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PubMed2001

What have we learned from pharmacokinetic and pharmacodynamic theories?

Pharmacokinetic characteristics and pharmacodynamic properties dictate antimicrobial response and, along with natural immune responses, clinical outcomes. As new agents are developed with long half-lives, we will lose the ability to differentiate between concentration-dependent and time-dependent properties. The area under the inhibitory concentration curve (AUIC) defines drug regimens as a ratio of drug exposure to minimum inhibitory concentration (MIC) and allows them to be compared with each other. With AUIC and agents with long half-lives, these comparisons are possible regardless of chemical classification or concentration or time-dependent activity. Historical examples of reduced drug exposure from decreased doses (i.e., cefaclor, clarithromycin, and ciprofloxacin), and thus low AUIC values, directly correlate with drug resistance. In the face of rising MICs (as is occurring worldwide with Streptococcus pneumoniae), close attention to appropriate dosing and concentration above the MIC may delay and potentially even prevent antibiotic resistance. Creating selective pressure on reliable antibiotics by inappropriately reducing their doses will undoubtedly challenge these agents and may destroy entire drug classes with similar mechanisms of action or resistance.

Animals↗
PubMed1998

Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.

As part of the ongoing multinational SENTRY antimicrobial resistance surveillance program, a total of 1,047 respiratory tract isolates of Streptococcus pneumoniae, 845 from 27 United States medical centers and 202 from seven Canadian institutions, were collected between February and June 1997 and characterized in a central laboratory. In the United States, the overall percentages of penicillin-intermediate strains and strains with high-level resistance to penicillin were 27.8% and 16.0%, respectively. In Canada, these values were 21.8% and 8.4%, respectively. Among the 31 centers in the United States and Canada that contributed at least 19 isolates, the combined rate of intermediate plus resistant strains varied between 24.0% and 67.8%. The in vitro activity of 19 other antimicrobials was assessed against all study isolates. Overall rates of resistance among selected agents in the United States and Canada, respectively, were as follows: amoxicillin, 18.1% and 10.5%; cefaclor, 38.3% and 26.2%; cefuroxime, 19.5% and 12.9%; cefpodoxime, 18.6% and 11.4%; cefepime, 8.2% and 4.5%; cefotaxime, 4.0% and 3.0%; macrolides (i.e., erythromycin, azithromycin, and clarithromycin), 11.7%-14.3% and 5.0%-7.4%; clindamycin, 3.5% and 3.5%; chloramphenicol, 3.9% and 4.0%; tetracycline, 10.2% and 10.9%; and trimethoprim-sulfamethoxazole, 19.8% and 15.8%.

Drug Resistance, Microbial↗
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↗
PubMed1996

Antimicrobials prescribed for otitis media in a pediatric Medicaid population.

Antimicrobial prescribing patterns for Tennessee Medicaid children having their first case of otitis media (OM) in at least nine months were studied. Tennessee Medicaid claims data for patients under 11 years whose first documented OM diagnosis in 1993 occurred in the fourth quarter and who had had an antimicrobial claim filed within two days of diagnosis were studied to determine antimicrobial prescribing patterns. Of 7357 children meeting the study criteria, 70% were less than three years of age, 65% were Caucasian, and 60% had a rural address. Twenty antimicrobials were prescribed. Amoxicillin was prescribed most frequently (53% of the time), followed by cefaclor; all first-line therapies (amoxicillin, ampicillin, erythromycin-sulfisoxazole, and trimethoprim-sulfamethoxazole) accounted for 64% of the prescriptions, but only one fourth of the costs. The highest use of first-line therapy was associated with children under three years of age; children without prior antimicrobial therapy, recent upper respiratory infection (URI), or recent sinusitis; children seen by emergency department physicians; and children seen by urban physicians. Tennessee Medicaid would have saved +68,250 if first-line therapy had been used for all children having their first occurrence of OM in the fourth quarter alone. The savings to the state were estimated at +300,000 or more in 1993 had first-line therapy been used for most first occurrences of OM in all four quarters plus even a small percentage of the estimated 30,000 remaining repeat OM cases. Amoxicillin was prescribed 53% of the time, and all first-line therapies 64% of the time, for children with their first case of OM in at least nine months. In children without recent antimicrobial therapy, URI, or sinusitis, first-line therapy was still used only 72% of the time.

