Meropenem: Difference between revisions

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<!-- Side effects and mechanisms -->
<!-- Side effects and mechanisms -->
Common side effects include nausea, diarrhea, constipation, headache, rash, and pain at the site of injection.<ref name=AHFS2017/> Serious side effects include [[Clostridioides difficile infection|''Clostridioides difficile'' infection]], [[seizures]], and [[allergic reactions]] including [[anaphylaxis]].<ref name=AHFS2017/> Those who are allergic to other [[β-lactam antibiotic]]s are more likely to be allergic to meropenem as well.<ref name=AHFS2017/> Use in pregnancy appears to be safe.<ref name=AHFS2017/> It is in the [[carbapenem]] family of medications.<ref name=AHFS2017/> Meropenem usually results in [[Bactericidal|bacterial death]] through blocking their ability to make a [[cell wall]].<ref name=AHFS2017/> It is resistant to breakdown by many kinds of [[β-lactamase]] enzymes, produced by bacteria to protect themselves from antibiotics.<ref name="pmid18713049"/><ref>{{cite book|doi=10.1016/B978-1-4160-4044-6.50253-3|quote=As with other β-lactam antibiotics, meropenem is bactericidal against susceptible bacteria because it inhibits bacterial cell wall synthesis. The trans configuration of the hydroxyethyl side chain and hydrogen atoms protect the parent β-lactam structure from inactivation by the most common β-lactamases, including almost all Bush groups 1 and 2 (Amber classes A, C, and D) β-lactamase–producing organisms, including those that produce ESBLs (Citrobacter, Enterobacter, E. coli, Klebsiella spp., and P. mirabilis) or AmpC β-lactamases (Citrobacter, Enterobacter, Pseudomonas, and Serratia) |chapter=Antibacterial Therapeutic Agents |title=Feigin and Cherry's Textbook of Pediatric Infectious Diseases |date=2009 |pages=3178–3227 |isbn=978-1-4160-4044-6 | vauthors = Michelow IC, McCracken GH }}</ref><ref name="pmid38360618">{{cite journal |vauthors=Ikenoue C, Matsui M, Inamine Y, Yoneoka D, Sugai M, Suzuki S |title=The importance of meropenem resistance, rather than imipenem resistance, in defining carbapenem-resistant Enterobacterales for public health surveillance: an analysis of national population-based surveillance |journal=BMC Infect Dis |volume=24 |issue=1 |page=209 |date=February 2024 |pmid=38360618 |pmc=10870673 |doi=10.1186/s12879-024-09107-4|doi-access=free }}</ref>
Common side effects include nausea, diarrhea, constipation, headache, rash, and pain at the site of injection.<ref name=AHFS2017/> Serious side effects include [[Clostridioides difficile infection|''Clostridioides difficile'' infection]], [[seizures]], and [[allergic reactions]] including [[anaphylaxis]].<ref name=AHFS2017/> Those who are allergic to other [[β-lactam antibiotic]]s are more likely to be allergic to meropenem as well.<ref name=AHFS2017/> Use in pregnancy appears to be safe.<ref name=AHFS2017/> It is in the [[carbapenem]] family of medications.<ref name=AHFS2017/> Meropenem usually results in [[Bactericidal|bacterial death]] through blocking their ability to make a [[cell wall]].<ref name=AHFS2017/> It is resistant to breakdown by many kinds of [[β-lactamase]] enzymes, produced by bacteria to protect themselves from antibiotics.