-resistant S. pneumoniae are found in Santiago, Chile, with the M phenotype predominating.

Adult↗

Single- and multistep selection study of the antipneumococcal activity of BMS-284756 compared to ciprofloxacin, levofloxacin, trovafloxacin and moxifloxacin.

Single- and Multi-step selection studies were used to test the ability of BMS-284756, ciprofloxacin, levofloxacin, trovafloxacin and moxifloxacin to yield resistant clones from 12 quinolone-susceptible and -resistant Streptococcus pneumoniae strains. Although all quinolones selected, to a greater or lesser degree, for resistant clones with mutations usually in parC or gyrA, BMS-284756 tended to select for resistant clones at a lower rate than other quinolones studied.

Anti-Infective Agents↗