Age Distribution↗
PubMed1995

High incidence of resistance to multiple antimicrobials in clinical isolates of Streptococcus pneumoniae from a university hospital in Korea.

One hundred thirty-one strains of Streptococcus pneumoniae isolated from clinical specimens between January 1991 and April 1993 were serotyped and tested for susceptibility to 10 antimicrobials by the agar dilution method. Five serotypes (6A, 6B, 14, 19F, and 23F) accounted for 67% of all isolates. Seventy percent of isolates were not susceptible to penicillin, exhibiting either intermediate resistance (37%) or high-level resistance (33%); 82% of isolates from children and 59% of those from normally sterile body fluids were resistant to penicillin. A significantly increased rate of penicillin resistance (P < .01, Fisher's exact or chi 2 test) was associated with hospitalization, an age of < or = 15 years, ongoing antimicrobial therapy at the time of isolation of the organism, nosocomial acquisition, and several specific serotypes (6, 14, 19F, and 23F). No penicillin-resistant strain showed beta-lactamase activity. Various proportions of the penicillin-resistant strains also displayed resistance to cefaclor (89%), cefotaxime (82%), chloramphenicol (65%), erythromycin (52%), and ciprofloxacin (15%), but none was resistant to teicoplanin or vancomycin. The prevalence of pneumococcal resistance documented in Korea in this study is among the highest figures published to date.

Adolescent↗
PubMed1995

Antimicrobial resistance of Streptococcus pneumoniae in Finland, 1987-1990.

A nationwide survey of the prevalence of antimicrobial resistance among Streptococcus pneumoniae isolates from the middle ear fluid of children with acute otitis media (639 strains) and from throat-swab samples of healthy children (149 strains) was conducted in Finland during 1987-1990. The MICs of penicillin, cephalothin, cefaclor, erythromycin, trimethoprim, and co-trimoxazole were determined by the agar dilution method. Low-level resistance to penicillin (MIC, 0.1-1 microgram/mL) was found in 1.7% of the otitis-related and 1.3% of the healthy-carrier strains. No highly penicillin-resistant strains (MIC, > or = 2 micrograms/mL) were found. Six multiresistant strains were detected, three of them possibly belonging to a previously identified clone present in Finland since 1985. Eighty-five percent of the resistant otitis-related strains, including 9 of the 11 moderately penicillin-resistant strains (4 of which were multiresistant), belonged to the three most common serogroups (6, 19, and 23).

Acute Disease↗
PubMed1995

Bacteriology of chronic otitis media, chronic sinusitis, and paranasal mucopyocele in Japan.

A bacteriologic study of cases of chronic otitis media, chronic sinusitis, and paranasal mucopyocele diagnosed at Gifu University Hospital was performed between 1989 and 1992. Bacteria were isolated from all of 13 samples of discharge from the ears of patients with chronic otitis media, all of 14 mucosal biopsy specimens from patients with chronic sinusitis, 8 of 10 aspirate samples from patients with chronic sinusitis, and 9 of 15 aspirates samples from patients with mucopyocele. Cultures often yielded polymicrobial growth, with an average of 3.1, 3.8, and 4.2 species per positive specimen from chronic otitis media, chronic sinusitis, and mucopyocele, respectively. The most commonly encountered anaerobes were Peptostreptococcus, Propionibacterium, and Prevotella species; the most common aerobes were Staphylococcus and Streptococcus species. One strain of Prevotella melaninogenica highly resistant to ampicillin and two strains of Peptostreptococcus resistant to cefaclor were found.

Adolescent↗
PubMed1995

Development of beta-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis in Finnish children, 1978-1993.

The frequency of beta-lactamase production was analyzed in a study of 1,452 strains of Moraxella catarrhalis and 2,738 strains of Haemophilus influenzae isolated from middle-ear fluid of children < 6 years of age at Tampere University Hospital in Tampere, Finland, between 1978 and 1993. In addition, 401 isolates of M. catarrhalis from similar samples collected in different parts of Finland in 1988-1990 were tested for beta-lactamase production; minimal inhibitory concentrations of ampicillin, cefaclor, cephalothin, erythromycin, tetracycline, and trimethoprim-sulfamethoxazole for these strains were determined. These data were compared with figures for the annual consumption of beta-lactam antimicrobials in the community in 1978-1993. A bimodal increase in the proportion of strains of M. catarrhalis producing beta-lactamase was detected: from 0 to 60% in 1978-1983 and from 60% to 80% in 1988-1990. Concurrently with the second increase, the consumption of cephalosporins increased substantially in the community. The frequency of beta-lactamase-producing strains of H. influenzae did not increase between 1978 and 1993.

