Cefaclor & Linezolid and Their Effectiveness against S. Aureus

Kaixuan Jin

Nanjing Foreign Language School, Nanjing, 210008, China

Keywords: Linezolid, Cefaclor, Antibacterial Drugs.

Abstract: Staphylococcus aureus is a common human pathogen that could cause skin and soft tissue infection.

Symptoms and severity of S. aureus SSTIs differ significantly, and complicated SSTI might require

antibacterial agents to treat. Both linezolid and cefaclor are effective against S. aureus infections. Linezolid

is an artificially synthesized antibacterial agent. It inhibits bacteria’s protein synthesis by binding to bacteria

ribosome and prohibiting the translation at an early stage. It could be delivered orally or intravenously.

Cefaclor is another human synthesized antibacterial agent. It could inhibit the synthesis of peptidoglycan by

binding to a type of penicillin binding protein, causing bacteria cell wall lysis. It is delivered orally. In this

work, the structures, mechanisms, limitations and economics of the two antibacterial agents would be briefly

discussed and the comparison between them would be shown clearly.

1 INTRODUCTION

The antibacterial properties of oxazolidinones were

first discovered in 1984. Years later, a research

program on oxazolidinone was performed. After

synthesis attempts and evaluations, scientists

discovered that linezolid had preferable

characteristics and further trials were done. Linezolid

was approved in the United States in 2000 and was

considered an effective drug against Gram-positive

bacteria (Hashemian, Farhadi, Ganjparvar 2018,

Ford, Zurenko, Barbachyn 2001). Linezolid could

bind with bacteria ribosome and inhibit the

translation process at the early stage (Foti, Piperno,

Scala, Giuffrè 2021).

Cefaclor originated from a type of fungus and

belongs to the cephalosporin family. It is effective

against both Gram-negative and Gram-positive

bacteria. Cefaclor’s mechanism is similar to that of

penicillin’s (Arsalan, Ahmad, Ali 2017, Jeong, Jang,

Cho, Lee 2021).

Staphylococcus aureus is a common type of

bacteria (Wertheim, Melles, Vos, van Leeuwen, van

Belkum, Verbrugh, Nouwen 2005). Infections caused

by S. Aureus included skin and soft tissue infections.

Abscesses on the skin is an example of S. Aureus skin

and soft tissue infection (Foti, Piperno, Scala, Giuffrè

2021). Both linezolid and cefaclor are effective in

treating infections caused by S. aureus (Hashemian,

Farhadi, Ganjparvar 2018, Arsalan, Ahmad, Ali

2017).

2 OVERVIEW OF DISEASE

Staphylococcus aureus is a Gram-positive bacterium.

It is spherical and its diameter is approximately 1 μm,

as shown in figure 1. It was first isolated by

Alexander Ogston from an infection in 1880 and in

1882 the term Staphylococcus was created by Ogston.

Further classifications were completed in the

following decades (Lakhundi, Zhang 2018).

Figure 1: S. aureus (Jensen, Koch, Aalbaek et al. 2017).

774

Jin, K.

Cefaclor Linezolid and Their Effectiveness against S. Aureus.

DOI: 10.5220/0011295000003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 774-779

ISBN: 978-989-758-595-1

Staphylococcus aureus is one of the most

common types of bacteria. About 50% of total human

population are continuously or discontinuously

carrying S. aureus (Wertheim, Melles, Vos, van

Leeuwen, van Belkum, Verbrugh, Nouwen 2005). It

causes various infections, including different types of

skin and soft tissue infections (SSTI), the severity of

which could differ significantly (Tong, Davis,

Eichenberger, Holland, Fowler 2015).

Abscesses on the skin is a typical SSTI caused by

S. aureus (Tong, Davis, Eichenberger, Holland,

Fowler 2015). Impetigo is another example of S.

aureus SSTI, shown in figure 2. Among children,

impetigo is the most common SSTI caused by

bacteria (Bangert, Levy, Hebert 2012). Other types of

SSTI could also be caused by S. aureus, despite being

less common (Tong, Davis, Eichenberger, Holland,

Fowler 2015).

Figure 2: Impetigo complicating other infection (Tong,

Davis, Eichenberger, Holland, Fowler 2015).

It remains unclear whether uncomplicated S.

aureus SSTIs would require antibacterial agents in

treatments (Tong, Davis, Eichenberger, Holland,

Fowler 2015), but for the complicated SSTI-generally

defined as situations where an operation would be

needed to cure the infection, or when an extension of

the swollen, infected area into deeper structures

occur, or situations where serious underlying diseases

exist (Sunderkötter, Becker, Eckmann, Graninger,

Kujath, Schöfer 2020) -treatments using antibiotics

might be required (Tong, Davis, Eichenberger,

Holland, Fowler 2015).

3 ABOUT LINEZOLID

3.1 Chemical Structures

Figure 3: Chemical structure of linezolid.

