Search PubMed⌕ Search

Biomedical subjects

Michael R Jacobs

Publications and source records attributed to Michael R Jacobs.

At least 55 records · Page 3Linked to original sources
PubMed2004

Antianaerobic activity of a novel fluoroquinolone, WCK 771, compared to those of nine other agents.

Agar dilution MIC methodology was used to compare the activity of WCK 771 with those of ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, piperacillin, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 350 anaerobes. Overall, the MICs (in micrograms per milliliter) at which 50 and 90%, respectively, of the isolates tested were inhibited were as follows: WCK 771, 0.5 and 2.0; ciprofloxacin, 2.0 and 32.0; levofloxacin, 1.0 and 8.0; gatifloxacin, 0.5 and 4.0; moxifloxacin, 0.5 and 4.0; piperacillin, 2.0 and 64.0; piperacillin-tazobactam, < or =0.125 and 8.0; imipenem, 0.125 and 1.0; clindamycin, 0.125 and 16.0; and metronidazole, 1.0 and >16.0.

Anti-Infective Agents↗
PubMed2004

In vitro activity of the new quinolone WCK 771 against staphylococci.

The activity of WCK 771, an experimental quinolone developed to overcome quinolone resistance in staphylococci and other bacteria, was determined against quinolone-susceptible and -resistant Staphylococcus aureus and S. epidermidis. WCK 771 MICs for 50 and 90% of the strains tested (MIC(50) and MIC(90), respectively) were 0.008 and 0.015 microg/ml for S. aureus (n = 43) and 0.015 and 0.03 microg/ml for S. epidermidis (n = 44) for quinolone-susceptible isolates, compared to ciprofloxacin values of 0.12 and 0.25 microg/ml and 0.25 and 0.5 microg/ml, respectively. Values for levofloxacin were 0.12 and 0.25 microg/ml and 0.12 and 0.25 microg/ml, those for clinafloxacin were 0.015 and 0.03 microg/ml and 0.015 and 0.03 microg/ml, those for moxifloxacin were 0.03 and 0.06 microg/ml and 0.06 and 0.12 microg/ml, and those for gatifloxacin were 0.06 and 0.12 microg/ml and 0.12 and 0.25 microg/ml, respectively. The WCK 771 MIC(50) and MIC(90), respectively, were 0.5 and 1 microg/ml for both species of staphylococci (n = 73 for S. aureus, n = 70 for S. epidermidis) for isolates highly resistant to ciprofloxacin (MIC(50) and MIC(90), >32 and >32 microg/ml, respectively). Values for levofloxacin were 8 and 32 microg/ml and 8 and 32 microg/ml, those for clinafloxacin were 1 and 2 microg/ml and 0.5 and 2 microg/ml, those for moxifloxacin 4 and >4 microg/ml and 4 and >4 microg/ml, and those for gatifloxacin were 4 and >4 microg/ml and 2 and >4 microg/ml, respectively. WCK 771 and clinafloxacin demonstrated MICs of 1 microg/ml against three vancomycin-intermediate strains. WCK 771 showed concentration-independent killing for up to 24 h at 2, 4, and 8 times the MICs against quinolone-resistant staphylococci and was also bactericidal after 8 h for high-density inocula (10(8) CFU/ml) of quinolone-resistant strains at 5 microg/ml, whereas moxifloxacin at 7.5 microg/ml was bacteriostatic. WCK 771 was not a substrate of the NorA efflux pump as evident from the similar MICs against both an efflux-positive and an efflux-negative strain. Overall, WCK 771 was the most potent quinolone tested against the staphylococci tested, regardless of quinolone susceptibility.

Anti-Bacterial Agents↗
PubMed2004

Fluoroquinolones as chemotherapeutics against mycobacterial infections.

