Bactericidal and Bacteriostatic Antibiotics

*Sachin M. Patil and Parag Patel*

#### **Abstract**

Of all the medications available to physicians worldwide, antibiotics play an essential role in inpatient and outpatient settings. Discovered in the early nineteenth century by Alexander Fleming, penicillin was the first antibiotic isolated from a mold. Dr. Gerhard Domagk developed synthetic sulfa drugs by altering the red dye used in chemical industries. Since then, multiple antibiotic classes have been discovered with varying antimicrobial effects enabling their use empirically or in specific clinical scenarios. Antibiotics with different mechanisms of action could be either bactericidal or bacteriostatic. However, no clinical significance has been observed between cidal and static antibiotics in multiple trials. Their presence has led to safer deep invasive surgeries, advanced chemotherapy in cancer, and organ transplantation. Indiscriminate usage of antibiotics has resulted in severe hospitalacquired infections, including nosocomial pneumonia, *Clostridioides difficile* infection, multidrug-resistant invasive bacterial infections, allergic reactions, and other significant side effects. Antibiotic stewardship is an essential process in the modern era to advocate judicial use of antibiotics for an appropriate duration. They play a vital role in medical and surgical intensive care units to address the various complications seen in these patients. Antibiotics are crucial in severe acute infections to improve overall mortality and morbidity.

**Keywords:** Sepsis, antibiotics, bactericidal, bacteriostatic, stewardship

#### **1. Introduction**

Antibiotic is a term used to define a chemical substance produced by one microorganism that stunts the metabolism and development of other organisms [1]. The antibiotic term was used initially for naturally acquired substances; however, now the term encompasses both natural and synthetic antimicrobial substances. Although penicillin was the first antibiotic isolated from the mold, it was superseded by sulfa drugs used by physicians to treat infections successfully [2]. Due to antibiotic use, the infectious disease death rate has declined from 280 per 100,000 to 60 per 100,000 in the 1950s [3]. A common belief is that cidal antibiotics are efficient than static antibiotics with no clinical evidence supporting it. Both cidal and static are invitro terms which, refer to the effect of antibiotic concentrations affecting bacterial growth at a predefined threshold. They cannot predict the infection outcome in vivo. Antibiotics targeting the organism's cell wall are mostly bactericidal, whereas those targeting protein syntheses are bacteriostatic. MIC (minimum inhibitory concentration) is the lowest antibiotic concentration, which

prevents visible growth at 24 hours. MBC (minimum bactericidal concentration) is the minimal concentration of antibiotics that causes bacterial death. Breakpoints for antibiotic MIC's are set by the the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and National Committee for Clinical and Laboratory Standards Institute (CLSI). A bactericidal antibiotic MBC is less than or equal to four folds above the MIC, accounting for a 1000-fold decline in bacterial density [4]. A bacteriostatic antibiotic achieves a > 1000-fold reduction at eight-fold above MIC or a 500-fold reduction in bacterial density at 4-fold above its MIC. They are still labeled as static despite the clear demonstration of bacterial killing. An antibiotic becomes more bactericidal as the MIC moves closer to the MBC. Bacteriostatic agents have an MBC to MIC ratio > than that for bactericidal antibiotics.

A systematic literature review revealed no confirmation that cidal agents are better than static agents [5]. In addition, there was no substantial difference in efficiency, including critically ill patients with severe infections and sepsis. Six trials demonstrated the superiority of static agent linezolid over cidal agents such as vancomycin [5]. A single trial showed the efficiency of cidal agent imipenem over tigecycline; however, the dose of tigecycline was small, and with increased appropriate dosing, the efficacy disappeared [6, 7]. A rapidly bactericidal agent such as daptomycin does not perform better than a slowly cidal agent such as vancomycin to treat right-sided infective endocarditis (IE) and staphylococcal bacteremia [8] . A synergistic combination of beta-lactam with aminoglycosides enhances the bactericidal effect with rapid blood clearance [9]. However, this synergistic combination has not improved clinical outcomes or mortality [10]. In the initial studies, static agents such as tetracyclines and macrolides were inferior to cidal agents in IE therapy [11]. This assumption can be erroneous as the static agents do not achieve adequate low blood concentrations to treat infective endocarditis effectively. A bacteriostatic antibiotic such as linezolid can attain sufficient bloodstream concentrations resulting in higher cure rates for IE [12]. Daptomycin, a rapidly bactericidal agent, is inferior to vancomycin in left-sided IE [13]. For an individual antibiotic to be effective, the importance of its pharmacokinetic-pharmacodynamic properties and attaining adequate drug levels at the infection site is substantial than static versus cidal properties used in predicting clinical efficacy. An intact immune system is critical for the efficacy of bacteriostatic agents, and bactericidal agents are preferred in immunosuppressed patients. Broad-spectrum agents cover many susceptible pathogens, whereas narrow-spectrum agents cover a limited number of pathogens. Broad-spectrum agents are used empirically in the therapy of lung and abdominal infections. Narrow-spectrum agents are used in a limited number of indications.

#### **2. Bacteriostatic antibiotics**

These include folate inhibitors (sulfonamides and trimethoprim) in **Table 1** (2A I), tetracyclines in **Table 2** (2A II), glycylcyclines in **Table 3** (2A III), macrolides in **Table 4** (2A IV), lincosamides in **Table 5** (2A V), oxazolidinones in **Table 6** (2A VI) and fusidic acid in **Table 7** (2A VII).

Dapsone can substitute sulfamethoxazole in the TMP-SMX combination for PCJ pneumonia in patients with allergies to sulfonamide antibiotics [89]. TMP-SMX is the drug of choice for Q-fever in pregnancy. An essential fact to remember is that TMP-SMX does not cover *pseudomonas* and should be avoided in streptococcal infections due to a higher incidence of resistance [90]. Iclaprim is a DHFR inhibitor with bactericidal activity against *methicillin-sensitive Staphylococcus aureus* (MSSA), *Methicillin-resistant* (MRSA), *beta-hemolytic Streptococcal spp,* and *Enterococcus*

*Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*


#### **Table 1.**

*2AI folate inhibitors: Sulfonamides & trimethoprim.*

*faecalis*. It undergoes hepatic clearance, and dose adjustment is needed in hepatic impairment. Tissue penetration is excellent in the lungs. It is effective without a sulfa moiety so that it can be used in patients with sulfa allergy. The side effects include nausea, headache, fatigue, and QT interval prolongation. Currently, it is under trials for SSTI and nosocomial pneumonia [91, 92].

Doxycycline is the drug of choice in bioterrorism caused by *Bacillus anthracis*, *Yersinia pestis*, *Francisella tularensis*, *Coxiella burnetti*, and *Brucella spp* [93]. In the medical intensive care unit (MICU), tetracyclines are the drug of choice in acute sepsis due to cholera, ehrlichiosis, *stenotrophomonas* infections, rickettsial disease, anaplasmosis, and PID.

In sepsis, tigecycline is used in MDR infections as a last resort, and the federal drug authority (FDA) has placed a boxed warning about this death risk. It can also be used effectively at a higher dosage in MDR hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).


#### **Table 2.**

*<sup>2</sup>A II tetracyclines.*


*Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*


#### **Table 4.**

*2A IV macrolides.*


Two other newer tetracycline derivatives have been released Eravacycline, a fluorocycline, and Omadacycline, an aminomethylcycline., while omadacycline has been approved for SSTI and CABP. In contrast, Eravacycline has been approved for cIAI [94, 95]. Similar to tigecycline, neither of these agents cover pseudomonas.


#### **Table 6.**

*2A VI oxazolidinones.*