<ref name="pmid18713049"/><ref>{{cite book|doi=10.1016/B978-1-4160-4044-6.50253-3|quote=As with other β-lactam antibiotics, meropenem is bactericidal against susceptible bacteria because it inhibits bacterial cell wall synthesis. The trans configuration of the hydroxyethyl side chain and hydrogen atoms protect the parent β-lactam structure from inactivation by the most common β-lactamases, including almost all Bush groups 1 and 2 (Amber classes A, C, and D) β-lactamase–producing organisms, including those that produce ESBLs (Citrobacter, Enterobacter, E. coli, Klebsiella spp., and P. mirabilis) or AmpC β-lactamases (Citrobacter, Enterobacter, Pseudomonas, and Serratia) |chapter=Antibacterial Therapeutic Agents |title=Feigin and Cherry's Textbook of Pediatric Infectious Diseases |date=2009 |pages=3178–3227 |isbn=978-1-4160-4044-6 | vauthors = Michelow IC, McCracken GH }}</ref><ref name="pmid38360618">{{cite journal |vauthors=Ikenoue C, Matsui M, Inamine Y, Yoneoka D, Sugai M, Suzuki S |title=The importance of meropenem resistance, rather than imipenem resistance, in defining carbapenem-resistant Enterobacterales for public health surveillance: an analysis of national population-based surveillance |journal=BMC Infect Dis |volume=24 |issue=1 |article-number=209 |date=February 2024 |pmid=38360618 |pmc=10870673 |doi=10.1186/s12879-024-09107-4|doi-access=free }}</ref>


<!-- History and culture -->
<!-- History and culture -->
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== Medical uses ==
== Medical uses ==
The spectrum of action includes many [[Gram-positive]] and [[Gram-negative]] bacteria (including ''[[Pseudomonas]]'') and  [[Anaerobic organism|anaerobic]] bacteria. The overall spectrum is similar to that of imipenem, although meropenem is more active against [[Enterobacteriaceae]] and less active against Gram-positive bacteria. Meropenem is effective against bacteria producing extended-spectrum β-lactamases but may be more susceptible to hydrolysis by metallo-β-lactamases produced by bacteria.<ref name=AHFS>{{ cite book | title= AHFS Drug Information | publisher= American Society of Health-System Pharmacists | year= 2006 | edition= 2006 }}</ref> β-lactamases are enzymes that bacteria produce to hydrolyze β-lactam antibiotics, breaking the β-lactam ring and rendering these antibiotics ineffective. This mechanism helps bacteria resist the effects of antibiotics like penicillins, cephalosporins, and carbapenems, making treatment more challenging.<ref name="pmid30061284">{{cite journal |vauthors=Bush K |title=Past and Present Perspectives on β-Lactamases |journal=Antimicrob Agents Chemother |volume=62 |issue=10 |pages= |date=October 2018 |pmid=30061284 |pmc=6153792 |doi=10.1128/AAC.01076-18}}</ref><ref name="pmid34778765">{{cite journal |vauthors=Mora-Ochomogo M, Lohans CT |title=β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates |journal=RSC Med Chem |volume=12 |issue=10 |pages=1623–1639 |date=October 2021 |pmid=34778765 |pmc=8528271 |doi=10.1039/d1md00200g |url=}}</ref><ref name="pmid20594363">{{cite journal |vauthors=Bush K |title=Bench-to-bedside review: The role of beta-lactamases in antibiotic-resistant Gram-negative infections |journal=Crit Care |volume=14 |issue=3 |page=224 |date=2010 |pmid=20594363 |pmc=2911681 |doi=10.1186/cc8892|doi-access=free }}</ref> While β-lactam ring in meropenem is more accessible to water molecules than in the other β-lactam antibiotics, that facilitates the hydrolysis process and faster degradation of meropenem's antibacterial properties in aqueous solutions, it is more resistant to degradation by β-lactamase enzymes produced by bacteria than the other β-lactam antibiotics.<ref>{{cite journal | doi=10.1093/jac/49.2.395 | title=Meropenem stability to β-lactamase hydrolysis and comparative in vitro activity against several β-lactamase-producing Gram-negative strains | date=2002 | journal=Journal of Antimicrobial Chemotherapy | volume=49 | issue=2 | pages=395–398 | pmid=11815587 | vauthors=Franceschini N, Segatore B, Perilli M, Vessillier S, Franchino L, Amicosante G}}</ref><ref name="pmid18713049"/>