The antimicrobial agents used in the treatment of mycobacterial infections have remained largely unchanged for several decades. Primary treatment of tuberculosis relies on four drugs, isoniazid, a rifamycin, pyrazinamide, and ethambutol (or streptomycin), and generally results in >95% cure in uncomplicated tuberculosis infection. Drug resistance greatly complicates treatment of this disease. Treatment of tuberculosis caused by multiply drug-resistant strains with "second-line" drugs remains complex, and is generally tailored to the individual patient and strain. Several of the fluoroquinolones have shown promise as second line drugs for treatment of active disease and, in combination with clarithromycin or azithromycin, ethambutol, and other agents, for treatment of Mycobacterium avium complex infection. While large clinical trials are not possible with second line drugs, clinical treatment data are available and suggest that the quinolones have various degrees of promise in treatment of these infections. Bacterial type II DNA topoisomerases, DNA gyrase and topoisomerase IV, are the targets of quinolones, and provide the genetic basis for quinolone activity in mycobacteria. Mutations in these enzymes results in resistance, and characterization of resistant mutants allows correlation of genotype with susceptibility phenotype. Structure-activity relationship studies have provided further insight into optimal use of quinolones in mycobacterial infections. Care should be taken in treating pneumonia with fluoroquinolones if there is a degree of suspicion of tuberculosis, since quinolone monotherapy may rapidly select for quinolone resistance, thereby removing that class of antibiotic from the small range of treatment options.

Animals↗
PubMed2004

Macrolide resistance in Streptococcus pneumoniae: clonality and mechanisms of resistance in 24 countries.

The clonality and mechanisms of macrolide resistance were studied among 345 macrolide resistant Streptococcus pneumoniae strains isolated from 24 countries. The mechanisms of macrolide resistance, serotypes and PFGE types of the strains were determined and representative strains of clones from each country were typed by MLST. Among strains tested 215 had the erm(B) gene, 92 the mef(A) gene, 14 had both erm(B) and mef(A), and 24 had alterations in ribosomal proteins [2 with A2059G substitutions in 23S rRNA, 21 with 69GTG71 to TPS change in L4, and one with erm(B) and deletion of leucine at position 68 in L22]. Serogroups 19, 6, and 23, and serotype 14 were the most common serotypes/serogroups. Dissemination of variants of sequence type (ST) 315 and ST156 were observed in Eastern and Central European countries. In Asiatic countries the most common sequence types were variants of ST236 among strains with mef(A) and ST180 among strains with erm(B). Strains with both erm(B) and mef(A) from Mexico and Singapore were variants of ST236. The widespread clone from Slovakia with ribosomal protein L4 mutation was a variant of ST226. Common clones were observed between Europe, Asia, and America. Overall, while serotypes/serogroups of macrolide resistant isolates were limited, multiple PFGE and MLST types were found, with clustering of common clones within countries.

Anti-Bacterial Agents↗
PubMed2004

Haemophilus influenzae: a significant pathogen in acute otitis media.

Haemophilus influenzae is a major pathogen in acute otitis media (AOM) causing disease that is not clinically distinguishable from that caused by Streptococcus pneumoniae. AOM caused by H. influenzae is particularly associated with older age and recurrent disease. Antibiotics differ in their ability to eradicate H. influenzae from the middle ear space. In the United States, widespread pneumococcal vaccination has increased the importance of H. influenzae as a major therapeutic challenge in the treatment of AOM.

Acute Disease↗
PubMed2003

Contribution of beta-lactamase and PBP amino acid substitutions to amoxicillin/clavulanate resistance in beta-lactamase-positive, amoxicillin/clavulanate-resistant Haemophilus influenzae.

The roles of beta-lactamase and alterations in penicillin-binding protein in the development of amoxicillin and amoxicillin/clavulanate resistance in two beta-lactamase-positive, amoxicillin/clavulanate-resistant (BLPACR) strains of Haemophilus influenzae were investigated. Seven beta-lactamase-negative, ampicillin-resistant (BLNAR) strains were also studied for comparison of their resistance mechanisms. All strains had been recovered from patients in Japan. The TEM type beta-lactamase of the two BLPACR strains had 100% homology with the amino acid sequences of published TEM-1 beta-lactamase, showing that amoxicillin/clavulanate resistance was not associated with mutations in this beta-lactamase. However, these strains, as well as the seven BLNAR strains, had multiple mutations in ftsI, which encodes penicillin binding protein 3 (PBP3). The transformation of H. influenzae Rd strain with amplified ftsI genes from two BLPACR and two BLNAR strains enabled the selection of amoxicillin/clavulanate-resistant transformants with the same mutations as their parent strains. We concluded that amoxicillin/clavulanate resistance in the two BLPACR strains was due to changes in PBP3. The possibility of the presence of an extended spectrum beta-lactamase was excluded in the BLPACR strains studied.

