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Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 11  

Review Article  

Ceftriaxone Resistance – A caution for judicial antibiotic use 

Janice Jacson Mandumpala 

From, Pharm D intern, Nirmala College of Pharmacy, Ernakulam, Kerala, India 

Corresponding to: Janice Jacson Mandumpala, Pharm D intern, Department of Pharmacy Practice, Nirmala College of Pharmacy, 

Ernakulam, Kerala, India. Email: janice.jacson@gmail.com 

ABSTRACT 

Ceftriaxone is a broad-spectrum antibiotic that is effective against both Gram-negative and Gram-positive isolates. Ceftriaxone 

resistance research is useful in determining its current status. As a result, we aimed to understand the prevalence of Ceftriaxone 

resistance in bacteria isolated from various clinical specimens. Resistance to ceftriaxone has been steadily increasing and demands 

immediate attention. Ceftriaxone resistance prevention mechanisms must be strictly enforced. The appropriate drugs should be chosen 

based on susceptibility patterns. In summary, ceftriaxone should be considered in the initial treatment of seriously ill patients with 

infections of unknown aetiology when Gram-negative aerobes (other than Pseudomonas species) are the suspected pathogens, and in 

patients with Gram-negative organisms with suspected or demonstrated resistance to other antibiotics. This review summarizes the 

advent of ceftriaxone resistance among various organisms across the globe. 

Keywords – Ceftriaxone, Resistance, Gonorrhoea, Salmonella, Shigella, Aeromonas, Enterobacter 

he third-generation cephalosporin ceftriaxone has good 

effectiveness against numerous gram-negative 

pathogens and excellent activity against the majority of 

gram-positive infections. Ceftriaxone has generally 

more antibacterial action against Gram-negative bacteria than 

the "first" and "second generation" cephalosporins, but less 

antibacterial activity than the previous generations of 

cephalosporins against numerous Gram-positive bacteria. 

Ceftriaxone has a long elimination half-life, allowing for twice- 

and once-daily treatment, the latter of which may result in 

significant cost savings. Ceftriaxone may replace other third-

generation cephalosporins as the treatment of choice for a range 

of serious infections due to its proven efficacy, safety, and 

practical dose schedule [1].  

In patients with bacterial meningitis, respiratory tract 

infections, urinary tract infections, soft tissue infections of the 

bone and joints, and gonorrhoea, clinical investigations have 

shown their effectiveness and safety. Except for diarrhea, which 

has often not necessitated changing the course of treatment, 

ceftriaxone has been well tolerated. Despite having modest 

action against Pseudomonas aeruginosa, ceftriaxone is not 

currently advised as the only antibiotic therapy for 

pseudomonal infections based on the available data. Infections 

caused by other "difficult" organisms, such as multidrug-

resistant Enterobacteriaceae, have been successfully treated 

with ceftriaxone [2].  

With the discovery of penicillin by Sir Alexander Fleming 

in 1928, the modern era of antibiotics began [3]. Since that time, 

antibiotics have revolutionized contemporary medicine and 

helped save countless lives [4]. In the 1940s, doctors began 

using antibiotics to treat severe infections. Unfortunately, 

almost all antibiotics that have been produced have eventually 

been associated with resistance, and this is also true of 

cephalosporins, notably ceftriaxone [5]. 

Mechanism of ceftriaxone resistance development 

There are multiple mechanisms that infectious agents use to 

resist the lethal action of antibiotics such as mutational 

resistance, acquisition of genetic material, increased drug efflux 

or, decreased drug intake [6]. Other complex mechanisms 

involve are biofilm formation and quorum [7]. Quorum sensing 

and biofilm formation is the common mechanism for antibiotic 

resistance among E. coli. In this, the cells adhere to each other 

on their surface using a self-produced matrix called the extra 

polymeric substance. This extra polymeric substance creates a 

barrier for the antibiotic to enter the bacteria, this promotes the 

emergence of antibiotic resistance and this is referred to as 

quorum sensing [8].  

However, this mechanism may not be applicable to gonococci. 