Anti-Bacterial Agents↗
PubMed1977

In vitro activity of five oral cephalosporins against anaerobic pathogenic bacteria.

The in vitro inhibitory activities of cefaclor and and cefatrizine, two new orally absorbed cephalosporin antibiotics, against 44 isolates of anaerobic pathogenic bacteria were measured using the agar dilution procedure of the World Health Organization-International Collaborative Study. Tests also were performed with cephalexin, cephaloglycin, and cephadrine, as well as with the parenteral cephamycin antibiotic cefoxitin. Cefoxitin was the most active antibiotic and inhibited the majority of isolates at a concentration of less than or equal to 4 microgram/ml. None of the oral cephalosporins was clearly superior against all of the anaerobic isolates; only cephadrine and cefatrizine appeared to have any potential clinical value.

Bacteroides↗
PubMed1994

Epidemiology of community-acquired Clostridium difficile-associated diarrhea.

The epidemiology of clinically recognized community-acquired Clostridium difficile-associated diarrhea was assessed in a retrospective cohort study of members of a health maintenance organization (HMO). Potential cases were identified through positive toxin assay results and confirmed by review of automated full-text medical records. Of 51 cases identified (7.7 per 100,000 person-years), 42 (82%) were diagnosed and treated exclusively in the ambulatory care setting; 33 cases occurred within 42 days after 494,491 exposures to antibiotics dispensed by an HMO pharmacy. Antibiotic-specific attack rates varied from 0 to 2040 cases per 100,000 exposures. Increased age was associated with C. difficile-associated diarrhea (P < .001). Age-adjusted antibiotic-specific attack rates were at least 10-fold higher (P < .05) for nitrofurantoin, cefuroxime, cephalexin plus dicloxacillin, ampicillin/clavulanate plus cefaclor, and ampicillin/clavulanate plus cefuroxime than for ampicillin or amoxicillin; several other antibiotics were associated with similar but not significantly increased risks.

Adolescent↗
PubMed1994

Serotype distribution and antimicrobial resistance patterns of invasive isolates of Streptococcus pneumoniae: Alaska 1986-1990.

From January 1986 through December 1990, 672 cases of invasive pneumococcal disease were identified. From these, 574 pneumococcal isolates were recovered from normally sterile sites (blood, cerebrospinal and pleural fluid); 92% were serotypes represented in the 23-valent pneumococcal polysaccharide vaccine. The most common serotypes from children < 2 years old were 4, 6B, 9V, 14, 18C, 19F, and 23F, recovered from 83% of Alaska Native and 75.1% of nonnative children with invasive disease. Moderate penicillin resistance (MIC, 0.1-1.0 micrograms/mL) was found in 3.8% of isolates. All were sensitive to chloramphenicol, vancomycin, rifampin, ceftriaxone, cefotaxime, cephalothin, and cefaclor. However, in the Yukon-Kuskokwim Delta region, 16.9% of isolates were moderately resistant to penicillin, and 10.8% were resistant to erythromycin and 6.2% to trimethoprim-sulfamethoxazole; the number resistant to two or more antibiotics increased significantly during surveillance. All multiply resistant isolates were serotype 6B, and all were from Alaska Native patients < 2 years old.

Adolescent↗
PubMed1995

Multiple antimicrobial resistance of pneumococci in children with otitis media, bacteremia, and meningitis in Slovakia.