Amino Acid Substitution↗
PubMed2003

Telithromycin post-antibiotic and post-antibiotic sub-MIC effects for 10 Gram-positive cocci.

Post-antibiotic effects (PAE) and post-antibiotic sub-MIC effects (PA-SME) of the ketolide telithromycin (HMR 3647) were determined for 10 Gram-positive cocci with various macrolide resistance mechanisms, including inducible and constitutive ribosomal methylase and macrolide efflux resistance genes. Strains tested included four Streptococcus pneumoniae, three Streptococcus pyogenes and three Staphylococcus aureus. Telithromycin MICs were 0.008-0.015 mg/L for pneumococci, 0.015-4.0 mg/L for S. pyogenes and 0.03 mg/L for staphylococci. PAE were determined after exposure of strains at 10 x MIC for 1 h. PA-SME were determined in the presence of 0.12x, 0.25x and 0.5x MIC of the agent after the initial 1 h exposure period. The PAE of telithromycin varied from 0.3 to 3.8 h; the PA-SME varied from 0.8 to 4.6 h, with maximal PA-SME varying from 1.5 to 4.6 h. PAE tended to be shortest for S. pyogenes (0.4-2.7 h) and S. aureus (0.3-2.4 h), compared to 1.5-3.8 h for S. pneumoniae. The duration of the PA-SME was similar for the three species tested. The low MICs for many strains as well as the PAE and PA-SME demonstrated in this study for telithromycin show promise for increasing the dosing interval of this ketolide, but will need verification by pharmacokinetic/pharmacodynamic and clinical studies.

Anti-Bacterial Agents↗
PubMed2003

The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents.

OBJECTIVES: The Alexander Project is a continuing surveillance study, begun in 1992, examining the susceptibility of pathogens involved in adult community-acquired respiratory tract infections (CARTI) to a range of antimicrobial agents. MATERIALS AND METHODS: This study tested the susceptibility of isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected between 1998 and 2000 to 23 antimicrobials. Minimum inhibitory concentrations of agents were determined using the broth microdilution method and interpreted according to NCCLS and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. RESULTS: In total, 8882 isolates of S. pneumoniae, 8523 isolates of H. influenzae and 874 isolates of M. catarrhalis were collected during 1998-2000 from centres in 26 countries. The world-wide prevalence of penicillin resistance (penicillin MICs > or = 2 mg/l) in isolates of S. pneumoniae was 18.2% over the study period, and the prevalence of macrolide resistance (erythromycin MICs > or = 1 mg/l) in this pathogen was 24.6%. Over the study period, macrolide resistance exceeded penicillin resistance in 19 of the 26 countries included in the study. Of the non-fluoroquinolone agents, the only oral agents to which over 90% of S. pneumoniae isolates were susceptible at both NCCLS and PK/PD breakpoints were amoxicillin (95.1%) and co-amoxiclav (95.5-97.9%). The prevalence of fluoroquinolone-resistant S. pneumoniae (ofloxacin MICs > or = 8 mg/l) was 1.1%. Gemifloxacin was the most potent fluoroquinolone tested against S. pneumoniae (99.9% susceptible). In isolates of H. influenzae, beta-lactamase production was 16.9%, whereas the prevalence of beta-lactamase-negative, ampicillin-resistant strains was low (0.2%). beta-Lactamase production in M. catarrhalis world-wide remained high over the period studied (92.1%). Using PK/PD breakpoints, the most active non-fluoroquinolone agents against H. influenzae were ceftriaxone (100% susceptible), cefixime (99.8%) and co-amoxiclav (98.1-99.6%). Co-amoxiclav, cefdinir and cefixime (100%) were the most active beta-lactams against M. catarrhalis. Both H. influenzae and M. catarrhalis were highly susceptible to the fluoroquinolones. CONCLUSIONS: These data demonstrate the continued evolution of and geographical variation in bacterial resistance and highlight the need for appropriate prescribing of antimicrobials in CARTI, using agents with adequate activity, based on local susceptibility profiles and PK/PD parameters.