The spectrum of action includes many [[Gram-positive]] and [[Gram-negative]] bacteria (including ''[[Pseudomonas]]'') and  [[Anaerobic organism|anaerobic]] bacteria. The overall spectrum is similar to that of imipenem, although meropenem is more active against [[Enterobacteriaceae]] and less active against Gram-positive bacteria. Meropenem is effective against bacteria producing extended-spectrum β-lactamases but may be more susceptible to hydrolysis by metallo-β-lactamases produced by bacteria.<ref name=AHFS>{{ cite book | title= AHFS Drug Information | publisher= American Society of Health-System Pharmacists | year= 2006 | edition= 2006 }}</ref> β-lactamases are enzymes that bacteria produce to hydrolyze β-lactam antibiotics, breaking the β-lactam ring and rendering these antibiotics ineffective. This mechanism helps bacteria resist the effects of antibiotics like penicillins, cephalosporins, and carbapenems, making treatment more challenging.<ref name="pmid30061284">{{cite journal |vauthors=Bush K |title=Past and Present Perspectives on β-Lactamases |journal=Antimicrob Agents Chemother |volume=62 |issue=10 |date=October 2018 |article-number=e01076-18 |pmid=30061284 |pmc=6153792 |doi=10.1128/AAC.01076-18}}</ref><ref name="pmid34778765">{{cite journal |vauthors=Mora-Ochomogo M, Lohans CT |title=β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates |journal=RSC Med Chem |volume=12 |issue=10 |pages=1623–1639 |date=October 2021 |pmid=34778765 |pmc=8528271 |doi=10.1039/d1md00200g |url=}}</ref><ref name="pmid20594363">{{cite journal |vauthors=Bush K |title=Bench-to-bedside review: The role of beta-lactamases in antibiotic-resistant Gram-negative infections |journal=Crit Care |volume=14 |issue=3 |page=224 |date=2010 |pmid=20594363 |pmc=2911681 |doi=10.1186/cc8892|doi-access=free }}</ref> While β-lactam ring in meropenem is more accessible to water molecules than in the other β-lactam antibiotics, that facilitates the hydrolysis process and faster degradation of meropenem's antibacterial properties in aqueous solutions, it is more resistant to degradation by β-lactamase enzymes produced by bacteria than the other β-lactam antibiotics.<ref>{{cite journal | doi=10.1093/jac/49.2.395 | title=Meropenem stability to β-lactamase hydrolysis and comparative in vitro activity against several β-lactamase-producing Gram-negative strains | date=2002 | journal=Journal of Antimicrobial Chemotherapy | volume=49 | issue=2 | pages=395–398 | pmid=11815587 | vauthors=Franceschini N, Segatore B, Perilli M, Vessillier S, Franchino L, Amicosante G}}</ref><ref name="pmid18713049"/>


Meropenem is frequently given in the treatment of [[febrile neutropenia]]. This condition frequently occurs in patients with [[hematological malignancies]] and cancer patients receiving anticancer drugs that suppress [[bone marrow]] formation. It is approved for complicated skin and skin structure infections, complicated intra-abdominal infections and [[Meningitis|bacterial meningitis]].