Antimicrobial activity of SK&F 88070, an expanded-spectrum cephalosporin with high and prolonged levels in blood

SK&F 88070 (7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3- [[[1-(2-sulfaminoethyl)-1H-tetrazol-5-yl]thio] methyl]-3-cephem-4-carboxylic acid) is a new parenteral cephalosporin with an expanded-spectrum profile of antibacterial activity, including activity against Pseudomonas aeruginosa, and with high and prolonged levels in sera of experimental animals. The activity of SK&F 88070 was compared with those of cefotaxime and other cephalosporins against more than 500 clinical isolates in vitro by microtiter twofold dilution tests in Mueller-Hinton broth. SK&F 88070 was extremely potent against all of the members of the family Enterobacteriaceae that were tested, including beta-lactamase-producing strains. Its activity against P. aeruginosa was comparable to those of cefotaxime, ceftizoxime, and moxalactam. SK&F 88070 was less potent than cefotaxime or ceftizoxime against Staphylococcus species but was comparable to moxalactam. It had in vivo activity against the same Bacteroides strains as did cefotaxime, although it was less potent. Both SK&F 88070 and cefotaxime had less activity when tested with high inoculum levels of most of the rarer gram-negative bacteria. There was a greater decrease in the activity of SK&F 88070 than of cefotaxime in the presence of human serum, reflecting the higher degree of binding of SK&F 88070 to serum proteins. SK&F 88070 had peak levels and half-lives in serum much greater than those of cefotaxime in experimental animals after parenteral administration. In mouse protection studies, SK&F 88070 was more effective than cefotaxime against gram-negative bacteria but less effective than cefotaxime against Staphylococcus aureus.     

Antimicrobial activity of human pancreatic juice and its interaction with antibiotics.

Pancreatic juice (PJ) should be a factor of variability in the antimicrobial activity of antibiotics eliminated by the pancreas during pancreatic infections. We studied its effects on the activity of antimicrobial drugs with different mechanisms of action. Samples of pure PJ were collected from 16 patients with stabilized external pancreatic fistulas. The antimicrobial activity of the juice at different concentrations (from 1.25 to 100%) alone and in combination with mezlocillin, imipenem, ceftriaxone, gentamicin, ofloxacin, and ciprofloxacin was studied by a microbiological method (continuous turbidimetric recording of bacterial growth). The human PJ showed dose-dependent antimicrobial activity that increased directly with the concentration. The activity of the antibiotics at bactericidal concentrations were not modified by the PJ, while the combination with subinhibitory concentrations produced the following variable and different effects: (i) additivity with mezlocillin, ceftriaxone, gentamicin, and ciprofloxacin and autonomy (no interaction) with imipenem and ofloxacin against Providencia rettgeri and (ii) additivity with ceftriaxone, ofloxacin, gentamicin, imipenem, and mezlocillin and autonomy with ciprofloxacin against Escherichia coli. In the presence of PJ, fluoroquinolones showed constant positive effects, while beta-lactams showed more variable antimicrobial activity. Antibiotic concentrations and PJ pharmacodynamics are the main factors determining the final effect of the interaction in vitro. These results may be useful in choosing antibiotics for the treatment of pancreatic infections when they are supplemented with the pharmacokinetic data for each drug.     

Comparative activity of glycopeptide antibiotics against coagulase-negative staphylococci embedded in fibrin clots.

The susceptibilities of 16 strains of coagulase-negative staphylococci to vancomycin and teicoplanin were determined by three microdilution methods run in parallel; (i) a reference method in which the medium was Iso-Sensitest broth, (ii) a method in which the organisms were suspended in plasma and (iii) one in which the bacteria were incorporated into a fibrin clot. In comparison with the reference method there was a less than two-fold change in the geometric mean MICs of both antibiotics in plasma, while in clot the increase was 12-fold for vancomycin and 28-fold for teicoplanin. MBCs showed a similar trend although the increase was greater for teicoplanin. These results suggest that protein binding may have a much greater impact on antimicrobial activity when the mobility of the protein is reduced within a clot.     

In vitro activity and spectrum of LY333328, a novel glycopeptide derivative.