The empirical formula of linezolid is C

(molecular weight: 337.35 g/mol) (Hashemian,

Farhadi, Ganjparvar 2018).

3.2 History

Oxazolidinones-the class linezolid belongs to-were

first used in 1978 due to their effectiveness against

plant diseases. In 1984, it was discovered that

oxazolidinones had antibacterial properties

(Hashemian, Farhadi, Ganjparvar 2018). In the

1990s, with the increasing need for potential new

antibacterial agents, scientists from Pharmacia

Corporation began a biochemistry research program

on oxazolidinone. After massive synthesis attempts

and evaluations, improvements of antibacterial

activity for the chemicals were achieved. Among

various chemicals, linezolid showed preferable

characteristics and was selected for further clinical

test and evaluation. Consequently, the trials proved

linezolid’s effectiveness in treating various Gram-

positive infections (Ford., Zurenko, Barbachyn

2001). In 2000, linezolid was officially approved in

the United States (Hashemian, Farhadi, Ganjparvar

2018).

3.3 Mechanism

Linezolid inhibits protein synthesis by binding with

bacteria ribosome and prohibiting the translation

process. The A-site of 50S subunit of the ribosome

would form bonding with linezolid, and the 30S

subunit would not be affected. The initiator-tRNA

would then be prohibited from binding with the

ribosome, which prevents the translation process at

an early stage. To be more specific, the binding would

occur at the upper part of the peptidyl transferase

Cefaclor Linezolid and Their Effectiveness against S. Aureus

775

center and hydrogen bond would be formed

(Hashemian, Farhadi, Ganjparvar 2018, Foti,

Piperno, Scala, Giuffrè 2021).

The mechanism of linezolid is unique as linezolid

inhibits the synthesis of protein at the early

translation stage. Linezolid is effective against not

only bacterial ribosome, but archaeal ribosome as

well. Human cells would not be inhibited by linezolid

(Foti, Piperno, Scala, Giuffrè 2021).

The 5-acylaminomethyl group binds with

ribosomes and is a pivotal structure for linezolid’s

activity. Electron-withdrawing group in the aryl ring

(the fluoride atom) could increase the activity of

linezolid. Changes with the extra substituents on the

proximal aromatic ring do not have direct effect on

the activity against bacteria but could alter various

characteristics of the chemical (Hashemian, Farhadi,

Ganjparvar 2018, (Chellat, Raguž, Riedl 2016).

3.4 Limitation

Drug resistance:

Although the unique mechanism of linezolid

makes it difficult for bacteria resistance to develop

(Hashemian, Farhadi, Ganjparvar 2018, (Chellat,

Raguž, Riedl 2016), bacteria resistance might still be

a potential issue. A research which included data

from various regions of the world concluded that

linezolid had a 99.9% rate of effectiveness against

Methicillin-resistant Staphylococcus aureus

(Shariati, Dadashi, Chegini, van Belkum, Mirzaii,

Khoramrooz, Darban-Sarokhalil, 2020), but it is still

possible that the percentage of S. aureus resistant

against linezolid is higher in certain particular areas.

The mechanism of bacteria resistance against

Linezolid could be associated with mutation of 23S

rRNA as linezolid binds with the ribosome at the 23S

part (Hashemian, Farhadi, Ganjparvar 2018).

Adverse effects:

Recorded side effects caused by linezolid include

the follows:

(a) Two patients were reported to develop

peripheral neuropathy (caused by damage to

neurological tissues outside of the brain and spinal

cord (Vital, Vital, Bouillot-Eimer, Brechenmacher,

Ferrer, Lagueny, 2004)) after a prolonged linezolid

treatment (Rho, Sia, Crum, Dekutoski, Trousdale,

2004).

(b) Anemia-a condition where blood haemoglobin

(a protein transporting oxygen) concentration is

relatively low for a person's age and gender (Sama,

Chiamo, Taiwe, Njume, Sumbele 2021) -could occur

due to linezolid’s direct effect on red cells

(Hashemian, Farhadi, Ganjparvar 2018,) (Vinh,

Rubinstein 2009).

3.5 Drug Economics

A research has been carried out to determine the cost

for patients who acquired methicillin-resistant

Staphylococcus aureus pneumonia in hospitals in the

United States. The patients received intravenous

linezolid in the standard dose 600 mg every 12 hours,

2 doses/day. The patients received antibiotics for 10

days (20 doses). Among all costs generated during the

treatment, drug cost using linezolid was $2189.

Assuming that cost for intravenous linezolid did not

vary significantly due to different factors, a

conclusion could be made that the average cost per

standard dose (600 mg) of intravenous linezolid was

approximately $109.45 (Patel, Shorr, Chastre,

Niederman, Simor, Stephens, Charbonneau, Gao,

Nathwani 2014).

Linezolid could be changed from intravenous to

oral among patients who are clinically stable

(Hashemian, Farhadi, Ganjparvar 2018). The cost for

patients might therefore decrease.

