# Current Promising Strategies against Antibiotic-Resistant Bacterial Infections
## 4 Developing Alternatives to Antibiotics
### Vaccines  
Vaccines are always the first choice to prevent infectious diseases. Compared to the relatively simpler viruses, fewer vaccines are clinically available for bacteria. As of 2019, FDA approved 65 and 32 vaccines to prevent diseases caused by viruses and bacteria, respectively. These bacteria were _B. anthracis_, _M. tuberculosis_, _Vibrio cholerae_, _Clostridium tetani_, _H. influenzae_, _Neisseria meningitidis_, _Yersinia pestis_, _S. pneumoniae_, and _Salmonella typhi_, which do not include the nosocomial ESKAPE pathogens. No vaccine against ESKAPE pathogens is available, though not for lack of trying as demonstrated by dozens of clinical trials that have failed so far. In earlier clinical trials, vaccinating whole cells or cell lysates of pathogens such as _K. pneumoniae_ and _S. aureus_ exhibited a limited protection with relatively high toxicity [125; 126]. StaphVAX, a vaccine that targeted _S. aureus_ capsular polysaccharide types 5 and 8 (CP5 and CP8), was assessed in two phase III studies and eventually displayed no benefit for the recipients with bacteremia [127]. The IsdB vaccine V710 also failed in a phase III randomized controlled trial of _S. aureus_ infection [128]. Pfizer's SA4 Ag vaccine, targeted multicomponent antigens MntC, ClfA, and both CP5 and CP8, was still insufficient in providing protective immunity against _S. aureus_ in the bloodstream and surgical site infections in patients who had undergone spinal surgery [129]. Two LPS-targeted vaccines were unsuccessful in reducing the rate of _P. aeruginosa_ colonization and the frequency of _P. aeruginosa_ infection in patients with cystic fibrosis [130; 131]. The vaccine IC43 consisting of two _P. aeruginosa_ OMPs, OprF, and OprI, had no significant effect on invasive _P. aeruginosa_ mortality and infections in a phase III study [132]. These clinical studies urge scientists to dissect disappointing results in the hope of finding ways to overcome failures. Recent studies strongly suggest that prior exposures to bacteria by colonization seem to cause the ineffectiveness of vaccines in humans. Such bacteria that are commonly found in human microbiota include _E. facecium_, _S. aureus_, _K. pneumoniae_, and some _Enterobacter_ strains [133; 134]. The pre-existing human-_S. aureus_ interaction jeopardizes immune responses to many staphylococcal antigens [135; 136; 137; 138]. Thus, in humans who have been previously exposed to _S. aureus_, new vaccination with those antigens is incapable of conferring protective immunity. Overcoming this obstacle of prior _S. aureus_ exposures can be achieved at least by immunizing the antigen epitopes that only develop protective immunity or that have no immune response during _S. aureus_ exposures. Staphylococcal protein A (SpA) is one such antigen that has no specific antibodies in humans and vertebrates after colonization or infection [139; 140]. Two improved nontoxic SpA variantswere developed and showed strong potential to reduce the rate of _S. aureus_ bloodstream infection and nasal colonization [141], and now are being further studied.