Reference methods were used to determine the potency of LY333328, a semisynthetic glycopeptide derivative with a key N-alkylation substitution, against 833 strains (393 gram-positive strains and representative gram-negative bacilli) with various defined resistance mechanisms. The MICs at which 90% of the isolates are inhibited (MIC90S) (in micrograms per milliliter) of LY333328 and the percentages of strains at < or = 8 micrograms/ml were as follows: for oxacillin-susceptible Staphylococcus aureus, 2 and 100%, and for oxacillin-resistant Staphylococcus aureus, 4 and 100%; for oxacillin-susceptible Staphylococcus epidermis, 4 and 100%, and for oxacillin-resistant Staphylococcus aureus, 8 and 96%; for Streptococcus serogroups A, B, C, and G, 0.25 to 1 and 100%; for Streptococcus pneumoniae < or = 0.015 to 0.06 and 100%; for Enterococcus faecalis, 2 and 100%; and for vancomycin-susceptible Enterococcus faecium, 0.25 and 100%, and for vancomycin-resistant Enterococcus faecium, 4 and 100%. LY333328 was not active (MIC50, > or = 16 micrograms/ml) against more than 400 representative strains of Enterobacteriaceae, pseudomonads, Acinetobacter spp., Stenotrophomonas maltophilia, Haemophilus influenzae, Moraxella catarrhalis, pathogenic Neisseria spp., and anaerobic gram-negative bacilli. Gram-positive anaerobes were LY333328 susceptible (MICs, < or = 2 micrograms/ml). Test methods and conditions may have affected MICs of LY333328, with most (species variation) agar dilution MICs being greater than the broth microdilution MICs.     

Safety and efficacy of glycopeptide antibiotics

It would be difficult to envision the practice of infectious diseases over the past 20 years without the availability of the glycopeptide antibiotics. The two agents currently in clinical use, vancomycin and teicoplanin, have proven remarkably versatile in many common applications. Several attributes of these agents account for this favourable profile: (i) their broad spectrum of activity against Gram-positive bacteria, including strains resistant to many other antimicrobials; (ii) their favourable pharmacokinetic properties that allow the once- or twice-daily dosing regimens that have made out-of-hospital therapy possible; and (iii) their generally good safety profiles which, along with their structural dissimilarity to beta-lactam and other antimicrobials, permits their use in many patients who are intolerant of other antibiotic regimens. It is not entirely surprising, therefore, that despite more than 40 years of clinical use and the interim appearance of bacterial strains resistant to this drug class, there remains continued interest in the development of newer members of the glycopeptide antibiotic class. This paper is intended to provide a global overview of the efficacy and safety of glycopeptide antibiotics currently in use, as background to understanding the need for and potential roles of new agents of this class.     

Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone.

Compound LB20304 is a fluoronaphthyridone carboxylic acid with a novel pyrrolidine substituent. This drug was compared with ciprofloxacin, levofloxacin, ofloxacin, and trovafloxacin against over 800 pathogens, most from blood stream infections, by National Committee for Clinical Laboratory Standards reference methods. LB20304 was the most active agent against gram-positive species including strains observed to be resistant to other fluoroquinolones and glycopeptides. The potency of LB20304 (MIC50, 0.03 micrograms/ml) against the Enterobacteriaceae was exceeded only by that of ciprofloxacin (0.015 micrograms/ml). It has limited activity against gram-negative anaerobes.     

Pharmacokinetics of glycopeptide antibiotics in children

Vancomycin (VAN) and teicoplanin (TEIC) are the glycopeptide antimicrobials commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection in pediatric patients. This study examined the relationship between the initial doses of glycopeptides and the trough serum concentrations of drugs in children, with the intent to determine their optimal dosing. Consecutive patients between 0 and 18 years of age, who between June 2003 and December 2010 were treated with VAN (n = 50) or TEIC (n = 187) for >48 h, were enrolled in this study. Patients were classified into three groups depending on the dose administered: lower than, equal to, or higher than the recommended dosage by each package insert. The patient’s age, body weight, dose of antimicrobial administered during the first 24 h, median trough serum concentrations between 48 and 72 h after the onset of treatment, and serum creatinine concentrations before and 3 and 7 days after its administration were recorded. Median trough concentrations for VAN and TEIC in the three dosage groups were 8.0, 8.5, and 13.0 μg/ml, and 11.8, 13.0, and 17.7 μg/ml, respectively. The median serum creatinine concentrations did not rise significantly between baseline and 3 and 7 days after the onset of treatment in any treatment group. Therapeutic serum concentrations of VAN and TEIC to treat MRSA infections, 15–20 and ≥20 μg/ml, respectively, were rarely reached by the administration of standard doses of drugs for children.     

Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics.

The pharmacokinetics and urinary excretion of nine glycopeptide antibiotics with diverse pIs (3.8 to 8.5) and lipophilicities were studied. The disposition of the aridicin antibiotics and their hydrolysis products were examined in male CD-1 mice after subcutaneous and intravenous administration and compared with the disposition of teicoplanin, ristocetin, and vancomycin. The total systemic clearance, half-life, volume of distribution, and urinary excretion were highly correlated with pIs. In general, as the pI decreased, the clearance, urinary recovery, and volume of distribution decreased, whereas the half-life increased. With those glycopeptides that had similar pIs, clearance decreased and half-life increased with increasing lipophilicity. The urinary recovery of the glycopeptides decreased with decreasing pI and increasing lipophilicity. Because vancomycin (pI = 8.0) is cleared by glomerular filtration, increased binding to serum is the likely mechanism of reduced renal clearance for glycopeptides with low pIs. These results are consistent with previous findings concerning the correlation of physical-chemical properties and the drug disposition of small organic molecules. Results of these studies also indicate that desirable pharmacokinetic properties can be incorporated into glycopeptides through semisynthetic modifications.     

Antimicrobial activity of quinupristin-dalfopristin combined with other antibiotics against vancomycin-resistant enterococci

Interactions between quinupristin-dalfopristin and six other antimicrobials were examined by checkerboard arrays against 50 clinical isolates of vancomycin-resistant Enterococcus faecium selected to represent a range of susceptibilities to individual agents. Unequivocal synergistic or antagonistic interactions at clinically relevant concentrations were infrequently encountered when the streptogramin was combined with chloramphenicol, ampicillin, imipenem, vancomycin, or teicoplanin. Combinations with doxycycline resulted in synergistic inhibition in 36% of checkerboards. Against 10 strains of Enterococcus faecalis, synergistic interactions were found when quinupristin-dalfopristin was combined with doxycycline (four strains), either glycopeptide (three strains), or ampicillin (two strains). Combination with quinupristin-dalfopristin increased the ampicillin MIC from 1 to 4 microg/ml for one strain. For 10 strains of E. faecium, interactions were also assessed by time-kill methods using concentrations of the agents attainable in human serum. Most of these antimicrobials augmented killing by quinupristin-dalfopristin to a minor degree. Against 2 of the 12 strains in this collection that were not highly resistant to gentamicin, the combination of quinupristin-dalfopristin (2 microg/ml) plus gentamicin (5 microg/ml) resulted in killing approaching 3 log(10) CFU/ml. With the exception of doxycycline, inhibitory interactions between quinupristin-dalfopristin and other agents tested against vancomycin-resistant strains of E. faecium were uncommon at clinically relevant concentrations.     

BRL 17421, a novel beta-lactam antibiotic, highly resistant to beta-lactamases, giving high and prolonged serum levels in humans

BRL 17421 is a new semisynthetic beta-lactam antibiotic with an unusual spectrum of antibacterial activity. The compound exhibits exceptional stability to a wide range of bacterial beta-lactamases and is active against the majority of Enterobacteriaceae, including strains highly resistant to many of the penicillins and cephalosporins currently available. Among the clinical isolates of Enterobacteriaceae tested, the frequency of strains resistant to BRL 17421 was found to be low, and there was a slow rate of emergence of resistance during in vitro studies. BRL 17421 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains. The compound was markedly less active against Pseudomonas aeruginosa and Bacteroides fragilis than against the Enterobacteriaceae. Against the gram-positive bacteria, BRL 17421 showed a very low level of activity. BRL 17421 was found to be 85% bound to human serum, and the antibacterial activity was diminished two- to fourfold in the presence of human serum. Against experimental infections in mice, the activity of BRL 17421 reflected the properties observed in vitro. Studies in human volunteers showed unusually high and prolonged serum concentrations of the compound after parenteral dosage, with a serum half-life of about 5 h, and approximately 85% of the dose was recovered unchanged in the urine. BRL 17421 was poorly absorbed after oral administration. The compound was well tolerated after intramuscular and intravenous administration in volunteers, with no adverse side effects.     

