There are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of β-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development. The combination of such inhibitors, which have broad activity against serine β-lactamases and may even inhibit some penicillin binding proteins, with carbapenems, cephalosporins or aztreonam, provides enhanced activity against multi-drug resistant Gram-negative bacteria. There are 6 molecules representing novel classes of antibiotics but only one of these, murepavadin, is expected to have activity against a Gram-negative pathogenic bacterium (Pseudomonas aeruginosa). Although the new analogues of existing classes, and novel combinations, have been designed to address specific resistance problems, it is by no means certain than they will not be affected by the general mechanisms of resistance, particularly decreased net flux across the Gram-negative outer membrane. The potential impact of resistance mechanisms on the new agents is assessed and the ways in which PK/PD studies are used to design dosing regimens for the new agents, especially combinations, as well as to improve dosing of existing antibiotics are discussed.

What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% ofPseudomonas aeruginosaisolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted forKlebsiella pneumoniae, Escherichia coli, Enterobacterspp. orBranhamellaspp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin againstPseudomonasspp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge ofPseudomonasspp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.

Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection.

Susceptibility of bacterial isolates to β-lactam antibiotics from U.S. clinical trials over a 5-year period

BACKGROUND--In addition to bronchodilator and anti-inflammatory therapy, exacerbations in patients with chronic obstructive pulmonary disease (COPD) are often treated with antibiotics. Haemophilus influenzae and Moraxella (Branhamella) catarrhalis, two important respiratory pathogens, may produce beta-lactamase which makes them resistant to ampicillin. Surveillance studies conducted in various countries have shown an increasing incidence of these beta-lactamase producing bacteria. Although this may simply be a consequence of the increasing use of antibiotics, it is possible that other factors are important. A study was undertaken to investigate whether clinical factors are related to the presence of beta-lactamase forming bacteria in the sputum of patients with COPD. METHODS--One hundred patients with COPD aged over 40 years were sequentially selected from an outpatient clinic on the basis of sputum culture results. Fifty had beta-lactamase positive (beta L+) and 50 had beta-lactamase negative (beta L-) bacteria in their sputum. Patients were included only if sputum culture results yielded one pathogen. The files of these patients were investigated for possible causative factors present during the two preceding years. RESULTS--Both groups were almost identical in terms of lung function, maintenance medication, and smoking history. The total number of antibiotic courses in the beta L+ group was higher, as were individual courses of cephalosporins, tetracyclines, and macrolides. The number of patients admitted to hospital was higher in the beta L+ group, but admissions were of equal duration in both groups. Patients admitted to hospital had poorer lung function. Risk factors for beta-lactamase producing bacteria were identified by logistic regression analysis which revealed an odds ratio for one course of antibiotics of 1.15 (95% CI 1.04 to 1.28). CONCLUSIONS--An increased number of antibiotic courses is related to a higher incidence of beta-lactamase producing bacteria and more patients had hospital admissions in the beta L+ group. beta-lactamase stable antibiotics were used more frequently in the beta L+ group, probably because prescribing was adapted to the presence of beta-lactamase producing bacteria. No other differences were found between the beta L+ and beta L- groups.

https://thorax.bmj.com/content/thoraxjnl/50/3/249.full.pdf

Relation between beta-lactamase producing bacteria and patient characteristics in chronic obstructive pulmonary disease (COPD).

The β-lactamase community currently recognizes two major classification schemes based either on function or structure. Historically, these enzymes were separated according to biochemical activities, with classification based on hydrolysis of specific substrates and the sensitivity to selected inhibitors. After penicillin was used more frequently in post-World War II medicine, the incidence of penicillinase-producing Staphylococcus aureus increased in one British hospital from ≥8% in 1945 to almost 60% of clinical isolates in less than five years. Examples of apparent cause and effect relationships include the discovery of cephalosporin C and subsequent introduction of cephalosporin analogs, together with the introduction of broad-spectrum penicillins, such as ampicillin, leading to the identification of plasmid-encoded broad-spectrum penicillinases such as TEM-1. This ubiquitous β-lactamase among the Enterobacteriaceae, with the ability to hydrolyze not only many penicillins but also the early cephalosporins such as cephalothin, became the most prevalent plasmid-encoded enzyme in epidemiological surveys of the late 1970s and early 1980s. In the compilation shown, geographical areas reasonably close to each other sometimes exhibit different regional enzyme patterns. The level of β-lactam resistance produced by an enzyme is determined by a number of factors besides its intrinsic hydrolytic activity. β-Lactamases are ancient enzymes, widespread in the microbial world, that in recent years have coevolved with β-lactam antibiotics as aminopenicillins, cephalosporins, cephamycins, oxyimino-cephalosporins, monobactams, and carbapenems have been developed to target new pathogens or to overcome existing resistance.

β-Lactam Resistance in the 21st Century

Resistance of bacteria to beta-lactam antibiotics has become a serious problem in the past several decades. Virtually all Staphylococcus aureus, many Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, many Enterobacteriaceae, many Pseudomonas aeruginosa and Bacteroides species possess beta-lactamases which hydrolyze to varying degree penems, penams, carbapenems, cephems, cephamycins and monobactams. The most common plasmid-mediated beta-lactamase is the so-called TEM beta-lactamase (Richmond Sykes type IIIa) which exists in Haemophilus, Neisseria and many of the Enterobacteriaceae. Techniques to overcome this resistance have been the development of beta-lactamase stable compounds and of beta-lactamase inhibitors. However, inducible chromosomally mediated beta-lactamases in species such as Enterobacter, Pseudomonas, Citrobacter and some Serratia have become an increasing problem with more widespread use of beta-lactamase stable cephalosporins.

A perspective on the present contribution of beta-lactamases to bacterial resistance with particular reference to induction of beta-lactamase and its clinical significance.

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A perspective on the present contribution of beta-lactamases to bacterial resistance with particular reference to induction of beta-lactamase and its clinical significance.