Gonococci develop resistance to beta-lactam antibiotics 

primarily by two mechanisms – one that is quickly acquired 

through the transfer of resistance plasmid that produces beta-

lactamases and the second one is the gradual acquisition of 

multiple resistance genes that promotes beta-lactam resistance 

[9]. The production of extended-spectrum beta-lactamases is 

the most commonly attributed mechanism of ceftriaxone 

T 

mailto:janice.jacson@gmail.com


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Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 12  

resistance in E.coli [10]. Additionally, a molecular analysis of 

Salmonella isolates with ceftriaxone resistance has 

demonstrated a higher production of the CMY-2 and the CTX-

M-3 beta-lactamases [11]. On the other hand, ceftriaxone 

resistance in Neisseria gonorrhoeae is a result of 

chromosomally mediated mutations at the three loci of penA, 

mtrR, and penB [12].  

Furthermore, the production of cephalosporinases also 

degrades cephalosporins and this is one such mechanism that 

promoted ceftriaxone resistance among Salmonella species. 

Since extended-spectrum beta-lactamases are mobile genetic 

materials and bacteria can acquire them through horizontal gene 

transfer from resistant bacteria, sensitive bacteria can acquire 

resistance to cephalosporins [13]. Also, several studies on the 

mechanism of resistance to third-generation cephalosporins, 

particularly ceftriaxone have suggested that clinical strains of 

Enterobacter cloacae are linked to the excessive production of 

chromosomal beta-lactamases [10, 14].  

Neisseria gonorrhoeae 

Antimicrobial resistance in Neisseria gonorrhoeae is a major 

public health concern globally. The most frequently prescribed 

antibiotics for Gonorrhoea are ceftriaxone, cefixime, 

azithromycin, spectinomycin, ciprofloxacin, and ofloxacin. 

Neisseria gonorrhoeae was initially susceptible to the majority 

of antimicrobials since the mid-1930s [15, 16]. But recently the 

resistant patterns in Neisseria gonorrhoeae have developed 

owing to its ability to develop or acquire antimicrobial 

resistance through most of the existing mechanisms. A few 

examples of the mechanisms Neisseria gonorrhoeae undergo to 

cater to antimicrobial resistance are as follows – inactivation, 

degradation of antimicrobials, alteration of the target 

antimicrobial, decreased antimicrobial influx, and increased 

generation of efflux transporters.  

Resistance of Neisseria gonorrhoeae to fluoroquinolones 

and ceftriaxone came into prominence after its first appearance 

in Japan which then further spread globally [17-20]. 

Furthermore, the first global failure for treating pharyngeal 

gonorrhoea with dual antibiotics (both 500 mg ceftriaxone and 

1g azithromycin) was first reported in the United Kingdom in 

2016 [21]. Dual therapy has been instituted due to the emerging 

resistance patterns, but countries such as Japan, China, 

Azerbaijan, Netherlands, Belarus, and Ukraine still use 

ceftriaxone 500mg-1g as empirical mono-therapy [22-24].  

With the evolving resistance patterns, what are the options 

available to the medical community? Repurposing the old 

antimicrobials, use of newer antimicrobials with mainly non-

human or invitro data availability, and novel antibiotics in 

clinical trials. Spectinomycin is a long-used antimicrobial for 

gonorrhoea with excellent susceptibility, but relatively lower 

success in treating pharyngeal gonorrhoea [25]. Therefore, 

spectinomycin can be used as a part of the dual regimen along 

with azithromycin to prevent the emergence of antimicrobial-

resistant strains [26].  

New antimicrobials with only non-human evidence have 

demonstrated relative potency against Neisseria gonorrhoeae 

and include avarofloxacin, delafloxacin, sitafloxacin, 

tigecycline, 2-acyl carbapenems and many others which have 

been reviewed elsewhere [27-29]. However, many of them are 

in stages of early development thus posing a challenge for their 

use within the clinical setting. Three antimicrobials 

solithromycin, zoliflodacin, and gepotidacin are novel orally 

administered drugs in clinical evaluation for uncomplicated 

gonorrhoea and particularly zoliflodacin appears very 

promising and requires attention [30]. Until a promising new 

effective treatments, rational use of ceftriaxone and 

azithromycin will help treat gonorrhoea with its severe 

complications.  

