David A. Preston

National collaborative study of the prevalence of antimicrobial resistance among clinical isolates of Haemophilus influenzae.

A total of 2,811 clinical isolates of Haemophilus influenzae were obtained during 1986 from 30 medical centers and one nationwide private independent laboratory in the United States. Among these, 757 (26.9%) were type b strains. The overall rate of beta-lactamase-mediated ampicillin resistance was 20.0%. Type b strains were approximately twice as likely as non-type b strains to produce beta-lactamase (31.7 versus 15.6%). The MICs of 12 antimicrobial agents were determined for all isolates. Ampicillin resistance among strains that lacked beta-lactamase activity was extremely uncommon (0.1%). Percentages of study isolates susceptible to cefamandole, cefaclor, cephalothin, and cephalexin were 98.7, 94.5, 87.3, and 43.3%, respectively. For 14 strains (0.5% of the total), chloramphenicol MICs were greater than or equal to 8.0 micrograms, and thus the strains were considered resistant. All of these resistant strains produced chloramphenicol acetyltransferase. In addition, all 14 strains were resistant to tetracycline; 11 produced beta-lactamase. The percentage of isolates susceptible to tetracycline was 97.7%. In contrast, erythromycin and sulfisoxazole were relatively inactive. The combination of erythromycin-sulfisoxazole (1/64) was more active than erythromycin alone but essentially equivalent in activity to sulfisoxazole alone. Finally, small numbers of clinical isolates of H. influenzae were resistant to trimethoprim-sulfamethoxazole and rifampin.

Biological Properties of Three 3-Heterocyclic-Thiomethyl Cephalosporin Antibiotics

Three new cephalosporin antibiotics, prepared by substitution of heterocyclic groups on 7-aminocephalosporanic acid, possess certain desirable chemical or biological properties. All three compounds are active in vitro against a variety of gram-positive and gram-negative bacteria. Minimal inhibitory concentrations (MIC) of these bactericidal antibiotics were not significantly affected by changes in pH or NaCl content of nutrient broth, or by the use of different inoculum sizes. However, agar-dilution MIC values were generally two- to fourfold lower than the MIC values in comparable broth-dilution tests. Stability to cephalosporinase by two of the compounds extended their antibacterial spectra over cephalothin and cephaloridine to include strains of Enterobacter sp. and indole-positive Proteus sp. Binding to serum proteins of the new cephalosporins was intermediate between cephalothin and cephaloridine. Excellent concentrations of the antibiotics were attained in mouse blood, after subcutaneous administration of 20 mg per kg. In vitro biological characteristics of the antibiotics were verified by successful therapy of experimental mouse infections. Regression lines were calculated to show the correlation of agar-dilution MIC values with zones of inhibition by the disc testing procedure. Because each of the three new cephalosporins has certain advantageous properties over cephalothin and cephaloridine, additional toxicological and pharmacological data should be obtained for all three compounds.

Prevalence of antimicrobial resistance among clinical isolates ofHaemophilus influenzae: A collaborative study

The prevalence of antimicrobial resistance was assessed among a total of 3,356 clinical isolates of Haemophilus influenzae obtained from 22 medical centers distributed throughout the United States during the period July, 1983 through June, 1984. All strains were examined for beta-lactamase production with a rapid acidometric assay and for resistance to ampicillin, chloramphenicol, cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin with a standardized disk diffusion procedure. The overall rate of beta-lactamase production was 15.2%, although results of disk diffusion tests suggested that the overall rate of ampicillin resistance was 19.5%. Twenty-one percent of encapsulated type b strains produced beta-lactamase; 12.1% of non-type b strains were beta-lactamase positive. Specific rates of beta-lactamase production obtained at individual study centers varied widely with no evidence of geographic clustering. The highest rates of beta-lactamase production were observed with isolates of H. influenzae recovered from infants and young children, and from blood and cerebrospinal fluid specimens. The overall rate of chloramphenicol resistance was 0.6%. The prevalence of cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin resistance was 9.9%, 2.4%, 2.8%, 6.4%, and 64.2%, respectively. beta-Lactamase positive isolates of H. influenzae had higher rates of resistance to all of the cephalosporins than did strains that lacked beta-lactamase.