4 ABOUT CEFACLOR

4.1 Chemical Structure

Figure 4: Chemical structure of cefaclor.

The empirical formula of cefaclor is

ClN

S (molecular weight: 368g/mol).

4.2 History

Cefaclor was originated from the fungus named

Acremonium (Arsalan, Ahmad, Ali 2017). Cefaclor

belongs to the second generation of the cephalosporin

family - antibacterial drugs that have β-lactam as their

activity center and resemble penicillin in mode of

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

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action. Cefaclor is more effective against Gram-

negative bacteria and less effective against Gram-

positive bacteria compared to the first generation of

cephalosporins (Arsalan, Ahmad, Ali 2017, Jeong,

Jang, Cho, Lee 2021).

4.3 Mechanism

The β-lactam ring is responsible for cefaclor’s anti-

bacterial activity (Arsalan, Ahmad, Ali 2017).

Cefaclor’s mechanism is shown in figure 5.

Penicillin-binding proteins are proteins which are

responsible for the final steps of the synthesis of

peptidoglycan-a pivotal substance in the formation of

bacteria cell walls (Sharifzadeh, Dempwolff, Kearns,

Carlson 2020). Cefaclor would bind to a particular

type of penicillin binding protein, which

consequently lead to the prohibition of the synthesis

of peptidoglycan and the lysis of cell wall. The

mechanism is similar to that of penicillin’s (Jeong,

Jang, Cho, Lee 2021).

Peptidoglycans are pivotal substances for

bacterial cell walls while the substance is not found

in human cells. Cefaclor’s damage to human cells is

therefore minimized (Jeong, Jang, Cho, Lee 2021).

Figure 5: Mechanisms of cephalosporins, including cefaclor (Das, Madhavan, Selvi, Das 2019).

4.4 Limitation

Drug resistance:

Drug resistance among bacteria has always been

a significant globally issue. Resistant rate would vary

across different regions due to various factors

(Arsalan, Ahmad, Ali 2017). Percentage of resistance

against cefaclor among S. aureus recorded in the last

ten years is shown in the table below.

Table 1: Bacteria resistance against cefaclor (Arsalan, Ahmad, Ali 2017).

% Resistance Year Region Reference

14.0 2015 Pakistan (Ayub, Fatima, Naqvi, Sheikh, Ali, Ayub 2015)

15.0 2015 Serbia (Stojanovic-Radic, Dimitrijevic, Stankovic, Aleksic,

cic 2016

)

66.66 Before 2012 India (Shaifali, Gupta, Mahmood, Ahmed 2012)

21.0 2011 Pakistan (Arsalan, Naqvi, Sabah, Bano, Ali 2014)

The mechanism of resistance against cefaclor is

related to bacteria’s production of β-lactamase, a

substance that could break down the β-lactam ring in

cefaclor and decrease cefaclor’s effectiveness

(Arsalan, Ahmad, Ali 2017).

Damage to the environment:

Cefaclor belongs to cephalosporins.

Cephalosporin wastewater could pose threats to the

environment. The wastewater mainly contains toxic

organic chemicals, inorganic salts which could

Cefaclor Linezolid and Their Effectiveness against S. Aureus

777

potentially threat survival of organisms in natural

environment (Das, Madhavan, Selvi, Das 2019,

Yang, Zuo, Li, Wang, Yu, Zhang 2016, Guo, Chen

2015).

Adverse effects:

(a) Diarrhoea (approximately 5.6% of patients)

have been reported after use of cefaclor. The effect is

relatively minor (Turik, Johns 1998).

(b) Hypersensitivity cases have been observed but

the cases are not life-threatening (Arsalan, Ahmad,

Ali 2017, Murray, Singer, Singer, Veldman 1980).

4.5 Drug Economics

Cefaclor is an oral antibacterial drug. Cost for the

drug would vary depending on brands and types. A

250 mg capsule of cefaclor might cost $1.5 to $2.1.

5 DISCUSSION

Linezolid has oral and intravenous way of delivery,

while cefaclor is an oral antibacterial agent. Various

relatively serious adverse effects induced by linezolid

are reported, but it is possible that some side effects

could be reduced by appropriate control of time or

dose while using the drugs.

Linezolid has a relatively unique mechanism and

has a lower rate of resistance among S. aureus

compared to cefaclor. It is possible that future study

could make linezolid & cefaclor more effective

against resistant bacteria by altering part of their

structures. Other characteristics of the drugs, such as

solubility, might also be improved in future studies.

6 CONCLUSION

The review mainly compared the origins,

mechanisms, limitations and drug economics of

Linezolid and Cefaclor. Their effectiveness against

infections caused by S. aureus, a typical type of

pathogen, was also briefly discussed. There are

similar issues for antibacterial agents with different

mechanisms, such as the global spread of drug

resistant bacteria. In future studies, both drugs might

be improved to become more effective against drug-

resistant bacteria. Modifications of a drug’s structure,

for instance, might improve the drug’s reactivity or

stability.

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