Aeromonas spp. 

Aeromonas species can cause a wide spectrum of intestinal and 

extra-intestinal infections (gastrointestinal tract syndromes, 

wound and soft tissue infections, urinary tract infections, and 

rarely septicaemia) [31]. They are Gram-negative rods, 

facultative anaerobes and oxidase-positive. Aeromonas species 

that are pathogenic for humans include Aeromonas 

hydrophila, Aeromonas sobria, Aeromonas trota, 

and Aeromonas caviae and are most commonly found in the 

aquactic life forms particularly fishes [32, 33].  

The sensitivity of Aeromonas can vary based on 

geographical location and diversity. The most common 

antibiotics employed for Aeromonas infections are 

fluoroquinolones and tetracyclines. Furthermore, third-

generation cephalosporins have also been recommended but in 

recent years, there has been an upward trend for resistance to 

ceftriaxone attributed to the beta-lactamase activity of 

Aeromonas [34].  

Aeromonas has been linked to the development of beta-

lactamases (ESBLs, AmpCBLs, and carbapenemases), efflux 

pumps, and changes in the outer membrane that result in 

decreased permeability as the mechanisms of resistance to 

third-generation cephalosporins. Aeromonas is known to carry 

various drug-resistance genes and has also demonstrated the 

ability to transfer such genes to various gram-negative bacteria. 

Multiple drug resistance among Aeromonas spp. have been 

reported from many parts of the world as well. Also, a 

concerning aspect of drug resistance among the 

Aeromonas spp. is the ability to bring about extra-intestinal 

infections that can be fatal with the existing multiple drug-

resistance genes [35]. A plausible cause for such increased 

spread of antibiotic resistance is rapid urbanization and the 

evolution of bacteria to survive such threats [36].  



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Salmonella spp. 

An alarming health issue that exists everywhere is salmonella 

infection. Effective steps should be taken to stop the issue from 

getting worse [11]. The preferred treatment for typhoid fever is 

ceftriaxone, however, the introduction of Salmonella Typhi 

which is resistant to it creates serious treatment problems. There 

are more and more sporadic instances of ceftriaxone-resistant 

S. Typhi, therefore reducing the chance that the patient won't 

respond to therapy and that outbreaks will spread throughout 

the neighbourhood must take precedence. Since 1988, 

Salmonella resistant to extended-spectrum cephalosporins has 

become an international problem. This public health issue had 

been reported in 43 countries by 2004. Traditional extended-

spectrum beta-lactamases, plasmid-mediated 

cephalosporinases, and most recently a class a carbapenemase 

were responsible for mediating resistance. The most 

extensively distributed of them is CMY-2. The two most 

prevalent serovars connected to extended-spectrum 

cephalosporins resistance in human infections are Salmonella 

enterica serotype Typhimurium and Salmonella enterica 

serotype Enteritidis [37]. 

The invasive infection caused by Salmonella enterica 

serotype Choleraesuis is usually typical. Most often extended-

spectrum cephalosporins or fluoroquinolones are utilized to 

treat resistant Salmonella infections [38]. However, there are 

increasing reports of fluoroquinolone resistance in the invasive 

serotype of Salmonella. In SC-B67, ceftriaxone resistance was 

linked to a plasmid-mediated blaCMY-2 that is commonly present 

on a particular ISEcp1-blaCMY-2-blc-sugE structure [39]. This 

conserved DNA segment, later given the designation Tn6092, 

has been identified in numerous Enterobacteriaceae and 

Salmonella serotypes from across the globe [40, 41]. In 

addition, ceftriaxone-resistant serotype Salmonella 

Typhimurium infections, which were previously uncommon in 

western Kenya, appeared quickly between 2009 and 2014 in 

countries in western Kenya, restricting the range of available 

treatments for serious infections. In order to direct proper 

therapy in diverse Asian and African nations, there is an urgent 

need for increased microbiologic diagnostic capability in 

clinical settings [42].  

Extended-spectrum –lactamases whose genetic elements 

can be found in plasmids or the chromosome, are typically 

responsible for the creation of resistance to ceftriaxone. 