Anti-Bacterial Agents↗
PubMed2003

Impact of antimicrobial resistance on health outcomes in the out-patient treatment of adult community-acquired pneumonia: a probability model.

Out-patient treatment of community-acquired pneumonia (CAP) is a major challenge in an era of increasing prevalence of antimicrobial resistance. However, data describing the clinical impact of such resistance are scarce. A probability model was developed to estimate the impact of antimicrobial resistance on clinical outcomes for adults with CAP, eligible for out-patient care. The model assumed patients would be evaluated at 48-72 h, with those failing to improve being either hospitalized or switched to a different antibiotic. Two strategies were considered: amoxicillin followed by erythromycin (amoxicillin/erythromycin) and erythromycin followed by levofloxacin (erythromycin/levofloxacin). Analyses were conducted based on susceptibility of the major pathogens in France and the UK. Primary model-generated outcome measures were the proportion of patients successfully treated with first-line therapy and the proportion of patients subsequently hospitalized. The model estimated that in France, the amoxicillin/erythromycin strategy would lead to 67.8% improving within 48-72 h and 12.7% subsequently being hospitalized, compared with 48.6% and 13.7% for erythromycin/levofloxacin. For the UK, first-line success and hospitalization rates were, respectively, 71.7% and 8.1% for amoxicillin/erythromycin, and 65.3% and 9.3% for erythromycin/levofloxacin. The model estimated that antimicrobial resistance was responsible for >40% of hospitalizations in France and 15% in the UK. These data suggest that in areas with substantially reduced levels of susceptibility, antimicrobial resistance may be a significant contributor to subsequent hospitalization in adults initially treated as out-patients for CAP. Choice of out-patient treatment strategy should consider local resistance rates in order to maximize the likelihood of early cure, thereby minimizing hospitalizations.

Adult↗
PubMed2003

Activity of nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: use of pharmacokinetic/pharmacodynamic breakpoints in the comparative assessment of beta-lactam and macrolide antimicrobial agents.

BACKGROUND: The application of pharmacokinetic (PK) and pharmacodynamic (PD) data in conjunction with minimum inhibitory concentrations (MICs) of antibacterial agents has been shown to allow for improved selection and appropriate dosing of antimicrobial agents for specific infections, increasing the likelihood of bacteriologic cure and, through this, reducing the risk for the development of resistant organisms. OBJECTIVES: This study was undertaken to provide data on current levels of resistance among common community-acquired bacterial species to 7 betalactam antimicrobial agents (including the combination product amoxicillin/clavulanate), azithromycin, and clarithromycin, determined through application of the PK/PD breakpoints based on time-above-MIC for the beta-lactams and the nonazalide macrolide clarithromycin, and on 24-hour serum area under the curve divided by MIC for the azalide macrolide azithromycin. METHODS: The antimicrobial products tested were amoxicillin/clavylanate, cefpodoxime, cefdinir, cefditoren, cefprozil, cefuroxime, cefixime, azithromycin, and clarithromycin. The bacterial species comprised 70 penicillin-susceptible, 68 penicillin-intermediate, and 69 penicillin-resistant strains of Streptococcus pneumoniae; 46 beta-lactamase-positive and 54 beta-lactamase-negative strains of Haemophilus influenzae; 49 strains of Moraxella catarrhalis; and 100 methicillin-sensitive strains of Staphylococcus aureus (MSSA). Strains were isolated from clinical specimens obtained from outpatient-acquired infections in 1 clinical center in the Northeast and 1 in the north-central area of the United States within the past 2 years. National Committee for Clinical Laboratory Standards microdilution MIC methodology was used. PK/PD breakpoints were obtained from previously published studies and were based on blood values. RESULTS: Amoxicillin/clavulanate was the product to which the greatest percentage of susceptible, intermediate, and resistant strains of pneumococci were sensitive at the PK/PD breakpoint, followed by cefditoren, cefpodoxime, cefuroxime, cefdinir, and cefprozil. None of the cephalosporins were active against penicillin-resistant pneumococci. Cefditoren and cefpodozime were the agents to which the greatest percentage of beta-lactamase-positive and beta-lactamase-negative strains of H influenzae were sensitive, followed by amoxicillin/clavulanate, cefdinir, and cefuroxime. Cefprozil was inactive against H influenzae. All of the beta-lactam products were active against M catarrhalis. All but cefpodoxime, cefditoren, and cefixime were active against MSSA. CONCLUSIONS: In this study, based on PK/PD breakpoints, amoxicillin/clavulanate had the best overall activity of the 9 antimicrobial products tested. Cefpodoxime and cefditoren were active against >or=90% of strains of penicillin-susceptible and penicillin-intermediate pneumococci, H influenzae, and M catarrhalis. The macrolides azithromycin and clarithromycin were active against penicillin-susceptible and penicillin-intermediate pneumococci and M catarrhalis; they were inactive against H influenzae and penicillin-resistant pneumococci.