Penicillin-resistant pneumococci have been isolated from middle ear fluid, blood, cerebrospinal fluid, and nasopharyngeal secretions of several hundred children in Slovakia since 1985; 116 of these isolates were serotyped and tested for susceptibility to antimicrobial drugs at the Centers for Disease Control and Prevention. To define the prevalence of drug-resistant pneumococci and identify risk factors for infection, laboratory and medical records were reviewed. Nearly all (96%) of the resistant strains tested were serotype 14. Of these, all were resistant to penicillin (MIC, 4-16 micrograms/mL); most were resistant to cefaclor, erythromycin, tetracycline, and chloramphenicol; and many had decreased susceptibility to trimethoprim-sulfamethoxazole and ceftriaxone. Frequent antibiotic use, prior hospitalization, and length of hospital stay (P < .001 for all 3) were associated with infection with resistant strains. These findings suggest the need for routine screening of pneumococcal isolates for penicillin resistance and highlight the importance of controlling globally the spread of resistant pneumococci.

Bacteremia↗
PubMed1983

Influence of beta-lactamase-producing strains of Branhamella catarrhalis and Haemophilus influenzae on certain beta-lactam antibiotics.

Ampicillin, benzylpenicillin, cefaclor and cefuroxime were exposed to strains of Branhamella catarrhalis and Haemophilus influenzae with and without ability to produce beta-lactamase. The antibiotics were dissolved in phosphate buffer at pH 6, 7 and 8 and the mean enzyme activity was calculated from decrease in peak heights by the HPLC technique. Cefuroxime was the most stable drug regardless of pH. For the other antibiotics, changes in pH influenced the results. In infectious processes factors like pH and pCO2 show some variation. This fact may influence the interaction between beta-lactams and beta-lactamases.

Anti-Bacterial Agents↗
PubMed1983

The permeability barrier of Haemophilus influenzae type b against beta-lactam antibiotics.

An evaluation was made of the role of the outer membrane of Haemophilus influenzae type b as a permeability barrier against beta-lactam antibiotics. Sonic extracts of H. influenzae containing beta-lactamase were assayed for the rates of hydrolysis of benzylpenicillin, ampicillin, cloxacillin, cephacetrile, cefazolin, cefamandole, cephalothin, cephaloridine, cephaloglycin, and cefaclor. Benzylpenicillin was hydrolyzed most rapidly, whereas cephacetrile, cephaloridine, and cephaloglycin were the poorest substrates for the beta-lactamase. The hydrolysis of these ten beta-lactams by intact cells was also determined; it was necessary to stabilize the cells with MgCl2 to prevent lysis and thereby to maintain the beta-lactamase in the periplasm. Calculations were made of the concentration of the antibiotics which had accumulated in the periplasm. The transmembrane permeability coefficient, C, was determined for the ten beta-lactam antibiotics. All of the compounds tested were able to diffuse across the outer membrane of H. influenzae type b very efficiently. The values of the permeability coefficient were compared with the partition coefficients of the antibiotics in a two-phase isobutanol/water mixture. For a ten-fold increase in hydrophobicity, there was a ten-fold decrease in the permeability coefficient. The outer membrane of haemophilus was not an effective barrier against the penetration of penicillins or cephalosporins. The activity of these compounds could be attributed either to their low hydrolysis by beta-lactamase or to the high affinity of binding to their sensitive targets.

Anti-Bacterial Agents↗
PubMed1985

Characterization of the plasmid-mediated beta-lactamase in Branhamella catarrhalis, with special reference to substrate affinity.

The plasmid-mediated Branhamella catarrhalis beta-lactamase BRO-1, also found in Moraxella nonliquefaciens, was characterized as regards substrate profile, isoelectric point and relative substrate affinity index (RSAI) to various substrates and compared in these aspects with the TEM-1 enzyme of Haemophilus influenzae. As measured by a biological assay and with high performance liquid chromatography (HPLC), BRO-1 was found to hydrolyse carbenicillin, mecillinam, methicillin and cefaclor with a higher rate than TEM-1. The only substrates having a relative rate of hydrolysis higher for TEM-1 than for BRO-1 were ampicillin and cephaloridine. The rates of hydrolysis registered with these two methods were comparable for all but 2 of 13 tested substrates. Isoelectric focusing yielded a main band at pH 5.6 and several satellite bands consistent with those reported by other authors for Branhamella enzymes having a substrate profile similar to that of BRO-1. A tenfold or higher difference in RSAI between BRO-1 and TEM-1 was recorded for five of the 15 compounds tested. BRO-1 seems to be the most common beta-lactamase in Bran. catarrhalis, irrespective of geographic origin. Its substrate profile, isoelectric pattern and RSAI differ from those of other known plasmid-mediated beta-lactamases described, thus justifying a specific designation.

