1. BRL 17421, a novel beta-lactam antibiotic, highly resistant to
beta-lactamases, giving high and prolonged serum levels in
humans.
1. B Slocombe,
2. M J Basker,
3. P H Bentley,
4. J P Clayton,
5. M Cole,
6. K R Comber,
7. R A Dixon,
8. R A Edmondson,
9. D Jackson,
10. D J Merrikin and
11. R Sutherland
ABSTRACT
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.
Novel beta-lactam antibiotics derivatives:
their new applications as gene reporters,
antitumor prodrugs and enzyme inhibitors.
Xing B, Rao J, Liu R.

2. Source
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore, 637616. Bengang@ntu.edu.sg
Abstract
Since the antibiotic properties of penicillin were first noticed in the beginning of last century,
beta-lactam based antibiotics have been well developed as miracle drugs for the therapy of
bacterial infectious diseases in clinics. Recently, these "old" antibiotics and their relevant
derivatives have also found new applications as gene reporters, anti-cancer prodrugs and enzyme
inhibitors. In this review, we will introduce the latest developments in the study of these new
applications based on literatures reported over the last decade. The first section covers the recent
developments of beta-lactam antibiotics as drugs against bacteria, the second section briefly
discusses the occurrence of bacterial resistance and mechanistic studies of beta-lactam resistance
in bacteria, the third section presents the current development of fluorogenic cephalosporin based
beta-lactam probes for real-time imaging of gene expression, and the fourth section describes
relevant studies on beta-lactam based substrates as anti-tumor prodrugs. Beta-lactam substrates
as protease inhibitors will be also described in the fifth section. The final section summarizes
future perspectives for beta-lactam antibiotic derivatives as scaffolds in the fields of molecular
imaging, drug delivery and enzymatic assays.
PMID:
18473935
[PubMed - indexed for MEDLINE]

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Pharmacology and Toxicology
Volume 14, 1974
REVIEW CONTENT
ABSTRACT
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ABSTRACT
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Newer Cephalosporins and "Expanded-Spectrum" Penicillins
Annual Review of Pharmacology
Vol. 14: 435-467 (Volume publication date April 1974)
DOI: 10.1146/annurev.pa.14.040174.002251

5. Ceftaroline: A New Cephalosporin with Activity Against Methicillin-Resistant
Staphylococcus aureus (MRSA)
Submit a Paper
Authors: Christopher Duplessis and Nancy F. Crum-Cianflone
Publication Date: 10 Feb 2011
Type: Review
Journal: Clinical Medicine Reviews in Therapeutics
Citation: Clinical Medicine Reviews in Therapeutics 2011:3
doi: 10.4137/CMRT.S1637
4,606 Article Views
Abstract
Microbial resistance has reached alarming levels, threatening to outpace the ability to counter
with more potent antimicrobial agents. In particular, methicillin-resistant Staphylococcus aureus
(MRSA) has become a leading cause of skin and soft-tissue infections and PVL-positive strains
have been associated with necrotizing pneumonia. Increasing reports of growing resistance to
glycopeptides have been noted, further limiting the efficacy of standard antibiotics, such as
vancomycin. Ceftaroline is a novel fifth-generation cephalosporin, which exhibits broad-
spectrum activity against Gram-positive bacteria, including MRSA and extensively-resistant
strains, such as vancomycin-intermediate
S. aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-resistant S. aureus (VRSA).
In addition to being an exciting new agent in the anti-MRSA armamentarium, ceftaroline
provides efficacy against many respiratory pathogens including Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis. Ceftaroline (600 mg intravenously every 12
hours) has been shown effective in phase III studies in the treatment of complicated skin and soft
tissue infections and community-acquired pneumonia. To date, this unique antibiotic exhibits a
low propensity for inducing resistance and has a good safety profile, although further post-