<ref name="pmid18713049">{{cite journal | doi=10.1086/590065 | title=Update on the Efficacy and Tolerability of Meropenem in the Treatment of Serious Bacterial Infections | date=2008 | journal=Clinical Infectious Diseases | volume=47 | pages=S41–S51 | pmid=18713049 | vauthors=Mohr Iii JF}}</ref><ref>{{Cite web |date=September 16, 2016 |title=Meropenem |url=https://medlineplus.gov/druginfo/meds/a696038.html |access-date=March 19, 2023 |website=MedlinePlus.gov |archive-date=March 19, 2023 |archive-url=https://web.archive.org/web/20230319204623/https://medlineplus.gov/druginfo/meds/a696038.html |url-status=live }}</ref><ref>{{Cite web | title = Merrem® IV (meropenem for injection) | work = Pediatric Postmarketing Pharmacovigilance Review | date = November 17, 2017 |url=https://www.fda.gov/media/110518/download | publisher = [[Food and Drug Administration]] |access-date=February 23, 2024|archive-date=March 5, 2021|archive-url=https://web.archive.org/web/20210305114129/https://www.fda.gov/media/110518/download|url-status=live}}</ref><ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/050706Orig1s034.pdf|title= Approval package for meropenem for injection |access-date=February 23, 2024|archive-date=April 12, 2021|archive-url=https://web.archive.org/web/20210412122257/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/050706Orig1s034.pdf|url-status=live}}</ref>
Meropenem is frequently given in the treatment of [[febrile neutropenia]]. This condition frequently occurs in patients with [[hematological malignancies]] and cancer patients receiving anticancer drugs that suppress [[bone marrow]] formation. It is approved for complicated skin and skin structure infections, complicated intra-abdominal infections and [[Meningitis|bacterial meningitis]].<ref name="pmid18713049">{{cite journal | doi=10.1086/590065 | title=Update on the Efficacy and Tolerability of Meropenem in the Treatment of Serious Bacterial Infections | date=2008 | journal=Clinical Infectious Diseases | volume=47 | pages=S41–S51 | pmid=18713049 | vauthors=Mohr Iii JF}}</ref><ref>{{Cite web |date=September 16, 2016 |title=Meropenem |url=https://medlineplus.gov/druginfo/meds/a696038.html |access-date=March 19, 2023 |website=MedlinePlus.gov |archive-date=March 19, 2023 |archive-url=https://web.archive.org/web/20230319204623/https://medlineplus.gov/druginfo/meds/a696038.html |url-status=live }}</ref><ref>{{Cite web | title = Merrem® IV (meropenem for injection) | work = Pediatric Postmarketing Pharmacovigilance Review | date = November 17, 2017 |url=https://www.fda.gov/media/110518/download | publisher = [[Food and Drug Administration]] |access-date=February 23, 2024|archive-date=March 5, 2021|archive-url=https://web.archive.org/web/20210305114129/https://www.fda.gov/media/110518/download|url-status=live}}</ref><ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/050706Orig1s034.pdf|title= Approval package for meropenem for injection |access-date=February 23, 2024|archive-date=April 12, 2021|archive-url=https://web.archive.org/web/20210412122257/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/050706Orig1s034.pdf|url-status=live}}</ref>
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Meropenem is effective in treating bacterial pneumonia, including hospital-acquired pneumonia.<ref name="drugs-monograph">{{cite web | url=https://www.drugs.com/monograph/meropenem.html | title=Meropenem Monograph for Professionals | access-date=December 9, 2017 | archive-date=January 20, 2011 | archive-url=https://web.archive.org/web/20110120143956/https://www.drugs.com/monograph/meropenem.html | url-status=live }}</ref>
Meropenem is effective in treating bacterial pneumonia, including hospital-acquired pneumonia.<ref name="drugs-monograph">{{cite web | url=https://www.drugs.com/monograph/meropenem.html | title=Meropenem Monograph for Professionals | access-date=December 9, 2017 | archive-date=January 20, 2011 | archive-url=https://web.archive.org/web/20110120143956/https://www.drugs.com/monograph/meropenem.html | url-status=live }}</ref>