Administration, Oral↗
PubMed2003

How can we predict bacterial eradication?

Antimicrobial efficacy is measured in vitro by determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of antimicrobials, but these values do not account for fluctuations of drug concentrations within the body or the time course of the drug's in vivo antibacterial activity. However, in vivo bacteriologic efficacy can be predicted by pharmacokinetic/pharmacodynamic (PK/PD) parameters, such as the time for which the serum drug concentration is above the MIC (T>MIC), the ratio of peak serum concentration to the MIC, and the ratio of the area under the 24-h serum concentration-time curve to the MIC (AUC/MIC). Different patterns of antibacterial activity correlate with different PK/PD parameters. For example, a T>MIC of 40-50% of the dosing interval is a good predictor of bacteriologic efficacy for penicillins, cephalosporins, and most macrolides, and an AUC/MIC ratio of at least 25 is required for efficacy with fluoroquinolones and azalides. The PK/PD breakpoint for susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest MIC met by the relevant PK/PD parameter for bacteriologic efficacy for that agent. These parameters have been validated extensively in animal models, as well as in many human studies where bacteriologic outcome has been determined. The PK/PD breakpoint of an agent is determined primarily by the dosing regimen, and generally applies to all pathogens causing disease at sites where extracellular tissue levels are similar to non-protein-bound serum levels. On this basis, many parenteral beta-lactams are active against almost all strains of Streptococcus pneumoniae, including 'penicillin-non-susceptible' strains, in all body sites except for the central nervous system. Application of PK/PD breakpoints to standard dosing regimens of oral beta-lactams predicts that agents such as cefaclor and cefixime will have efficacy only against penicillin-susceptible strains of S. pneumoniae, while cefuroxime axetil, cefpodoxime and cefdinir will be effective against all penicillin-susceptible as well as many penicillin-intermediate strains. However, the most active oral beta-lactams, amoxicillin and amoxicillin-clavulanate, have predicted efficacy against all penicillin-susceptible and -intermediate pneumococci, as well as against most penicillin-resistant strains, at amoxicillin doses of 45-90 mg/kg per day in children and 1.75-4.0 g/day in adults. These predictions are supported by evidence from animal studies of bacteriologic efficacy. The use of PK/PD parameters to predict bacterial eradication therefore allows an evidence-based approach to the selection of appropriate antimicrobial therapy.

Animals↗
PubMed2003

Cefotaxime-resistant bacteria colonizing older people admitted to an acute care hospital.