6. marketing data and clinical experience are needed. In summary, ceftaroline provides an
additional option for the management of complex multidrug resistant infections, including
MRSA.
Ceftobiprole: A New Cephalosporin for
MRSA Infection
Ceftobiprole had clinical cure rates similar to vancomycin plus ceftazidime for skin and skin-
structure infections due to gram-negative and gram-positive organisms, including methicillin-
resistant Staphylococcus aureus.
Dealing with complicated skin and skin-structure infections has become more challenging
because of the emergence of antibiotic-resistant bacterial strains (particularly methicillin-
resistant Staphylococcus aureus [MRSA]). Ceftobiprole, a new cephalosporin with a high
affinity for penicillin-binding protein 2a, may provide another option for treating such infections.
Its MIC90 for MRSA is 2 µg/mL and for Enterobacteriaceae is 4 µg/mL.
In a recent industry-sponsored, multinational, randomized, double-blind trial involving 828
patients with various complicated skin and soft-tissue infections, researchers compared
intravenous ceftobiprole (500 mg every 8 hours for 7–14 days) to vancomycin (1000 mg every
12 hours) plus ceftazidime (1000 mg every 8 hours). Outcomes were assessed at a test-of-cure
visit conducted 7 to 14 days after therapy was completed.
In intent-to-treat analysis, clinical cure rates were similar between study arms across the study
population (82% for ceftobiprole vs. 81% for vancomycin plus ceftazidime). Rates were also
similar between arms among patients with MRSA infections (90% vs. 86%). Adverse events
were uncommon and were comparable between the two arms.
Comment: These data support the addition of ceftobiprole to our growing armamentarium of
agents with activity against MRSA. As an editorialist notes, potential benefits of ceftobiprole
include bactericidal activity, a broad general spectrum of antibacterial activity, and low potential
for the development of resistance. However, more trials are needed before this agent receives
unreserved endorsement.
— Neil M. Ampel, MD
Published in Journal Watch Infectious Diseases March 19, 2008

7. Citation(s):
Noel GJ et al. A randomized, double-blind trial comparing ceftobiprole medocaril with
vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-
structure infections. Clin Infect Dis 2008 Mar 1; 46:647.
Original article (Subscription may be required)
Medline abstract (Free)
Widmer AF. Ceftobiprole: A new option for treatment of skin and soft-tissue infections due to
methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008 Mar 1; 46:656.
Original article (Subscription may be required)
Medline abstract (Free)
Cefmenoxime (SCE-1365), a new Cephalosporin: In Vitro Activity, Comparison with Other
Antimicrobial Agents, Beta-Lactamase Stability, and Disk Diffusion Testing with Tentative
Interpretive Criteria
Peter C. Fuchs,1 Ronald N. Jones,2 Clyde Thornsberry,3 Arthur L. Barry,4 E. Hugh Gerlach,5 and Herbert M. Sommers6
Author information ► Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The in vitro activity of cefmenoxime (SCE-1365) was evaluated in a multiphased collaborative investigation. Over 7,500 consecutive clinical
isolates were tested in five laboratories, and greater than 90% of the following organisms were inhibited by cefmenoxime at the following
concentrations: Enterobacteriaceae and non-enterococcal streptococci, ≤0.125 μg/ml; Staphylococcus aureus, ≤2.0 μg/ml; and
nonfermenting gram-negative bacilli and Bacteroides fragilis group, ≤32 μg/ml. Both beta-lactamase-producing and -nonproducing
Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by cefmenoxime at ≤0.03 μg/ml. The spectrum of cefmenoxime was
similar to that of other, newer cephalosporins, particularly cefotaxime. A pronounced inoculum effect was found with some species upon
increasing inocula from 105 to 107 colony-forming units per ml, resulting in an approximate eightfold increase in minimum inhibitory
concentrations. Cefmenoxime was bactericidal when tested with inocula of 105 colonyforming units per ml, and mean differences between
the minimum inhibitory concentration and the minimum lethal concentration were less than one log2 dilution. No significant hydrolysis of
cefmenoxime by five different beta-lactamases was detectable, and cefmenoxime exhibited marked inhibition of type I beta-lactamases.
Regression and error rate-bounded analyses of results of disk diffusion and reference broth microdilution susceptibility tests were performed
on 421 bacterial isolates, and the following tentative zone size breakpoints are proposed: ≥22 mm, susceptible; ≤14 mm, resistant; and 15 to
21 mm, moderately susceptible (indeterminate). These data and cross-resistance studies with other newer cephalosporins indicate marked
similarity of in vitro activity within this group of drugs, particularly between cefmenoxime, moxalactam, and cefotaxime. Any one of these
could serve as the representative for the disk diffusion testing of this group of drugs if comparable minimum inhibitory concentration
breakpoints were used for each drug.