Mezlocillin: a new acyl ureidopenicillin. Antimicrobial activity and combination effects with four aminoglycoside antibiotics.

Mezlocillin (Baypen), carbenicillin and mezlocillin combined with gentamicin, sisomicin, tobramycin and amikacin, respectively, were tested in vitro against 325 fresh clinical isolates of pathogenic gram-negative bacteria using the tube dilution procedure. The new acyl ureidopenicillin has a greater antimicrobial activity than carbenicillin against nearly all species tested. The comparison of the effectiveness of the mezlocillin-aminoglycoside combinations demonstrates the superiority of mezlocillin-sisomicin against Escherichia coli, Klebsiella, Serratia and Proteus spp., whereas mezlocillin-tobramycin is most active against gentamicin-sensitive Pseudomonas aeruginosa, and mezlocillin-amikacin against Enterobacter and gentamicin-resistant P. aeruginosa. The combination effects achieved in the majority of strains were addition or synergism. The resistance rate and the bactericidal efficacy of mezlocillin were clearly improved when mezlocillin was combined with aminoglycoside antibiotics. Mezlocillin-amikacin showed the lowest resistance rate (10.2%) followed by mezlocillin-sisomicin (12.3%), mezlocillin-gentamicin (15.1%) and mezlocillin-tobramycin (18.5%). In most species, mezlocillin-sisomicin has proved to be the combination with the best bactericidal potency.     

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus.

The in vitro and in vivo antibacterial activities of SM-17466, a new 1 beta-methyl carbapenem, were evaluated against a wide range of clinical bacterial isoaltes and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 micrograms/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteriodes fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 microgram/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin-resistant strain (50% inhibitory concentration, 5.9 micrograms/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.     

Mechanism of action of the mannopeptimycins, a novel class of glycopeptide antibiotics active against vancomycin-resistant gram-positive bacteria

The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C(55)-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.     

A40926, a new glycopeptide antibiotic with anti-Neisseria activity

In the course of a search for glycopeptide antibiotics having novel biological properties, we isolated A40926. Produced by an actinomycete of the genus Actinomadura, A40926 is a complex of four main factors which contain a fatty acid as part of a glycolipid attached to the peptide backbone. Its activity was, in most respects, similar to that of other glycopeptides, such as vancomycin and teicoplanin. However, in addition to inhibiting gram-positive bacteria, A40926 was very active against Neisseria gonorrhoeae. A40926 was rapidly bactericidal for N. gonorrhoeae clinical isolates at concentrations equal to or slightly higher than the MIC. In mice, levels in serum were higher and more prolonged than those of an equivalent subcutaneous dose of teicoplanin. These properties suggest that A40926 may have potential in the therapy of gonorrhea.     

Antimicrobial activity of seven oral antibiotics against selected community- and hospital-acquired pathogens

The in vitro activity of seven oral antibiotics (ciprofloxacin, cephalexin, cefaclor, cefadroxil, cefuroxime, cefixime, and amoxicillin/clavulanate) was tested against 355 hospital-acquired pathogens and 342 community-acquired organisms. Whereas Staphylococcus aureus and Escherichia coli were the most common pathogens isolated in community-acquired infections, Enterobacter, Klebsiella, and Pseudomonas were isolated most frequently in hospital-acquired infections. All antibiotics with the exception of cefixime were active against the methicillin-susceptible staphylococci. Ciprofloxacin was the most active antibiotic against the members of the family Enterobacteriaceae and Pseudomonas. The community-acquired organisms tended to be more susceptible to antibiotics than the hospital-acquired organisms. Thus selection of oral antibiotics for the management of patients with hospital-acquired infections should be based on knowledge of the susceptibility patterns of hospital isolates.