Anti-Bacterial Agents↗
PubMed1985

Characterization of a new beta-lactamase from Fusobacterium nucleatum by substrate profiles and chromatofocusing patterns.

Seven beta-lactamase-producing Fusobacterium nucleatum strains were isolated from patients with recurrent tonsillitis. The isolates were highly resistant to phenoxymethylpenicillin, benzylpenicillin, ampicillin, piperacillin and cloxacillin. They were all sensitive to cefaclor, cephaloridine, cefotaxime, cefoxitin, latamoxef (moxalactam) and imipenem. Penicillinase activity was found intracellularly after 20 h incubation. Specific activity of the unpurified penicillinase varied among the strains between 0.24-9.3 U/mg protein. The enzyme hydrolysed ampicillin and benzylpenicillin more rapidly than piperacillin. Cephalothin and imipenem were hydrolysed at rates less than 1% of benzylpenicillin. Chromatofocusing experiments eluted the beta-lactamases from all strains at a single peak between pH 5.1-5.2.

Anti-Bacterial Agents↗
PubMed1987

Antibiotic interaction of amoxycillin and clavulanic acid against 132 beta-lactamase positive Haemophilus isolates: a comparison with some other oral agents.

We studied the specific beta-lactamase inhibitory activity of clavulanic acid in association with amoxycillin against 132 beta-lactamase producing Haemophilus isolates. Inhibitory synergy between amoxycillin and clavulanic acid (ratio 2:1) was found in 131/132, partial synergy or antagonism in none; bactericidal synergy was found in 124/131, partial synergy in 4 and antagonism in 1. In comparison, inhibitory synergy between trimethoprim and sulphamethoxazole (ratio 1:19) was found in only 39/104 beta-lactamase positive strains, partial synergy in 42 and antagonism in 3 and bactericidal synergy in 18/104, partial synergy in 8 and antagonism in 3. The amoxycillin-clavulanic acid combination expressed significantly (P less than 0.001) more frequent synergy, at both inhibitory and bactericidal levels, than the trimethoprim-sulphamethoxazole combination. The synergy of amoxycillin-clavulanic acid resulted in a significant decrease of MIC90 (greater than or equal to 32.0-2.0 mg/l) and MBC90 (greater than or equal to 32.0-4.0 mg/l) of amoxycillin; the synergy of trimethoprim-sulphamethoxazole resulted in a significant decrease of MIC90 (8.0-2.0 mg/l) of trimethoprim but did not change MBC90. The amoxycillin-clavulanic acid combination was also more active than cefaclor or erythromycin alone against the 132 beta-lactamase producing strains.

Amoxicillin↗
PubMed1987

Comparative susceptibilities of ampicillin and chloramphenicol resistant Haemophilus influenzae to fifteen antibiotics.

Eighty-three isolates of ampicillin and chloramphenicol resistant Haemophilus influenzae were tested for susceptibility to fifteen antibiotics by the agar dilution method. Fifty-four were from paediatric patients with H. influenzae disease and 29 from nasopharyngeal carriers (pre-school children). Twenty-five strains belonged to serotype b, one to serotype a, one to serotype c and the rest were non-typable. All strains produced beta-lactamase and inactivated chloramphenicol in a rapid bioassay, suggesting the production of chloramphenicol-acetyltransferase. The most active drugs were ceftriaxone, cefotaxime, latamoxef, aztreonam and desacetyl-cefotaxime (MIC90: 0.03, 0.06, 0.12, 0.25 and 0.25 mg/l, respectively). Cefuroxime, rifampicin and imipenem (MIC90 1 mg/l), and the combination of amoxycillin and clavulanic acid (MIC90 2:1 mg/l), also showed good activity. Cefaclor, erythromycin, tetracycline, trimethoprim, sulfamethoxazole and cotrimoxazole were the least active of the drugs studied. The excellent in-vitro activity of the new beta-lactam agents against H. influenzae resistant to ampicillin and chloramphenicol offers a therapeutic alternative in the treatment of serious infections caused by these micro-organisms.

Ampicillin↗