In Vitro Activities of LY333328 and Comparative Agents against Nosocomial Gram-Positive Pathogens Collected in a 1997 Global Surveillance Study

ABSTRACT The in vitro activity of LY333328 was evaluated for 1,479 nosocomial gram-positive pathogens isolated in 12 countries during 1997. LY333328 MICs at which 90% of the isolates tested were inhibited for Enterococcus faecalis (n = 351),Enterococcus faecium (n = 100),Staphylococcus aureus (n = 593), coagulase-negative Staphylococcus species (n = 325), and Streptococcus pneumoniae(n = 110) were 1, 1, 2, 2, and 0.015 μg/ml, respectively. LY333328 demonstrated potent activity against isolates of vancomycin-resistant enterococci, oxacillin-resistant staphylococci, and penicillin-resistant pneumococci.

Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to sixteen antibiotics.

Ampicillin-resistant and -susceptible strains of Haemophilus influenzae were tested for susceptibility to 16 antibiotics. Chloramphenicol and a new cephalosporin, cefamandole, were most active with minimal inhibitory concentrations (MICs) for all bacteria tested between 0.5 to 2.0 μg/ml. All but two organisms were susceptible to tetracycline. Ampicillin-resistant strains of H. influenzae were less susceptible (MIC, 4 to 32 μg/ml) to carbenicillin and ticarcillin than ampicillin-susceptible organisms (MIC, 0.25 to 1.0 μg/ml). A rapid assay for β-lactamase, utilizing a chromogenic cephalosporin substrate, detected enzyme production in all 17 ampicillin-resistant strains of H. influenzae. Images

Prevalence of antimicrobial resistance among clinical isolates of Haemophilus influenzae. A collaborative study

The prevalence of antimicrobial resistance was assessed among a total of 3,356 clinical isolates of Haemophilus influenzae obtained from 22 medical centers distributed throughout the United States during the period July, 1983 through June, 1984. All strains were examined for beta-lactamase production with a rapid acidometric assay and for resistance to ampicillin, chloramphenicol, cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin with a standardized disk diffusion procedure. The overall rate of beta-lactamase production was 15.2%, although results of disk diffusion tests suggested that the overall rate of ampicillin resistance was 19.5%. Twenty-one percent of encapsulated type b strains produced beta-lactamase; 12.1% of non-type b strains were beta-lactamase positive. Specific rates of beta-lactamase production obtained at individual study centers varied widely with no evidence of geographic clustering. The highest rates of beta-lactamase production were observed with isolates of H. influenzae recovered from infants and young children, and from blood and cerebrospinal fluid specimens. The overall rate of chloramphenicol resistance was 0.6%. The prevalence of cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin resistance was 9.9%, 2.4%, 2.8%, 6.4%, and 64.2%, respectively. beta-Lactamase positive isolates of H. influenzae had higher rates of resistance to all of the cephalosporins than did strains that lacked beta-lactamase.

Activities of the semisynthetic glycopeptide LY191145 against vancomycin-resistant enterococci and other gram-positive bacteria.

LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin- and teicoplanin-resistant enterococci of < or = 4 micrograms/ml for 50% of isolates and < or = 16 micrograms/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 micrograms/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.

Susceptibility of multiply resistant Haemophilus influenzae to newer antimicrobial agents

One hundred and six isolates of Haemophilus influenzae from a national antimicrobial surveillance study demonstrated resistance to two or more of 10 primary antimicrobial agents by mechanisms other than or in addition to beta-lactamase. Of particular note were strains multiply resistant to ampicillin (by beta-lactamase production), chloramphenicol, trimethoprim/sulfamethoxazole, and tetracycline in various combinations. All of the aforementioned strains were shown to be highly susceptible to amoxicillin/clavulanate, the second generation cephalosporins cefuroxime and cefonicid, and the third generation cephalosporins cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, moxalactam, and cefixime. However, 68 strains that demonstrated resistance or marginal susceptibility (MIC greater than or equal to 2 micrograms/ml) to ampicillin by mechanisms other than beta-lactamase, also demonstrated reduced susceptibility to amoxicillin/clavulanate (MICs up to 8 micrograms/ml) and the second generation cephalosporins (MICs up to 32 micrograms/ml). While the latter strains were susceptible to the third generation cephalosporins, MICs were often 10-fold higher than MICs of ampicillin susceptible isolates or of beta-lactamase producing isolates. All of the multiply antimicrobial-resistant strains were highly susceptible (MIC less than or equal to 0.25 micrograms/ml) to the two quinolones ciprofloxacin and pefloxacin.

