Abstract

Infection is one of the most important reasons for the increase in the number of deaths worldwide; it can be a bacterial or viral infection. As a result, there are many effective drugs against this infection, especially bacterial ones. Cefepime (CP) is one of the fourth generations of cephalosporins and is distinguished from others in that it can kill both positive and negative bacteria. Therefore, this study focused on the chemical properties of the drug, its uses, and its stability against bacteria. All analysis methods for this drug in pharmaceutical preparations, blood, or plasma were also presented. One of the important problems in these methods is using toxic solvents, which poses a danger to society and the environment. The presentation of these solvents will allow companies to manufacture and use more effective and less toxic solvents.

1. Introduction

Cefepime (CP) is one of the commonly used fourth-generation cephalosporins. Cefpirome and cefaclidine are other fourth-generation antibiotics. CP has adequate β-lactamase stability but with a low affinity for extended spectrum. The broad spectrum of CP is imposed to cover a wide range of positively and negatively pathogens [14]. Compared with ceftazidime from the fourth generation in vitro, CP has intensified activity against Gram (+) bacteria, excluding the species sensitive to methicillin, such as Streptococcus pneumoniae and Staphylococcus aureus [5, 6]. CP is more effective against extended-spectrum β-lactamase Gram (−) bacteria than other oxyimino-cephalosporins commercially available. [79].

The cefepime’s chemical structure is displayed in Figure 1. The basic cephem ring at position 7 is modified chemically to increase the cephalosporins’ stability against β-lactamase enzymes. Similarly, other antibiotics CP such as ceftazidime, cefoperazone, ceftizoxime, and ceftriaxone from the third-generation contain a 2-amino thiazolyl acetamido group substituted with an oxyimino in the same position. However, unlike other third-generation cephalosporins, CP possesses a cephem nucleus substituted with a positively charged NMR, making it a zwitterion [2]. This zwitterionic property permits penetration of CP to Gram (+) bacteria’s porin channels rapidly [10, 11]. CP is used effectively to treat severe urinary and respiratory tract infections, as well as infections of the skin, soft tissues, and the women’s reproductive tract among patients with febrile neutropenia. Treatment of pneumonia in cystic fibrosis patients with this medication is superior to that with ceftazidime.

CP is considered an empirical monotherapy for pneumonia; it is widely used currently in hospitals for this approved indication and given to the patient with abdominal, urinary tract, febrile neutropenia, and skin or soft tissue infections. An earlier systematic published review of empirical monotherapy for the treatment of febrile neutropenia found CP to be associated with a higher mortality rate than other β-lactam antibiotics. It was unclear how the higher mortality rate was explained. CP was associated with more superinfections than other β-lactams, though the difference was not significant statistically. [12]. The authors in [1] established that the overall death rate was significantly lower in patients suffering from P. aeruginosa infections if treated with extended infusion CP.

2. Stability

In aqueous solutions, either acidic or basic, CP undergoes rapid degradation, resulting in hydrolysis (opening) of the β-lactam ring and simultaneous release of the side chain in the R-2 position from its particle. Because of hydrolysis of the β-lactam ring and separation of the NMP particle, two degradation products have been observed, neither of which demonstrate antimicrobial activity.2-[((2-amino-4-triazolyl) (methoxyimino)acetyl) amino] acetaldehyde is one of them [5]. The rate at which CP degrades in aqueous solutions, just like other β-lactam antibiotics, is determined by temperature, light, solvent composition, pH, antibiotic concentration, and the type of packaging. [7].

3. Chemistry

Cephalosporins, in general, contain a 4-membered β-lactam cycle connected to a 6-membered dihydrothiazine cycle [8]. The molecular weight of CP is 571.5 g, and its molecular formula is CI9H25N6O5S2·Cl·HCl·H2O. CP named chemically as (6R,7R)-7-((E)-2-(2-aminothiazol-4-yl)- 2-(methoxyimino) -acetamido)-3-((1-methylpyrrolidin-1-ium-1-yl) methyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- 2-carboxylate, its structure is shown in Figure 1, and it is characterized by high solubility in water. Furthermore, it is supplied as intravenous (IV) and intramuscular (IM) administration in doses equivalent to 2 g, 1 g, and 0.5 g of CP. It is formulated as a hydrochloride salt and used with L-arginine, adjusting the reconstituted solution at pH 4–6. [8].

