Newsletter Vol. 30 No. 1


The Lack of Novel Antibiotic and Vaccine Development to Combat Resistance

Victor K.E. Lim, MBBS, M.Sc.
Executive Dean of Medicine and Health
International Medical University of Kuala Lumpur

 



Introduction
The discovery of antibiotics was one of the most significant events in medical history and is said to have added a decade to the life expectancy of man [1]. Together with vaccination, clean water and other public health measures, mortality from infectious diseases was dramatically reduced to the extent that by the 1950s and 1960s, many thought that infectious diseases were no longer a major public health challenge. In 1967, William Stewart – the Surgeon General of the United States of America – was purported to have said that “The time has come to close the book on infectious diseases and declare the war against pestilence won.” There is now some dispute as to whether Stewart actually made this infamous pronouncement [2]. This optimism has now been shown to be unfounded due to various reasons, among which is the emergence of antibiotic resistance.

Antibiotic resistance
Resistance is not a new phenomenon. Sir Alexander Fleming in his Nobel Lecture warned that, “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body” [3]. The resistome is defined as the collection of all the antibiotic resistance genes and their precursors both in pathogenic and non-pathogenic bacteria [4]. Recent studies of the soil resistome have revealed the presence of genes encoding antibiotic resistance to a wide variety of antibiotics, including synthetic compounds like quinolones and newer antimicrobials like Synercid and daptomycin. It would appear that the development of antimicrobial resistance had been going on in nature long before antibiotics came into medicinal use. The environment – in particular, the soil – is regarded as an important reservoir of antibiotic resistance determinants [5].

Antibiotic resistance is a major challenge worldwide. It is seen in Gram-positive as well Gram-negative organisms; in healthcare-associated as well as community-acquired infections. The Infectious Diseases Society of America had identified six organisms as being the most problematic; the so-called ESKAPE organisms (namely Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp.)

New antibiotic development
In their 2008 report on the pipeline of new antimicrobial agents, the IDSA concluded that the number of new agents in the pipeline is disappointing and there were no agents solely for the purposes of countering Gram-negatives or the emerging carbapenemases. It is unlikely that there will be any major advance in ability to treat antibiotic-resistant infections [6].

A similar European report came to the same conclusions. A gap exists between multidrug-resistant bacteria and the development of new antibiotics. Resistance to antibiotics is high among bacteria that cause serious infections in humans. Resistance is increasing among certain Gram-negative bacteria. Very few antibacterial agents with new mechanisms of action are under development to meet the challenge and there is a particular lack of new agents for multidrug-resistant Gram-negative bacteria [7].

There is a significant decrease in the involvement of top pharmaceutical companies in the area of anti-microbial drug development. The reasons are understandable. The cost of bringing a product from bench to bedside is prohibitively high. Antibiotics are usually used for short durations, and new potent antibiotics are often kept in reserve to be used only in patients who have not responded to more conventional agents. Many of the novel agents have been developed by small companies which are willing to take higher risks. However, they will still need the involvement and resources of large companies for future clinical trials and commercialization.

The number of new agents is therefore unsurprisingly small. New agents which have entered Phase II and Phase III development include a novel aminoglycoside, ACHN-490. ACHN-490 has been shown to be active in vitro against multi-resistant Klebsiella pneumoniae and E.coli, including strains which are carbapenem-resistant.8  A new fluoroketolide, CEM-101, has been shown to be active against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes [9]. This agent could be potentially useful in the treatment of community-acquired pneumonia in regions where the prevalence of macrolide resistance is high. NXL-104, a beta-lactamase inhibitor, effectively inhibits Class A ESBLs, Class C enzymes, and Class A carbapenemases. This would make it a promising agent to combine with current beta-lactam agents against multidrug-resistant Gram-negatives including those that produce the KPC carbapenemase [10]. A new cephalosporin, CXA-101, has been found to have good activity against Pseudomonas aeruginosa, including strains which were resistant to imipenem [11]. TP-434 is a fluorocycline derivative of tetracycline and has activity against multidrug-resistant Gram-positive and Gram-negative organisms – including tetracycline–resistant Enterobacteriaceae [12]. Radezolid and torezolid are novel oxazolidinones which have activity against linezolid-resistant strains [13].

Vaccine development
A logical approach, in the face of increasing antibiotic resistance, would be the development of vaccines to prevent the infections. An early trial of a conjugated Staphylococcus aureus vaccine (StaphVAX) had shown some promise in conferring partial protection to patients on hemodialysis [14]. Results from a later, larger Phase III trial were unfortunately not as encouraging. A clinical trial of another staphylococcal vaccine (V710) was abandoned in 2011 after it failed to show any benefit. There have been numerous attempts to develop a vaccine against Pseudomonas aeruginosa. Although many pre-clinical trials have been conducted, there are very few clinical trials and no Pseudomonas aeruginosa vaccine is currently licensed for clinical use [15]. A Pseudomonas aeruginosa flagella vaccine had been shown to reduce the occurrence of pseudomonas infection among vaccinated subjects [16]. It would appear that the use of vaccines to combat increasing antibiotic resistance, especially among nosocomial infections, still has some way to go.

Conclusions
The emergence of resistance is threatening the usefulness of antibiotics. There is a dearth of new agents to meet the challenge of resistant strains. Vaccines are an alternative strategy, but it will still be some time before these vaccines can be in routine clinical use. Antibiotic stewardship is therefore crucial to contain resistance and to prolong the useful lives of available agents. A concerted effort employing a multifaceted strategy is essential at international, national and institutional levels, and we need to work together to meet this challenge.
 




References
1. McDermott W, Rogers DE. Social ramifications of control of microbial disease. The Johns Hopkins Medical Journal 1982; 151:302-12.
2. Spellberg B, Stewart WH. Mistaken or maligned? Clin Infect Dis 2008; 47:294.
3. Fleming A. Penicillin. Nobel Lecture, December 11, 1945. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/
fleming-lecture.html
. Accessed 20 October 2011.
4. Wright GD. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Reviews Microbiology 2007; 5:175-86.
5. D’Costa VM, McGrann KM, Hughes DW, Wright GD. Sampling the Antibiotic Resistome. Science 2006; 311:374-7.
6. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1–12.
7. ECDC/EMEA Joint Technical Report. The bacterial challenge: time to react a call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/Report/
2009/11/WC500008770.pdf
. Accessed 20 October 2011.
8. Landman D, Babu E, Shah S et al. Activity of a novel aminoglycoside, ACHN-490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City. J Antimicrob Chemother 2010; 65:2123-7.
9. McGhee P, Clark C, Kosowska-Schick M et al. In-vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms. Antimicrob Agents Chemother 2010; 54:230-8.
10. Stachyra T, Levasseur P, Pechereau MC et al. In vitro activity of the beta-lactamase inhibitor NXL 104 against KPC-2 carbapenamase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 2009; 64:326-9.
11. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother 2011; 55:2390-4.
12. Grossman TH, Starosta AL, Fyfe C et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother 2012 (published on-line ahead of print on 21 February 2012) doi:10.1128/AAC.06187-11. Accessed 30 April 2012.
13. Locke JB, Finn J, Hilgers M. Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Antimicrob Agents Chemother 2010; 54:5337-43.
14. Shinefield H, Black S, Fattom A et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving haemodialysis. New Engl J Med 2002; 346:491-6.
15. Doring G, Pier GB. Vaccines and immunotherapy against Pseudomonas aeruginosa. Vaccine 2008; 26:1011-24.
16. Doring G, Meisner C, Stern M. A double-blind randomized placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients. Proc Natl Acad Sci USA 2007; 104:11020-5.
 




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