In 2017, the U.S. [[Food and Drug Administration]] (FDA) granted approval for the combination of [[meropenem/vaborbactam|meropenem and vaborbactam]] to treat adults with complicated [[urinary tract infections]].<ref>{{cite press release|title=FDA approves new antibacterial drug|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug|website=U.S. [[Food and Drug Administration]] (FDA)|date=March 24, 2020|access-date=March 5, 2022|archive-date=April 23, 2019|archive-url=https://web.archive.org/web/20190423191933/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573955.htm|url-status=dead}}{{PD-notice}}</ref>
In 2017, the U.S. [[Food and Drug Administration]] (FDA) granted approval for the combination of [[meropenem/vaborbactam|meropenem and vaborbactam]] to treat adults with complicated [[urinary tract infections]].<ref>{{cite press release|title=FDA approves new antibacterial drug|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug|website=U.S. [[Food and Drug Administration]] (FDA)|date=March 24, 2020|access-date=March 5, 2022|archive-date=April 23, 2019|archive-url=https://web.archive.org/web/20190423191933/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573955.htm}}{{PD-notice}}</ref>


==Administration==
==Administration==
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Reconstituted (dissolved) meropenem degrades over time.<ref name="emc"/><ref name="pmid38842523">{{cite journal|pmid=38842523 |date=2024 |title=Current practices and challenges of outpatient parenteral antimicrobial therapy: A narrative review |journal=The Journal of Antimicrobial Chemotherapy |volume=79 |issue=9 |pages=2083–2102 |doi=10.1093/jac/dkae177 |pmc=11368434 | vauthors = Wolie ZT, Roberts JA, Gilchrist M, McCarthy K, Sime FB }}</ref><ref name="pmid39203022">{{cite journal |vauthors=Ortega-Balleza JL, Vázquez-Jiménez LK, Ortiz-Pérez E, Avalos-Navarro G, Paz-González AD, Lara-Ramírez EE, Rivera G |title=Current Strategy for Targeting Metallo-β-Lactamase with Metal-Ion-Binding Inhibitors |journal=Molecules |volume=29 |issue=16 |date=August 2024 |page=3944 |pmid=39203022 |pmc=11356879 |doi=10.3390/molecules29163944 |doi-access=free |url=}}</ref><ref name="pmid31205331">{{cite journal | doi=10.1177/0018578718779009 | title=Stability of Meropenem After Reconstitution for Administration by Prolonged Infusion | date=2019 | journal=Hospital Pharmacy | volume=54 | issue=3 | pages=190–196 | pmid=31205331 | pmc=6535930 | vauthors=Fawaz S, Barton S, Whitney L, Swinden J, Nabhani-Gebara S}}</ref> The degradation may be associated with color change of the solution, typical for a hydrolysis of the [[amide bond]] of the β-lactam ring as seen with most β-lactam antibiotics,<ref name="pmid23163348">{{cite journal |vauthors=Palzkill T |title=Metallo-β-lactamase structure and function |journal=Ann N Y Acad Sci |volume=1277 |issue= 1|pages=91–104 |date=January 2013 |pmid=23163348 |pmc=3970115 |doi=10.1111/j.1749-6632.2012.06796.x|bibcode=2013NYASA1277...91P }}</ref> while particularly for meropenem the color is changing from colorless or pale yellow to vivid yellowish.<ref name="pmid26448659"/> Upon reconstitution, the meropenem infusion solution, prepared with 0.9% sodium chloride, exhibits both chemical and physical stability for a duration of 3 hours at a temperature up to {{Value|25}}°C. If refrigerated ({{Value|2|-|8}}°C), the stability extends to 24 hours. However, when the product is reconstituted in a 5% dextrose solution, it is used immediately to ensure its efficacy.