Delineation of the Relative Antibacterial Activity of Cefamandole and Cefamandole Nafate

By conventional laboratory evaluation procedures, the in vitro antibacterial activities of cefamandole and its O-formyl ester, cefamandole nafate, appear virtually identical. When the activities of these two compounds were examined for their ability to lyse log-phase cultures of susceptible bacteria, however, cefamandole was found to be about 10 times more active than cefamandole nafate. Cefamandole nafate was shown to be rapidly converted to cefamandole in bacteriological media, with a half-life of less than 1 h at a pH of 7.0 or above. At pH 6.0, in log-phase inhibition experiments, however, cefamandole nafate is more stable, allowing delineation of the activity between cefamandole and cefamandole nafate. The efficacy of cefamandole was identical to that of cefamandole nafate in treating experimental animal infections, indicating that rapid conversion of cefamandole nafate to cefamandole occurs in vivo.

Assumed versus approved breakpoints.

In our opinion, recent articles by Jacobs et al. (1) and Zhanel et al. (4) disseminated misleading information. Our first objection is that the authors failed to abide by the journals policy of not assigning interpretive MIC breakpoints in the absence of approved breakpoints. The Instructions to Authors are explicit on this point: “The percentage of strains susceptible and/or resistant to an antibiotic at its breakpoint concentration may be given only if an appropriate breakpoint has been approved, as by the National Committee for Clinical Laboratory Standards, 940 W. Valley Rd., Suite 1400, Wayne, PA 19087-1898. In the absence of approved breakpoints, authors cannot assign breakpoints, use breakpoints from related antibiotics, or use a range of concentrations to report a cumulative display of percent susceptible/resistant strains.” Jacobs et al. and Zhanel et al. reported percent susceptibility of Streptococcus pneumoniae to cefaclor using assumed breakpoints. Zhanel et al. assumed breakpoints that are approved for cefuroxime, and Jacobs et al. used breakpoints derived by application of pharmacodynamic (PD) principles. The use of an assigned breakpoint for susceptibility (≤0.5 μg/ml) resulted in fewer than a quarter and just over half of the penicillin-susceptible S. pneumoniae (PSSP) strains being classified as susceptible to cefaclor, respectively, in the two papers. Those findings are inconsistent with long-standing clinical experience and with NCCLS recommendations. Since its registration, cefaclor has proven itself, time and time again, effective in treatment of infections caused by PSSP. Since the early 1990s, NCCLS has recommended reporting all PSSP strains as susceptible to cefaclor (2). That recommendation remains in the most recent iteration of NCCLS interpretive standards (3), which also includes the recently adopted cefaclor-specific pneumococcal MIC breakpoint for susceptibility, ≤1 μg/ml. Our second objection concerns the lack of attention to detail that Jacobs et al. used in abstracting their manuscript. Within the body of the article, they compared their PD breakpoint with the NCCLS established breakpoint for Haemophilus influenzae. Even though there is considerable explanation of this comparison within the text, this information was not included in the abstract. Unfortunately, the abstract includes only the susceptibility rate (2%) derived using the PD breakpoint, without mentioning the result determined using the NCCLS breakpoint (79%). It is well accepted that the majority of individuals screening articles, through either literature searches or personal reading, review only the abstracts of published manuscripts. Therefore, neglecting to include the percent susceptible by the NCCLS breakpoint only serves to allow the casual reader to misinterpret the published work. We are troubled by these irregularities since they represent both a disregard for your journals Instructions to Authors and a breakdown in the refereeing process that was designed to ensure the scientific rigor of the journal. Occurrences such as these only serve to misinform the reader and to tarnish the reputation of this journal in the eyes of the scientific community.