**3.1 Current therapies**

Many of the existing therapies for bacterial infections function via similar mechanisms of action. In general antibiotics inhibit one of three cellular mechanisms including: protein synthesis (aminoglycosides, macrolides, tetracyclines, and others including streptomycin, chloramphenicol, linezolid, quinupristin/dalfopristin); cell wall synthesis (carbapenems, cephalosporins, glycopeptides, and penicillins); or topoisomerase activity (quinolones) (Lexi Comp, Inc., 2011). There are a few select antibiotics that have a unique mechanism of action including: daptomycin, which binds to the cell membrane and causes rapid depolarization thus inhibiting synthesis of nucleic acids and proteins; trimethoprin-sulfamethoxazole, which interferes substantially with bacterial folic acid synthesis; and metronidazole, which results in breakdown of DNA helical structure (Lexi-Comp, Inc., 2011). Table 3 summarizes selected current antibiotics used for bacterial disease and infection, specifically those currently indicated for infections caused by organisms that have been added to the "superbug" list.

Superbugs: Current Trends and Emerging Therapies 285

In regards to the specific organisms which have documented resistant strains, the following drugs demonstrate efficacy: The imipenem/cilastatin combination has been effective against resistant gram negative bacilli such as the ESBL-producing *E.coli* and *Klebsilla* species and the *Enterobacter* species and *Psendomonas aeruginosa.* Ceftoaxime has demonstrated efficacy against some penicillin-resistant pneumococci. Treatment of *MRSA* and *MSSA* has been successful with daptomycin. The primary quinolones used for drug resistant *S. pneumoniae* are levofloxacin and moxifloxacin. Chloramphenicol, although quite toxic, has demonstrated activity against many vancomycin-resistant enterococci. Perhaps the most notable is linezolid, which is a newer antibiotic designed to inhibit bacterial protein synthesis, albeit by binding the bacterial 23S ribosomal RNA of the 50S subunit and preventing formation of the 70S subunit. This antibiotic has been effective against vancomycin-resistant *Enterococcus faecium* (VRE), nosocomial pneumonia caused by both methicillin susceptible and methicillin resistant forms of *Staphylococcus aureus* as well as *Streptococcus pneumoniae* including those that are multidrug resistant. Also of worthy attention is the relatively few side effects documented for patients treated with linezolid (Lexi-Comp, Inc., 2011). Table 4 summarizes selected infections as well

as recommended and alternative treatment combinations.

Aminoglycosides

Species Cephalosporins, 3rd Generation

Choramphenicol

Vancomycin

*Pseudomonas Aeruginosa*

*Aspergillu*s

*Sallmonella*

*Enterococcus* Species

*Staphylococcus aureus*, Methicillin-Resistant

*Clostridium* 

*Neisseria* 

Bordetella

pertussis Erythromycin

treatments (Lexi-Comp, Inc., 2011).

Species Voriconazole

**Pathogen Recommended Adult Drug Therapy Alternative Drug Therapy** 

Imipenem and Cilastatin or

Ciprofloxacinplus Penicillins, extended Spectrum or Aztreonam

Posaconazole

Ciprofloxacin

Spectinomycin

Amphotericin B (Lipid Complex), Echinocandins, Itraconazole,

Ampicillin, Sulfamethoxazole and Trimethoprim, Chloramphenicol,

Vancomycin plus Gentamicin or Penicillin G Plus Streptomycin or Ampicillin plus Streptomycin

Daptomycin, Doxycycline, linezolid, Quinupristin and Dalfopristin, Sulfamethoxazole and Trimethoprim

Azithromycin, Clarithromycin, Tetracycline, Sulfamethoxazole and Trimethoprim, Chloramphenicol

Meropenem plus Aminoglycosides or

Ceftazidime plus Aminoglycosides or Penicillins, Extended-Spectrum plus Aminoglycosides or Cefepime plus

Penicillin G plus (Gentamicin or Streptomycin) or Ampicillin plus (Gentamicin or Streptomycin); Vancomycin-resistant Enterococcus: Linezolid, Quinupristin and Dalfopristin, Doxycycline,

*difficle* Metronidazole vancomycin

*gonorrhoeae* Cefixime, Ceftriaxone Monotherapy: Cefotaxime,

Table 4. Summary of selected infectious organisms and the recommended and alternative


Table 3. Selected antibiotic therapeutics and selected common uses. Data were compiled with Lexi-Comp Online in August 2011. Spp=species; CAP=community acquired pneumonia; MDRSP = multidrug-resistant *S. pneumoniae;* U/LRT = upper/lower respiratory tract; UTI = urinary tract infection; HAP = hospital acquired pneumoniae (Lexi-Comp, Inc., 2011).