<ref name="emc">{{cite web | url=https://www.medicines.org.uk/emc/product/9074/smpc#about-medicine | title=Meropenem 1g powder for solution for injection/Infusion - Summary of Product Characteristics (SMPC) - (Emc) | access-date=February 22, 2024 | archive-date=February 22, 2024 | archive-url=https://web.archive.org/web/20240222192556/https://www.medicines.org.uk/emc/product/9074/smpc#about-medicine | url-status=live }}</ref> The degradation of meropenem in a water-based solution is affected by factors such as pH, temperature, initial concentration, and the specific type of infusion solution used.<ref name="pmid26448659">{{cite journal |vauthors=Tomasello C, Leggieri A, Cavalli R, Di Perri G, D'Avolio A |title=In Vitro Stabilifighty Evaluation of Different Pharmaceutical Products Containing Meropenem |journal=Hosp Pharm |volume=50 |issue=4 |pages=296–303 |date=April 2015 |pmid=26448659 |pmc=4589882 |doi=10.1310/hpj5004-296}}</ref> Meropenem solutions should not be frozen.<ref name="drugs-meropenem">{{cite web | url=https://www.drugs.com/pro/meropenem.html | title=Meropenem: Package Insert | access-date=February 23, 2024 | archive-date=February 23, 2024 | archive-url=https://web.archive.org/web/20240223014439/https://www.drugs.com/pro/meropenem.html | url-status=live }}</ref><ref name="pmid31447546">{{cite journal |vauthors=Foy F, Luna G, Martinez J, Nizich Z, Seet J, Lie K, Sunderland B, Czarniak P |title=An investigation of the stability of meropenem in elastomeric infusion devices |journal=Drug Des Devel Ther |volume=13 |issue= |pages=2655–2665 |date=2019 |pmid=31447546 |pmc=6682764 |doi=10.2147/DDDT.S212052|doi-access=free }}</ref>
Reconstituted (dissolved) meropenem degrades over time.<ref name="emc"/><ref name="pmid38842523">{{cite journal|pmid=38842523 |date=2024 |title=Current practices and challenges of outpatient parenteral antimicrobial therapy: A narrative review |journal=The Journal of Antimicrobial Chemotherapy |volume=79 |issue=9 |pages=2083–2102 |doi=10.1093/jac/dkae177 |pmc=11368434 | vauthors = Wolie ZT, Roberts JA, Gilchrist M, McCarthy K, Sime FB }}</ref><ref name="pmid39203022">{{cite journal |vauthors=Ortega-Balleza JL, Vázquez-Jiménez LK, Ortiz-Pérez E, Avalos-Navarro G, Paz-González AD, Lara-Ramírez EE, Rivera G |title=Current Strategy for Targeting Metallo-β-Lactamase with Metal-Ion-Binding Inhibitors |journal=Molecules |volume=29 |issue=16 |date=August 2024 |page=3944 |pmid=39203022 |pmc=11356879 |doi=10.3390/molecules29163944 |doi-access=free |url=}}</ref><ref name="pmid31205331">{{cite journal | doi=10.1177/0018578718779009 | title=Stability of Meropenem After Reconstitution for Administration by Prolonged Infusion | date=2019 | journal=Hospital Pharmacy | volume=54 | issue=3 | pages=190–196 | pmid=31205331 | pmc=6535930 | vauthors=Fawaz S, Barton S, Whitney L, Swinden J, Nabhani-Gebara S}}</ref> The degradation may be associated with color change of the solution, typical for a hydrolysis of the [[amide bond]] of the β-lactam ring as seen with most β-lactam antibiotics,<ref name="pmid23163348">{{cite journal |vauthors=Palzkill T |title=Metallo-β-lactamase structure and function |journal=Ann N Y Acad Sci |volume=1277 |issue= 1|pages=91–104 |date=January 2013 |pmid=23163348 |pmc=3970115 |doi=10.1111/j.1749-6632.2012.06796.x|bibcode=2013NYASA1277...91P }}</ref> while particularly for meropenem the color is changing from colorless or pale yellow to vivid yellowish.<ref name="pmid26448659"/> Upon reconstitution, the meropenem infusion solution, prepared with 0.9% sodium chloride, exhibits both chemical and physical stability for a duration of 3 hours at a temperature up to {{Value|25}}°C. If refrigerated ({{Value|2|-|8}}°C), the stability extends to 24 hours. However, when the product is reconstituted in a 5% dextrose solution, it is used immediately to ensure its efficacy.