OBJECTIVES: To determine the frequency of fecal colonization by cefotaxime-resistant gram-negative bacilli in older patients living in the community and in long-term care facilities (LTCFs) admitted to an acute care hospital. DESIGN: Case-control, point prevalence study. SETTING: Hospital. PARTICIPANTS: One hundred forty-three patients aged 65 and older. MEASUREMENTS: Rectal swab cultures, antibiotic drug sensitivity, beta lactamase isolation, and clonal identity. RESULTS: Of the 190 surveillance cultures obtained from 143 patients, 26 cefotaxime-resistant gram-negative isolates from 22 patients were recovered. The prevalence rate of cefotaxime-resistant isolates on admission was 13.3% (19/143). A logistic regression model using cefotaxime colonization as the dependent variable found that multiple comorbidities, admission to a surgical service, and having a diagnosis of infection on presentation and a transfusion history were factors associated with the presence of colonization. These four clinical items accurately classified 74% of patients colonized. Antibiotic use and nursing home residence were not associated with the presence of colonization by cefotaxime-resistant organisms. Twelve of the cefotaxime-resistant isolates (46%) were identified as Pseudomonas aeruginosa, and 14 (54%) were other gram-negative bacilli. In six of the 14 isolates that were not P. aeruginosa (36%), it was possible to demonstrate the presence of an AmpC beta-lactamase related to the CMY-2 beta-lactamase, a plasmid-borne cephalosporinase. CONCLUSION: These data raise awareness that there are community- and LTCF-dwelling older patients colonized with gram-negative enteric bacilli resistant to third-generation cephalosporins on admission to the hospital. The "reservoir of resistant bacteria" in older people is no longer confined to LTCFs.

Aged↗
PubMed2003

Diversity of ampicillin-resistance genes in Haemophilus influenzae in Japan and the United States.

Clinical isolates of Haemophilus influenzae from Japan (n = 296) and the United States (n = 100) were tested by the microdilution method for susceptibility in vitro to 10 beta-lactam antibiotics and molecular mechanisms of beta-lactam resistance. For all isolates, PCR was used to identify six elements, including beta-lactamase-producing ampicillin (AMP)-resistance (BLPAR) and beta-lactamase-nonproducing AMP-resistance (BLNAR) genes as follows: (1) TEM-1 type beta-lactamase gene, (2) ROB-1 type beta-lactamase gene, (3) part of normal ftsI gene encoding PBP3, which is involved in septal peptidoglycan synthesis, (4) a portion of the ftsI gene possessing some amino acid substitutions commonly detected in BLNAR strains, (5) p6 gene encoding P6 membrane proteins specific to H. influenzae, and (6) serotype b capsule gene. In Japanese and U.S. isolates, respective prevalences of each resistance class in Japan and the United States were 55.1% and 46% for beta-lactamase-nonproducing, AMP-susceptible (BLNAS); 3.0% and 26% for the TEM-1 type beta-lactamase gene; 0% and 10% for the ROB-1 type; 26.4% and 13% for low-BLNAR with a low degree of AMP resistance; and 13.2% and 0% for BLNAR strains. A few remaining isolates were beta-lactamase-producing strains with a mutation in the ftsI gene. MICs of all beta-lactam agents against low-BLNAR strains were 2-8 times higher than against BLNAS. MICs of cephalosporin antibiotics against BLNAR strains were 16-32 times higher than against BLNAS. The rank order of beta-lactam MIC90 values against BLNAR strains was piperacillin = ceftriaxone = cefditoren (0.25 microg/ml), meropenem (0.5), cefotaxime (1), AMP = cefpodoxime (8), cefdinir (16), amoxicillin (16), and cefaclor (64). Serotype b isolates were few in both countries (2.4% in Japan, 3% in the United States). Differences in proportions of respective AMP-resistant genes in H. influenzae isolates between the two countries might reflect differences in antibiotic agents ordinarily given to outpatients with community-acquired bacterial infections.

Ampicillin Resistance↗
PubMed2003

Bactericidal activity of daptomycin against Streptococcus pneumoniae compared with eight other antimicrobials.