CP is cited as an antibiotic from the fourth generation because its activity is a broad spectrum, and it has a high resistance to hydrolysis by β-lactamase [12]. CP possesses a quaternary positively charged nitrogen atom, thus, it is called a zwitterion. This character makes CP neutral enough and increases its ability to penetrate bacterial membranes [13]. CP has a side chain with a 2-amino thiazolyl acetamido group at position 7 and is substituted with the alpha-oxyimino group. The 2-carboxy-2-propoxyimino group in CP is replaced by the alkoxyimino group at position 7, as is the case with cefotaxime, ceftriaxone, and ceftazidime. [14] This is expected to increase its stability against β-lactamases by avoiding the entrance of these enzymes into the nucleus. The antistaphylococcal activity is improved by substituting the group (7-[2-carboxy-2-propoxyimino]) in its side chain with an alkoxyimino substituent. Therefore, CP has a similar gram (−) spectrum and better antistaphylococcal activity than ceftazidime [14].

4. Mechanism of Action

The E. coli porin channel penetration by CP, cefaclidine, and cefpirome is at least 5–10 times faster than ceftazidime and cefotaxime. CP has stability against plasmid-mediated β-lactamase SHV-1 and SHV-2, OXA-1 and OXA-3, PSE-1, and PSE-2, and TEM-1 and TEM-2 [2]. The relative hydrolysis rates correspond to that of cefpirome [15,16], cefotaxime, latamoxef, and ceftazidime but are lesser than cefoperazone. Testing CP against 326 members of the Enterobacteriaceae found that it is more active than moxalactam, cefoperazone, cefotaxime, cefpirome, and ceftazidime. Because CP has a low empathy for the major chromosomally mediated 13-lactamase, it is probably less influenced by the nonhydrolytic barrier mechanism of bacterial resistance. CP may demonstrate to be a powerful therapy for microbial infections that are unaffected by other antimicrobials. For instance, in a new study, CP resistance rarely appeared among cefotaxime and ceftazidime-resistant Pseudomonas aeruginosa mutants [17].

5. Indications and Side Effects

The use of cefepime for treating UTIs in children has been perceived as safe and effective with the least adverse effects. Considering its broad spectrum of antimicrobial activity, it is a convenient candidate for early empiric curing of critically ill children, especially those who suffer from anatomical abnormalities of the urinary tract in which antibiotic-resistant microbes may be present less commonly [1820] as well as infections of the skin and skin structure can be treated with CP. Besides treating bacterial infections, CP is used to cure gynecologic and intraabdominal infections, febrile neutropenia, bacteremia, meningitis, and long-term bronchopulmonary infections associated with cystic fibrosis in pediatric patients [8]. The effect of the combination of nacubactam as a β-lactamase inhibitor and CP against Escherichia coli and Klebsiella pneumonia, which are carbapenem-resistant, was reported in [21] by the authors in [22]. Cefepime is highly effective in treating COVID-19 patients with moderate and severe symptoms. Cefepime has a highly antiviral effect and is effective against large-scale viruses, including SARS and MERS. When combined with antibiotics or steroids, cefepime is considered more effective than when taken alone.

There should be a consideration for CP neurotoxicity in older patients with myoclonus who are suffering recently from alterations in mental status and renal impairment [2326]. Seizures are the most common adverse reaction of cefepime on the central nervous system. It can also cause encephalopathy [27, 28]. Several drugs are known to cause nephrotoxicity, notably beta-lactamase inhibitors, and cephalosporins. Despite a few severe side effects, cefepime is a widely prescribed fourth-generation cephalosporin. Numerous reports suggested that cefepime may produce neurotoxicity, but there is no evidence that it causes acute interstitial nephritis. [29].

