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

Cephalexin (10 μg/mL) inactivates an enzyme known as penicillin-binding protein (PBP), which disturbs the synthesis of the polymer peptidoglycan (PG) [1]. Numerous Gram-positive and Gram-negative microbes are inhibited by cephalexin, which has MIC values of 2, 2, 2, 2, 4, 4.4 and 5.7 μg/mL for Proteus rettgeri, respectively [2].

Cephalexin (0-50 mg/kg; oral; 3.5 hr) exhibits antibacterial action against male Swiss-Webster mice 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.

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Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin.[2]

Absorption, Distribution and Excretion
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. Peak plasma concentrations in patients taking 250 mg of cefalexin are 7.7 mcg/mL, and in patients taking 500 mg, peak plasma concentrations are 12.3 mcg/mL. Over 90% of cefalexin is excreted in the urine via glomerular filtration and tubular secretion after 6 hours, with an average urinary recovery rate of 99.3%. Cefalexin is not excreted unchanged in the urine. 5.2–5.8 liters. 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 decrease in plasma drug concentration… Over 90% of the drug is excreted unchanged in the urine within 6 hours, primarily via tubular secretion. ...Even in patients with impaired renal function, therapeutically effective concentrations can still be achieved in the urine. Cefalexin is well absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 1 hour after administration, with levels of approximately 9 μg/mL after oral administration of 250 mg and 18 μg/mL after oral administration of 500 mg. Food intake may delay absorption. Cefalexin is also excreted via bile. Absorption and excretion of cefalexin are impaired in newborns, with 24-hour urinary recovery rates ranging from 5% to 66% of the daily oral dose. For more complete data on absorption, distribution, and excretion of cefalexin (14 items in total), please visit the HSDB records page. Metabolites/Metabolites: Cefalexin is not metabolized in the body. Biological Half-Life: The half-life of cefalexin is 49.5 minutes on an empty stomach and 76.5 minutes after food, but these differences are not statistically significant. The results of this study differ. Less than 10% to 15% of the drug binds to plasma proteins, and plasma drug concentrations decline rapidly; the half-life of cefalexin is typically approximately 40 minutes. In rats, the average ratio of bone to serum concentration of cefalexin was 1:9 within 0.25–4 hours after oral administration. Despite the concentration differences, the half-life in bone and serum was similar. After administration of 1 g or 2 g of cefalexin, the time to peak concentration, elimination half-life, absorption half-life, and volume of distribution were similar. The half-life of cefalexin in the serum of adults with normal renal function is 0.5–1.2 hours. It has been reported that the half-life of this drug in neonatal serum is approximately 5 hours, and in children aged 3–12 months it is approximately 2.5 hours. In one study, the half-life of this drug in the serum of adults with a creatinine clearance of 9.2 mL/min was 7.7 hours, and in the serum of adults with a creatinine clearance of 4 mL/min it was 13.9 hours.

Interactions
Probenecid can effectively slow urinary clearance of cephalexin and prolong the duration of its systemic antibacterial activity. Cephalosporins may be affected by concomitant use with sulfinpyrazone. Reduced renal tubular secretion leads to higher serum drug concentrations and longer durations of action, thereby enhancing drug activity. Furosemide may enhance the nephrotoxicity of cephalosporins. /Cephalexins/ Hypoprothrombinemia caused by high doses of salicylates and/or cephalosporins, as well as the risk of gastrointestinal ulcers or bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, or sulfinpyrazone, may increase the risk of bleeding. Cephalosporins For more complete data on the interactions of ceftriaxone (6 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Mice oral LD50: 1.6-4.5 g/kg/monohydrate/
Mice intraperitoneal LD50: 0.4-1.3 g/kg/monohydrate/
Rat oral LD50: >5.0 g/kg/monohydrate/
Rat intraperitoneal LD50: >3.7 g/kg/monohydrate/

[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.

Therapeutic Uses

Cephalexin's antibacterial spectrum is similar to that of penicillin…Penicillin G is generally more effective against cocci and Gram-positive bacilli. …Most penicillinases do not affect cephalexin…
Cephalexins are highly effective against a wide range of mild to severe infections caused by Gram-positive and Gram-negative bacteria.
Cephalexins are…the first-line treatment for Klebsiella pneumoniae infections. …They are…important adjunctive therapies and are often used as an alternative to penicillin.
For more complete data on the therapeutic uses of cephalexin (9 types), please visit the HSDB record page.
Drug Warnings

When renal function is impaired, the doctor must adjust the dosage or dosing interval.
Cephalexins should not be used to treat bacterial meningitis. This applies to all pathogenic microorganisms. …Cephalexins have poor permeability in cerebrospinal fluid. Cephalosporins
Enterococcal infections are generally unaffected by these antibiotics…Cephalosporins cannot cure enterococcal endocarditis, even when used concurrently with gentamicin or streptomycin. Cephalosporins
Enterobacterial (aerobic) infections are often resistant to these antibiotics. Cephalosporins
For more complete data on drug warnings for cephalexin (20 in total), please visit the HSDB records page.

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Pharmacodynamics
Cephalexin (also known as cephalosporin) is a first-generation cephalosporin antibiotic. It is one of the most commonly used antibiotics and is often used to treat superficial infections caused by minor wounds or lacerations. It is effective against most Gram-positive bacteria by inhibiting the cross-linking reaction between N-acetylmuramic acid and N-acetylglucosamine in the cell wall, leading to cell lysis.

C16H17N3O4S

347.89

347.093

C, 55.32; H, 4.93; N, 12.10; O, 18.42; S, 9.23

15686-71-2

Cephalexin hydrochloride;59695-59-9;Cephalexin monohydrate;23325-78-2;Cephalexin hydrochloride monohydrate;105879-42-3;Cephalexin (lysine);53950-14-4;Cephalexin-d5;2101505-56-8; 15686-71-2 (free); 38932-40-0 (sodium)

27447

White to light yellow solid powder

1.5±0.1 g/cm3

727.4±60.0 °C at 760 mmHg

196-198°C

393.7±32.9 °C

0.0±2.5 mmHg at 25°C

1.700

0.65

3

6

4

24

600

3

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

ZAIPMKNFIOOWCQ-UEKVPHQBSA-N

InChI=1S/C16H17N3O4S/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)/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

Cephacillin; Cefalexin; Keflex; Cepexin; Carnosporin

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)

H2O : ~10 mg/mL (~28.79 mM)

Solubility in Formulation 1: 25 mg/mL (71.97 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with heating and sonication.

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