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Drug Saf. 1993 Aug;9(2):132-42.
Adverse effects of newer cephalosporins. An
update.
Thompson JW, Jacobs RF.
Source
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock.
Abstract

9. While classifications into generations according to antimicrobial activity has helped clinicians
incorporate the increasing number of cephalosporins into their pharmacological repertoire,
adverse effects among the different agents fail to follow similar categories. In general,
cephalosporins are fairly well tolerated antibiotics, and toxicity has been limited to specific
agents. Subtle differences in chemical structure and pharmacokinetics can influence the potential
for adverse effects. The route of administration may result in minor adverse reactions, including
thrombophlebitis and pain. The most common adverse effects of cephalosporins are allergic
reactions, occurring in 0.9 to 3.2% of patients. Cephalosporins have very rarely been associated
with haematological toxicity (less than 1% of patients), but specific agents have been associated
with neutropenia, hypoprothrombinaemia, haemolytic anaemia, and problems with platelet
production and function. Other reactions include localised gastrointestinal disturbances,
hepatotoxicity (e.g. biliary sludging), nephrotoxicity and mild central nervous system effects.
The cephalosporins are generally well tolerated in the paediatric population. Very few
interactions have been observed between cephalosporins and other drugs, largely because
cephalosporins do not affect the microsomal P450 hepatic enzyme system. While cephalosporins
are considered to be relatively 'safe' drugs, the introduction of newer members warrants
continued careful observation for reporting of adverse drug reactions.
PMID:
8397890
[PubMed - indexed for MEDLINE]
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Clin Pharmacokinet. 1995 May;28(5):361-84.
Clinical pharmacokinetics of newer
cephalosporins.
Klepser ME, Marangos MN, Patel KB, Nicolau DP, Quintiliani R, Nightingale CH.
Source
Department of Pharmacy Research, Hartford Hospital, Connecticut, USA.
Abstract
Several new cephalosporins have been developed in recent years. These agents include several
oral and parenteral agents with extended activity against Gram-negative pathogens. The
pharmacokinetic literature for these agents is quite extensive; therefore, we have summarised this
information and presented it in tabular form for critical comparison. With a few exceptions, the
newer cephalosporins share similar pharmacokinetic properties. Cefixime, cefetamet pivoxil and
ceftibuten differ from the others in that they exhibit nonlinear pharmacokinetic properties. The
nonlinear nature of these agents is reflected by decreasing maximal concentrations with
escalating doses of cefixime and cefetamet pivoxil, decreasing area under the serum
concentration-time curve with increasing doses for cefixime, and a reduced bioavailability with
large doses of ceftibuten. Attention to such characteristics aid the clinician in selecting
appropriate dosage regimens that will optimise drug absorption. The majority of agents are
primarily renally eliminated; however, renal elimination accounts for only 20% of cefixime
elimination. The pharmacokinetic parameters noted for the newer cephalosporins are not
influenced by multiple-dose administration, suggesting lack of drug accumulation over time. The
pharmacodynamics of antimicrobials should be considered when extrapolating pharmacokinetic
information into the clinical arena. In the case of the beta-lactams, the time which drug

11. concentrations remain above some critical threshold, such as the minimal inhibitory
concentration, appears to have the greatest influence on bactericidal activity. Therefore, it is
important to select dosage regimens that will optimise the time serum concentrations remain
above this threshold. We present an evaluation of these agents with respect to their activity
against a variety of pathogens in an effort to demonstrate a pharmacokinetically-based process of
antimicrobial selection.
PMID:
7614776
[PubMed - indexed for MEDLINE]
Infection
1977, Volume 5, Issue 4, pp 224-227
Beta lactamase resistance of newer
cephalosporins and antimicrobial
effectiveness against gram-negative bacilli
Dr. W. E. Farrar,
N. M. O'Dell
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Summary
Three newer cephalosporins (cefamandole, cefoxitin and cefazaflur) were investigated, in
comparison with three older agents (cephalothin, cephaloridine and cefazolin) to determine their
stability to β-lactamases of gram-negative bacilli, and to correlate this with their antibacterial
activity. Nine of the 17 bacterial strains employed produced broad-spectrum β-lactamases; the
remaining eight produced cephalosporinases. The cephalosporins were highly active against
bacteria producing broad-spectrum β-lactamases; they were less active against organisms
producing cephalosporinases. All of the cephalosporinase-producing strains were resistant to
cephalothin and cephaloridine. With the other cephalosporins the correlation between hydrolysis
by cephalosporinases and resistance of the organisms was poor. Four of eight cephalosporinase-
producing strains were resistant to cefoxitin, which was completely resistant to hydrolysis by the
β-lactamases. Cefozolin, cefamandole and cefazaflur inhibited several of these strains in spite of
destruction by the β-lactamase. Several cephalosporins need to be used in antimicrobial
susceptibility testing of gram-negative bacilli.