6. Analytical Methods for Determining CP

It is extremely imperative to quantify CP to manage bioequivalence and bioavailability studies besides pharmacokinetic parameters for curing observation. There are about 58 methods proposed for its analysis, either in pharmaceutical dosage forms, serum, or in plasma. These methods were collected from Google Scholar, PubMed, Web of Science, Scopus, and Science Direct. In this work, determination of CP by reverse phase-HPLC and HPLC, as shown in Table 1, was prevalent. With HPLC techniques, quantitative studies are characterized by the efficiency, specificity, speed, and accuracy with tracking capabilities. Table 2 contains micellar electrokinetic chromatographic methods. Some potentiometric and electrochemical methods are mentioned in Table 3, while the chromatographic technique is combined with other techniques such as LC, and HPLC. UPLC, MS, and MEKC are cited in Table 4. One of the commonly used techniques was UV absorption spectroscopy, which is used alone or with other techniques and based on colorimetry, fluorometry, and other spectrophotometric methods. All these methods are stated in Table 5. Table 6 includes gas chromatographic methods. Most of the summarized methods utilized different chemically toxic solvents as shown in all tables. Consequently, it is awfully significant for development and verification to select the analytical methods to be applied to reduce the number of toxic products. This is because it may destroy the environment, the instruments used, and the operators. To minimize such issues, it is imperative to pick an apparatus that is more specific and as sensible as other, which has low costs of analysis and therefore reduces power depletion (a factor that directly affects the last price of an outcome). It needs smaller quantities of solvents or that can recognize lower concentrations, it can retrieve dangerous solvents (in order to reduce the risk of pollution in the surroundings), and it can guide pharmaceutical companies and researchers to consume nontoxic solvents and enhance the habitat to decrease the risk of contamination. Hence, the analysis should take the contribution of universities and research centers into consideration to verify the quality of drugs and their safety in application to the public.

7. Conclusions

Cefepime is one of the important drugs from the cephalosporin group as it is distinguished from the rest of the group by its resistance to bacteria, which allows it to work on many positive and negative bacterial pathogens. The drug’s stability is due to the chemical modification of its structure in the 7-position of the cephem ring, and the cephem nucleus substituted with a positively charged N-methyl-pyrrolidine, making it a zwitterion. This zwitterionic property permits penetration of the drug to Gram (+) bacteria’s porin channels rapidly, so it is used effectively to treat severe urinary and respiratory tract infections. Furthermore, many recent studies have proven its worth in treating cases of skin, soft tissues, and the women’s reproductive tract among patients with febrile neutropenia either it is found to be superior in the treatment of pneumonia in cystic fibrosis patients, which drew the attention of many researchers to analyse this drug in several methods in its dosage forms or in plasma or serum, and the most common analysis methods for this drug are HPLC.

Abbreviations

CP:Cefepime
ACN:Acetonitrile
NaOH:Sodium hydroxide
KOH:Potassium hydroxide
MeOH:Methanol
PB:Phosphate buffer
PDPB:Potassium dihydrogen phosphate buffer
SDPM:Sodium dihydrogen phosphate monohydrate
C40H84BrN:Tetradecyl ammonium bromide
GC:Guard column
DPHP:Dibasic potassium hydrogen phosphate
AA:Ammonium acetate
SDS:Sodium dodecyl sulfate
MEKC:Micellar electrokinetic chromatography
CZE:Capillary zone electrophoresis
Na2HPO4:Disodium hydrogen phosphate
FSC:Fused-silica capillary
V:Voltage
ASV:Adsorptive stripping voltammetry
VAMS:Volumetric absorptive microsampling
DPP:Differential pulse polarography
AE:Auxiliary electrode
WE:Working electrode
RE:Reference electrode
SPE:Solid-phase extraction
LC/MS/MS:Liquid chromatography-tandem mass spectrometry
GC FID:Gas chromatography-flame ionization detection
UHPLC:Ultra-high-performance liquid chromatography
UPLC–MS/MS:Ultraperformance liquid chromatography-tandem mass spectrometry
SCX:High-performance hydrophilic strong cation exchange
HILIC LC-MS/MS:Interaction chromatography
IC-CD:Ion chromatography-conductivity detection
AFB:Ammonium formate buffer
AA:Ammonium acetate
GC:Gas Chromatography
CG:Carrier gas
COT:Column oven temperature
NMP:N-methylpyrrolidine
FTIR:Fourier transform infrared spectroscopy
EXW:Excitation wavelength
EMW:Emission wavelength.

Conflicts of Interest

The author declares that there are no conflicts of interest regarding the publication of this paper.