**Aminoglycosides** 

Kanamycin Infections caused by *E. coli*, *E. aerogenes*, *K. pneumoniae*, *Acinetobacter* spp **Carbapenems** 

Meropenem Meningitis caused by *S. pneumoniae*, *N. meningitidis*; skin infections **Cephalosporins**  Cefotaxime Infections of RT, skin, bone, UT due to gram(- bacilli (not *Pseudomonas*),

*pneumoniae*, *Enterobacter* spp; *Enterobacter* spp **Glycopeptides**  Vancomycin Infections caused by staphylococcal spp, streptococcal spp, *C. difficile* **Lipopeptide**  Daptomycin Infections due to gram+ organisms; endocarditis caused by MSSA or

**Macrolides**  Azithromycin Infections of U/LRT, skin; CAP, infections due to *S. aureus*, *S. pneumoniae*

**Penicillins**  Ampicillin Infections due to non-β-lactamase-producing organisms, streptococci,

**Quinolones** 

**Tetracyclines**  Doxycycline Infections caused by *Chlamydia*, *Mycoplasma*, *N. gonorrhoeae*, *Clostridium,*

**Others**  Chloramphenicol Infections due to organisms resistant to other antibiotics caused by *N.* 

Table 3. Selected antibiotic therapeutics and selected common uses. Data were compiled with Lexi-Comp Online in August 2011. Spp=species; CAP=community acquired pneumonia; MDRSP = multidrug-resistant *S. pneumoniae;* U/LRT = upper/lower respiratory tract; UTI = urinary tract infection; HAP = hospital acquired pneumoniae (Lexi-Comp, Inc., 2011).

Penicillin G Sepsis, pneumonia, endocarditis, meningitis; infections due to gram+

Ciprofloxacin Infections of the UT, LRT, skin, bone infections; gonorrhea; HAP

Moxifloxacin CAP, MDRSP, bronchitis, skin infections, intra-abdominal infections **Sulfonamides** 

Clarithromycin Infections due to *S. pneumoniae*, *S. aureus, S. pyogenes,*

Levofloxacin CAP, MDRSP, HAP, UTI, skin infections

*pneumoniae*

Infections of LRT, UT, bone, skin; infections due to gram+ bacteria (*S. aureus*, *Streptococcus* spp), resistant gram- bacilli (including EBSLproducing *E. coli, Klebsiella* spp, *Enterobacter* spp, *P. aeruginosa*)

gram+ cocci (not enterococcus), many penicillin-resistant pneumococci.

UTIs due to *E. coli, K. pneumoniae*; infections of skin due to methicillinsusceptible staphylococci; pneumonia due to *S. pneumoniae, K.* 

pneumococci, meningococci, some *Salmonella*, *Enterobacter*, *Klebsiella*

UTIs due to *E. coli*, *Klebsiella* & *Enterobacter* spp, bronchitis due to S*.* 

HAP caused by *S. aureus* (including *MRSA*) or *S. pneumoniae* (including multidrug-resistant strains), skin infections, CAP caused by gram+ organisms, Vancomycin-resistant *E. faecium* (VRE) infections