Organisms that produce CTX-M-type ESBLs constitute a 

particularly major public health danger globally among the 

variety of antibiotic-resistant Gram-negative bacteria 

pathogens that are currently recognised [43]. An extremely 

invasive zoonotic bacterium called S. choleraesuis produces a 

devastating systemic infection in people. A significant 

treatment issue has arisen due to the emergence and growth of 

S. choleraesuis resistance to ceftriaxone and ciprofloxacin. 

Sirirat et al have demonstrated high frequency of antimicrobial 

resistance in Salmonella Choleraesuis among 414 nontyphoidal 

Salmonella isolates from bacteremic patients in Thailand. S. 

choleraesuis isolates had high rates of ceftriaxone (58.3%) and 

ciprofloxacin (19.6%) resistance. The clonal spread of S. 

choleraesuis isolates harbouring blaCMY-2 as well as the 

dissemination of the self-transferable blaCTX-M-14-carrying 

IncFIIs, IncFII, and IncI1 plasmids and the blaCMY-2-carrying 

IncA/C plasmid as well as the high frequency of resistance to 

extended-spectrum cephalosporins (3rd and 4th generation 

cephalosporins).  

The first occurrence of ceftazidime-hydrolyzing CTX-M-55 

in S. choleraesuis isolates has been documented; between 2012 

and 2016, this variant's abundance among ESC-resistant S. 

choleraesuis isolates grew rapidly. The dispersion of IncA/C 

plasmids carrying both blaCTX-M-55 and qnrS1 among 

ciprofloxacin-resistant S. choleraesuis isolates expressing 

D87G in GyrA was the cause of the spread of clone pulsotype 

B3. The high frequencies of co-resistance to ESCs and 

ciprofloxacin (51.3%) from 2012 to 2016 were reportedly 

caused by these isolates. As a result of travel and commerce in 

animal food items, this study highlights the significance of 

having an action plan to prevent the spread of antibiotic 

resistance in S. choleraesuis [44-46].  

Shigella spp. 

In the underdeveloped world, shigellosis is one of the major 

causes of diarrheal illnesses. An estimated 165 million cases 

and 1.1 million fatalities worldwide (mainly in underdeveloped 

nations) occur each year. Shigellosis patients have been advised 

to have antibiotic therapy because it can shorten the duration of 

the causative organism's faecal excretion and limit the clinical 

course of the illness, lowering the risk of complications and 

infection transmission [47, 48]. The growing resistance of 

Shigella spp. to effective antimicrobial treatments, however, is 

a significant issue [49]. Shigella isolates that are resistant to a 

variety of medications, including sulphonamides, tetracyclines, 

ampicillin, trimethoprim-sulphamethoxazole (SXT), and 

nalidixic acid, have been reported from many different nations 

over the years [50].  

Azithromycin, mecillinam, ciprofloxacin, ceftriaxone, and 

cefixime are examples of novel antimicrobials that have been 

proven to be successful in treating multidrug-resistant Shigella-

associated illnesses. However, Shigella strains resistant to 

ceftriaxone have emerged [51, 52]. Fluoroquinolones are the 

sole available antibiotic therapy for such MDR Shigella-

associated illnesses due to the dearth of other options. 

Fluoroquinolones must be used carefully and wisely to prevent 

the rapid emergence and spread of resistance, as evidenced by 

the discovery of decreased susceptibility to fluoroquinolones in 

a significant fraction of Shigella strains and completely 

fluoroquinolone-resistant S. dysenteriae Type 1 [53, 54]. 

According to a study conducted by Gu B et al, a lower average 



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Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 14  

prevalence of ceftriaxone resistance among Shigella spp. was 

found in Europe-America countries. In contrast, Asia and 

Africa saw a clear increasing trend in ceftriaxone resistance, 

especially after 2007. Ceftriaxone resistance was present on 

average at a rate of 5% in Asia and Africa, which is 6 times 

higher than that of Europe and North America. In addition, 

Asia-Africa had resistance rates to ceftriaxone, cefotaxime, and 

ceftazidime that were up to 142%, 226%, and 62%, 

respectively, between 2010 and 2012. This warrants rapid 

action [55].  