A spectrum of pneumococci with varying susceptibilities to beta-lactams, macrolides and quinolones was tested for susceptibility to nine antibiotics, including the novel lipopeptide daptomycin. Daptomycin was active against all strains (MIC range </=0.5 mg/L; MIC(50) 0.125 mg/L; MIC(90) 0.25 mg/L). All pneumococci were susceptible to vancomycin, teicoplanin, linezolid and quinupristin/dalfopristin, with MICs < 4.0 mg/L. Time-kill assays with eight strains demonstrated that daptomycin (2 x MIC) was bactericidal in seven of eight strains tested at 24 h, with >90% killing at 1 h.

4-Quinolones↗
PubMed2003

Worldwide trends in antimicrobial resistance among common respiratory tract pathogens in children.

BACKGROUND: Respiratory tract infections among children are a common reason for health care provider visits and the primary reason for antimicrobial prescribing in this population. The increased prevalence of resistance among Streptococcus pneumoniae and Haemophilus influenzae pathogens poses a serious challenge in the successful treatment of respiratory tract infections caused by these pathogens. METHODS: This paper reviews worldwide trends in antimicrobial resistance among common respiratory tract pathogens, highlighting data obtained from the pediatric population where available. RESULTS: S. pneumoniae resistance to beta-lactams is mediated through alterations in the penicillin-binding proteins and macrolide resistance to acquisition of efflux or methylation genes. The mechanisms of resistance to the fluoroquinolones include target enzyme alterations via genetic mutations and transport out of the bacterial cell via an efflux pump. Beta-lactamase production is the primary mechanism of resistance to penicillins among H. influenzae isolates. Although S. pneumoniae with reduced susceptibility to penicillin was first documented > 30 years ago, resistance has increased at an alarming rate worldwide in the past decade. According to recent surveillance data, the worldwide prevalence of S. pneumoniae with reduced susceptibility to penicillin is 18.2%. Beta-lactamase production among H. influenzae ranges from approximately 4% in Russia to 26% in the United States and to 31% in France. The prevalence of beta-lactamase-negative, ampicillin-resistant H. influenzae remains very low (< 1%) worldwide, except in Japan, where the incidence is higher. In general, the highest rates of resistance are observed in isolates obtained from children, and risk factors for infection with a resistant pathogen include young age, the site of infection, day-care center attendance and recent antimicrobial use. CONCLUSIONS: Increased prevalence of antimicrobial resistance among respiratory tract pathogens isolated from children and adults is evident worldwide. Treatment of infections caused by S. pneumoniae and H. influenzae with older agents or ineffective dosing regimens may not eradicate infections and may contribute to the spread of resistance. These observations confirm the need for appropriate antimicrobial use to halt or at least limit the spread of resistance.

Bacterial Infections↗
PubMed2003

Macrolide resistance: an increasing concern for treatment failure in children.

BACKGROUND: Antimicrobial treatment of pediatric respiratory tract infections has evolved during the past 30 years as a result of antimicrobial resistance. The focus of antimicrobial therapy in these conditions has shifted from penicillins to other agents because of the dramatic increase in antimicrobial resistance among common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. It is important for clinicians to understand how resistance develops so that they can help prevent this phenomenon from occurring with other antimicrobials. METHODS: This article reviews the published literature on resistance to macrolide antimicrobials among common pediatric respiratory tract pathogens and clinical and bacteriologic outcomes of infections with these pathogens. RESULTS: Resistance among common pediatric respiratory tract pathogens to macrolides occurs through two main mechanisms, alteration of the target site and active efflux. Although resistance patterns vary by geographic region, the widespread use of macrolides has contributed to the emergence of both types of macrolide-resistant organisms. Conditions that favor the selection and proliferation of resistant strains include children with repeated, close contact who frequently receive antimicrobial treatment or prophylaxis, such as children who attend day care. Recent US surveillance data show that 20 to 30% of S. pneumoniae are resistant to macrolides, with approximately two-thirds of macrolide-resistant strains associated with an efflux mechanism and the remainder associated with a ribosomal methylase. Additionally, although less well-known, virtually all strains of H. influenzae have an intrinsic macrolide efflux pump. As resistance to macrolides has increased, clinical failures have resulted, and these agents are no longer considered appropriate for empiric first line antimicrobial therapy of acute otitis media and sinusitis unless patients are truly penicillin-allergic. Therefore, other antimicrobials are recommended for the empiric treatment of children with respiratory tract infections, including higher doses of amoxicillin and amoxicillin/clavulanate (90 mg/kg/day amoxicillin), cefuroxime axetil and intramuscular ceftriaxone. CONCLUSIONS: As resistance to macrolides increases and clinical failures in children become more common with this class of antimicrobials, judicious use of antimicrobials is needed. This includes limiting antimicrobial use for viral infections and using the most effective agents when antimicrobials are clinically indicated, such as higher doses of amoxicillin and amoxicillin/clavulanate. Application of these principles may prevent proliferation and further development of resistance.

