Bacterial cell wall synthesis; penicillin binding proteins (PBPs); cephalosporin antibiotic

Cefalexin monohydrate (10 μg/mL) inactivates an enzyme known as penicillin-binding protein (PBP), which disturbs the synthesis of the polymer peptidoglycan (PG) [1]. A wide range of Gram-positive and Gram-negative microorganisms can be inhibited by cephalexin (Cefalexin) monohydrate; the MIC values of tarda, Alcaligenes sp, and Proteus rettgeri are 2, 2, 2, 2, 4, 4.4, and 5.7 μg/mL, respectively[2].

The antibacterial activity of cefalexin monohydrate (0–50 mg/kg; oral; 3.5 hours) is demonstrated against male Swiss-Webster mice that are infected with microorganisms [2].

Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.[1]

Animal/Disease Models: Bacterially infected male Swiss-Webster mice [2]
Doses: 0-50 mg/kg
Route of Administration: po (po (oral gavage)) 3.5 hrs (hrs (hours))
Experimental Results: Against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus and several Antimicrobial activity against Gram-negative bacteria in mice.

Absorption
Cefalexin is well absorbed in the upper gastrointestinal tract, with an oral bioavailability approaching 100%. Cefalexin is not absorbed by the stomach but rather by the upper small intestine. The peak plasma concentration in patients taking 250 mg of cefalexin is 7.7 mcg/mL, and in patients taking 500 mg, the peak plasma concentration is 12.3 mcg/mL.
Excretion
Cefalexin is excreted in the urine after 6 hours via glomerular filtration and tubular secretion. Over 90% of cefalexin is excreted in the urine, with an average urinary recovery rate of 99.3%. Cefalexin is excreted unchanged in the urine.
Volume of Distribution
5.2–5.8 L.
Clearance
The clearance rate in one subject was 376 mL/min.
Less than 10% to 15% of the drug binds to plasma proteins, leading to a rapid decline in plasma drug concentration…Over 90% of the drug is excreted unchanged in the urine within 6 hours, primarily through renal tubular secretion. …Even in patients with impaired renal function, therapeutically effective concentrations can still be achieved in the urine.
Cephalexin…is readily absorbed from the gastrointestinal tract. After oral administration of 250 mg and 500 mg, peak plasma drug concentrations are approximately 9 μg/mL and 18 μg/mL, respectively, reached approximately 1 hour after administration. Food intake may delay absorption.
Absorption and excretion of cephalexin are impaired in newborns, with 24-hour urinary recovery rates ranging from 5% to 66% of the daily oral dose.

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Metabolism/Metabolites
Cephalexin is not metabolized in the body.

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Biological Half-Life
The half-life of cephalexin is 49.5 minutes on an empty stomach and 76.5 minutes after eating, but the difference between these two time points was not statistically significant in this study. The half-life of cephalexin in the serum of adults with normal renal function is 0.5–1.2 hours. It has been reported that the half-life of cephalexin in the serum of newborns is approximately 5 hours, and in children aged 3–12 months, it is approximately 2.5 hours. One study showed that the half-life in the serum of adults with a creatinine clearance of 9.2 ml/min is 7.7 hours, and in adults with a creatinine clearance of 4 ml/min, it is 13.9 hours.

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Protein Binding
The binding rate of cephalexin to serum proteins (including serum albumin) is 10–15%.

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Limited information suggests that low concentrations of cephalexin in breast milk after maternal administration generally do not adversely affect breastfed infants. Cephalexin is an alternative treatment for mastitis. There are reports that cephalosporins occasionally disrupt the infant's gut microbiota, leading to diarrhea or thrush, but these effects have not been fully assessed. There has been one rare case of a severe allergic reaction in an infant who had previously received intravenous cefazolin, and whose mother began taking cephalexin while breastfeeding. It is safe for breastfeeding women to take cephalexin.
◉ Effects on Breastfed Infants
In a prospective follow-up study, seven breastfeeding mothers reported taking cephalexin (dosage not specified). Two of these mothers reported their infants developing diarrhea. No rashes or candidiasis were reported in infants exposed to cephalexin.
A prospective controlled study surveyed mothers who called the information service center about adverse reactions in their breastfed infants. One in 11 infants exposed to cephalexin reported diarrhea while their mothers were receiving cephalexin treatment.
One woman received intravenous cefotaxime 1 gram every 6 hours for 3 days. Her breastfed infant developed green, loose stools, severe diarrhea, discomfort, and crying. The mother's regimen was subsequently changed to oral cephalexin 500 mg plus oral probenecid 500 mg four times daily for 16 days. During this period, the infant continued to have diarrhea. The authors believe the diarrhea may be related to cephalexin in the breast milk.
A 4-month-old infant received intravenous cefazolin for a urinary tract infection. Nine days after discharge and discontinuation of cefazolin, the infant developed a vesicular rash covering most of the body and was diagnosed with toxic epidermal necrolysis (TEN). The infant was breastfed by the mother (the extent of breastfeeding was not specified), who had started taking cephalexin two days before the onset of symptoms. A lymphocyte transformation test performed 4 weeks after the end of TEN treatment revealed that the infant was allergic to both cefazolin and cephalexin. The infant's reaction may have been due to an initial allergic reaction to cefazolin, followed by a cross-reaction with cefazolin in breast milk.
◉ Effects on breastfeeding and breast milk
As of the revision date, no relevant published information was found.

[1]. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell. 2014 Dec 4;159(6):1300-11.

[2]. Cefadroxil, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother. 1977 Feb;11(2):324-30.

Cephalexin monohydrate is the hydrated form of cephalexin, composed of equimolar amounts of cephalexin and its hydrate. It is an antibacterial drug. It contains cephalexin. It is a semi-synthetic cephalosporin antibiotic with antibacterial activity similar to cefadroxil or cefotaxime, but slightly weaker. It is effective against both Gram-positive and Gram-negative bacteria. See also: Cephalexin (note moved to).

C16H19N3O5S

365.404

383.07

C, 52.59; H, 5.24; N, 11.50; O, 21.89; S, 8.77

23325-78-2

Cephalexin;15686-71-2;Cephalexin hydrochloride;59695-59-9;Cephalexin-d5 monohydrate;Cephalexin hydrochloride monohydrate;105879-42-3;Cephalexin (lysine);53950-14-4

62921

White to off-white solid powder

1.5g/cm3

727.4ºC at 760 mmHg

393.7ºC

3.27E-22mmHg at 25°C

154 ° (C=0.5, H2O)

1.409

4

7

4

25

600

3

CC1=C(N2[C@@H]([C@@H](C2=O)NC(=O)[C@@H](C3=CC=CC=C3)N)SC1)C(=O)O.O

AVGYWQBCYZHHPN-CYJZLJNKSA-N

InChI=1S/C16H17N3O4S.H2O/c1-8-7-24-15-11(14(21)19(15)12(8)16(22)23)18-13(20)10(17)9-5-3-2-4-6-9;/h2-6,10-11,15H,7,17H2,1H3,(H,18,20)(H,22,23);1H2/t10-,11-,15-;/m1./s1

(6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate

Cefibacter; Cefalival; Cephalexin monohydrate; 23325-78-2; Cephalexin hydrate; cefalexin monohydrate; cefalexin hydrate; Cephalexin (monohydrate); Keforal; Novolexin; Cephalexin hydrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~6.67 mg/mL (~18.25 mM)
H2O : ~2 mg/mL (~5.47 mM)

Solubility in Formulation 1: ≥ 0.67 mg/mL (1.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.67 mg/mL (1.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.67 mg/mL (1.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 8.33 mg/mL (22.80 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)