This phenomenon could have a number of explanations. 

The major cause is regional variations, which have a direct 

impact on socioeconomic position. Individuals in more 

developed regions (such as Europe and America) typically 

receive better care after contracting an infection than people in 

less developed nations (Asia-Africa). Second, flaws in medical 

infrastructure and facilities are also significant factors. Pakistan 

and other Asian-African nations lack the infrastructure 

necessary to track antimicrobial resistance on a national scale 

[56]. In addition, cheap antibiotics are widely accessible from 

both licensed and unlicensed sources in many Asian and 

African nations, which contributes to drug addiction and a high 

rate of resistance [57]. Third, the lack of access to safe drinking 

water and inadequate sanitation lead to the emergence of MDR 

strains of Shigella. Malnutrition is one of the underlying factors 

that raise the risk of diarrhoea and is widespread in Asian and 

African nations [58].  

Enterobacter cloacae 

The environmental pathogen Enterobacter cloacae complex 

(ECC), which is common, is a significant cause of nosocomial 

infections. The therapeutic importance of each species within 

ECC is less understood since standard techniques used in 

clinical laboratories cannot distinguish between species within 

ECC.Gram-negative rods resistant to third-generation 

cephalosporins are included in the broad spectrum of 

antibacterial activity of carbapenems. The main cause of 

ceftriaxone resistance is the pre-existing presence of resistant 

clones (also known as "derepressed mutants") in the 

Enterobacter populations. The majority of resistant clones 

generate substantial levels of beta-lactamases, and some of 

them exhibit decreased Porin F expression together with 

enhanced Porin C expression.  

In a HPLC-based approach conducted by Pechere et al the 

author used HPLC to determine the outer membrane 

permeability in intact cells, and the results revealed that 

imipenem penetrated three times more quickly than 

ceftriaxone. Furthermore, imipenem penetration was 

unaffected in a Porin F defective mutant, in contrast to 

ceftriaxone. This implied that imipenem has a different route, 

possibly Porin C, then ceftriaxone. The affinity for PBPs, as 

determined by computation, and the rate of beta-lactamase 

hydrolysis under experimental settings that were believed to be 

physiologically relevant were comparable for the two 

antibiotics. Thus, selective permeability of the outer membrane 

appears to be the main cause of imipenem's action against 

ceftriaxone-resistant E. cloacae [59]. Because ECC isolates 

display intrinsic AmpC -lactamases, such as CMH, ACT, and 

MIR with numerous variations, they are innately resistant to 

ampicillin, amoxicillin-clavulanate, and first and second-

generation cephalosporins [60]. Antibiotic usage has led to the 

emergence and global spread of multidrug resistant (MDR) 

ECC strains [61]. Third-generation cephalosporin resistance is 

also brought on by the acquisition of genes encoding extended 

spectrum -lactamase (ESBL). Additionally, treatment is 

becoming challenging due to the advent and rising prevalence 

of carbapenem-resistant ECC. MDR strain infections typically 

result in increased mortality, lengthier hospital stays, and 

higher expenses, having a significant influence on worldwide 

public health [62]. 

CONCLUSION 

Antibiotic resistance should be prevented by reducing the 

irrational misuse of antibiotics, but designing successful 

interventions to do so will require a greater knowledge of the 

practices and financial incentives associated with antibiotic 

administration. Although increased cephalosporin resistance is 

frequently attributed to a single factor (PBP modification, beta-

lactamase action, or impermeability), an organism's response to 

a drug frequently reflects the interaction of several factors. 

There is a need to develop methods, such as mathematical 

models, to aid in identifying the interplay of factors that lead to 

ceftriaxone resistance. 

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Mandumpala                                                                                                                A caution for judicial antibiotic use 

 

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How to cite this article: Janice Jacson Mandumpala.  Ceftriaxone 

Resistance – A caution for judicial antibiotic use. Indian J Pharm 

Drug Studies. 2023: 2(1); 11-16. 

Funding: None                              Conflict of Interest: None Stated 

 