Child↗
PubMed2003

Bacteriologic and clinical efficacy of oral gatifloxacin for the treatment of recurrent/nonresponsive acute otitis media: an open label, noncomparative, double tympanocentesis study.

BACKGROUND: Gatifloxacin is an 8-methoxyfluoroquinolone with good activity against respiratory pathogens. OBJECTIVES: To document the bacteriologic and clinical efficacy of gatifloxacin in recurrent/nonresponsive acute otitis media (AOM). METHODS: One hundred sixty patients 6 to 48 months of age with recurrent/nonresponsive AOM received gatifloxacin suspension (10 mg/kg once daily for 10 days). Recurrent AOM was defined as > or =3 AOM episodes during the previous 6 months or > or =4 AOM episodes during the previous 12 months. Nonresponsive AOM was defined as AOM occurring < or =14 days after completing antibiotic treatment or not improving after > or =48 h of therapy. Middle ear fluid (MEF) obtained by tympanocentesis pretreatment (Day 1) and 3 to 5 days after initiation of treatment (Days 4 to 6) was cultured. Additional MEF cultures were obtained if clinical failure or recurrence of AOM occurred. Bacteriologic failure was defined by culture-positive MEF during treatment. Patients were followed until Days 22 to 28. Susceptibility was determined by broth microdilution. RESULTS: One hundred twenty-eight (80%) patients completed treatment, and 32 discontinued the study prematurely (adverse events, 17; lost to follow-up, 10; consent withdrawal, 3; and laboratory abnormalities, 2). From 89 patients (median age, 1 year; median number of prior AOM episodes, 4; range, 0 to 12), 121 pathogens were recovered: Haemophilus influenzae, 74 (61%); Streptococcus pneumoniae, 36 (30%); Moraxella catarrhalis, 9 (7%); and Streptococcus pyogenes, 2 (2%). The 36 S. pneumoniae isolates were susceptible to gatifloxacin (MIC50 0.25 microg/ml); 26 of 36 (72%) were penicillin-nonsusceptible (15 fully resistant). All 74 H. influenzae isolates were susceptible to gatifloxacin (MIC < or = 0.03 mg/ml). Fourteen of 74 (19%) and 9 of 9 (100%) H. influenzae and M. catarrhalis isolates, respectively, produced beta-lactamase. Bacteriologic eradication was achieved for 118 of 121 (98%) pathogens: 74 of 74 H. influenzae; 34 of 36 (94%) S. pneumoniae; 9 of 9 M. catarrhalis; and 1 of 2 S. pyogenes. Clinical improvement/cure at end of treatment was seen in 103 of 114 (90%) clinically evaluable patients. Clinical recurrence of AOM after completion of therapy occurred in 31 patients. Of the 27 recurrent AOM cases in which tympanocentesis was performed, there were 16 (59%) new infections, 4 (15%) culture-negative results and only 7 (26%) true bacteriologic relapses. Adverse events were recorded in 21 of 160 (13%) patients: vomiting, 16; diarrhea, 3; maculopapular rash, 2. No articular adverse events were recorded. CONCLUSION: Gatifloxacin is efficacious and safe for the treatment of recurrent/nonresponsive AOM.

Acute Disease↗