*B. anthracis*, uncommon gram- & + organisms; syphilis; CAP

*meningitidis*, *Salmonella*; vancomycin-resistant enterococci

organisms (generally not *S. aureus)*, some gram- organisms

Gentamicin Infections due to gram- organisms & gram+ *Staphylococcus*

**Generic Common Uses** 

*MRSA*

Imipenem/ Cilastatin

Cefepime

Trimethoprim-Sulfamethoxazole

Linezolid

In regards to the specific organisms which have documented resistant strains, the following drugs demonstrate efficacy: The imipenem/cilastatin combination has been effective against resistant gram negative bacilli such as the ESBL-producing *E.coli* and *Klebsilla* species and the *Enterobacter* species and *Psendomonas aeruginosa.* Ceftoaxime has demonstrated efficacy against some penicillin-resistant pneumococci. Treatment of *MRSA* and *MSSA* has been successful with daptomycin. The primary quinolones used for drug resistant *S. pneumoniae* are levofloxacin and moxifloxacin. Chloramphenicol, although quite toxic, has demonstrated activity against many vancomycin-resistant enterococci. Perhaps the most notable is linezolid, which is a newer antibiotic designed to inhibit bacterial protein synthesis, albeit by binding the bacterial 23S ribosomal RNA of the 50S subunit and preventing formation of the 70S subunit. This antibiotic has been effective against vancomycin-resistant *Enterococcus faecium* (VRE), nosocomial pneumonia caused by both methicillin susceptible and methicillin resistant forms of *Staphylococcus aureus* as well as *Streptococcus pneumoniae* including those that are multidrug resistant. Also of worthy attention is the relatively few side effects documented for patients treated with linezolid (Lexi-Comp, Inc., 2011). Table 4 summarizes selected infections as well as recommended and alternative treatment combinations.


Table 4. Summary of selected infectious organisms and the recommended and alternative treatments (Lexi-Comp, Inc., 2011).

Superbugs: Current Trends and Emerging Therapies 287

fewer recurrent episodes of *C. difficle* infection than patients taking vancomycin (Louie et al., 2011). Another potential antibiotic worth considering is referred to as kibdelomycin, which was selected based on screening against multiple engineered strains of S. aureus. Although the structure identified was unique, it was found to function as a type II topoisomerase inhibitor and has demonstrated activity primarily against gram positive bacteria. Although it functions as a topoisomerase inhibitor, it is unique in the fact that it specifically inhibits the ATPase activity of bacterial type II topoisomerases (Phillips et al., 2011). Another promising publication in *Nature* suggests that a new inhibitor (GSK299423) has demonstrated broad spectrum activity by inhibiting DNA gyrase. The promising detail about this inhibitor is that crystal structures have indicated that the inhibitor binds to a noncatalytic site on the DNA gyrase, as compared to the binding site for most fluoroquinolones, thus representing a new class of antibiotics and making this a prime target for further

**3.3 Therapeutic concerns and the need for continued antibiotic development** 

The concern over the current antibiotics available is that the majority function via one or two general mechanisms. Currently the carbapenems are "last line" therapy for many resistant bacteria; the emergence of the NDM-1 gene demonstrates not only an organism's ability to withstand treatment from the majority of available antibiotics, but also demonstrates the threat of effective transposition based spreading from the gene. Many "newer" antibiotics function via some slight variation of previous mechanisms, for example inhibiting protein synthesis by binding one of the ribosomal subunits at a different location or a with a different affinity. Bacteria are likely to rapidly develop resistance mechanisms for antibiotics that function so similarly. Currently there are very few approved antibiotics with novel mechanisms and the "drug development pipeline" does not include a substantial number of

The emergence of the multidrug resistance element NDM-1 suggests the urgency for the development of drastically novel function antibiotics. The over publicized, and perhaps mispublicized, evolution of "superbugs" has forced both public and government attention to the uncertain nature of our microbial defense. The necessity of government support through funding is essential in order to develop drugs that are positioned to enter the "pipeline." Considering the time required for drug development, the risk of global spread of resistance

Data clearly demonstrate a rise in the number of resistant organisms as well as in increase in the number of multidrug resistant bacteria. Based on the relative mutation rate and gene transfer rates, there is indeed a global concern over a future inability to treat bacterial infection effectively and without toxic side effects. Today's medical treatments and surgical capabilities have advanced modern medicine just as the discovery and development of penicillin marked a turning point in therapeutics. Emerging resistant mechanisms and organisms place the world on a path not only similar to an era before penicillin, but also to an era where medical surgical procedures become impossible to the risk of infection. New

development (Bax et al., 2010).

new designs.

is alarming.

**4. Conclusion** 

**4.1 Prevention of antibiotic resistance** 