<ref name="emc">{{cite web | url=https://www.medicines.org.uk/emc/product/9074/smpc#about-medicine | title=Meropenem 1g powder for solution for injection/Infusion - Summary of Product Characteristics (SMPC) - (Emc) | access-date=February 22, 2024 | archive-date=February 22, 2024 | archive-url=https://web.archive.org/web/20240222192556/https://www.medicines.org.uk/emc/product/9074/smpc#about-medicine | url-status=live }}</ref> The degradation of meropenem in a water-based solution is affected by factors such as pH, temperature, initial concentration, and the specific type of infusion solution used.<ref name="pmid26448659">{{cite journal |vauthors=Tomasello C, Leggieri A, Cavalli R, Di Perri G, D'Avolio A |title=In Vitro Stabilifighty Evaluation of Different Pharmaceutical Products Containing Meropenem |journal=Hosp Pharm |volume=50 |issue=4 |pages=296–303 |date=April 2015 |pmid=26448659 |pmc=4589882 |doi=10.1310/hpj5004-296}}</ref> Meropenem solutions should not be frozen.<ref name="drugs-meropenem">{{cite web | url=https://www.drugs.com/pro/meropenem.html | title=Meropenem: Package Insert | access-date=February 23, 2024 | archive-date=February 23, 2024 | archive-url=https://web.archive.org/web/20240223014439/https://www.drugs.com/pro/meropenem.html | url-status=live }}</ref><ref name="pmid31447546">{{cite journal |vauthors=Foy F, Luna G, Martinez J, Nizich Z, Seet J, Lie K, Sunderland B, Czarniak P |title=An investigation of the stability of meropenem in elastomeric infusion devices |journal=Drug Des Devel Ther |volume=13 |issue= |pages=2655–2665 |date=2019 |pmid=31447546 |pmc=6682764 |doi=10.2147/DDDT.S212052|doi-access=free }}</ref>


There is a bit of a paradox with meropenem that the [[amide bond]] in the β-lactam ring of meropenem makes it resistant to many β-lactamases (penicillinases), which are enzymes produced by bacteria that can break down penicillin and related antibiotics such as meropenem.<ref name="pmid39282166">{{cite journal |vauthors=Saikia S, Chetia P |title=Antibiotics: From Mechanism of Action to Resistance and Beyond |journal=Indian J Microbiol |volume=64 |issue=3 |pages=821–845 |date=September 2024 |pmid=39282166 |doi=10.1007/s12088-024-01285-8 |pmc=11399512 |pmc-embargo-date=September 1, 2025 |url=}}</ref><ref>{{cite journal|doi=10.1128/microbiolspec.vmbf-0016-2015 |title=Mechanisms of Antibiotic Resistance |date=2016 |journal=Microbiology Spectrum |volume=4 |issue=2 |pmid=27227291 |pmc=4888801 | vauthors = Munita JM, Arias CA }}</ref> This resistance is due to the stability of the β-lactam ring in meropenem, which is less susceptible to hydrolysis by these enzymes.<ref name="pmid34129337">{{cite journal |vauthors=Bahr G, González LJ, Vila AJ |title=Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design |journal=Chem Rev |volume=121 |issue=13 |pages=7957–8094 |date=July 2021 |pmid=34129337 |pmc=9062786 |doi=10.1021/acs.chemrev.1c00138 |url=}}</ref> However, meropenem is not stable in the presence of water.<ref name="pmid36450742">{{cite journal |vauthors=Wilamowski M, Sherrell DA, Kim Y, Lavens A, Henning RW, Lazarski K, Shigemoto A, Endres M, Maltseva N, Babnigg G, Burdette SC, Srajer V, Joachimiak A |title=Time-resolved β-lactam cleavage by L1 metallo-β-lactamase |journal=Nat Commun |volume=13 |issue=1 |page=7379 |date=November 2022 |pmid=36450742 |pmc=9712583 |doi=10.1038/s41467-022-35029-3 |bibcode=2022NatCo..13.7379W |url=}}</ref><ref name="pmid33874825">{{cite journal |vauthors=Palermo G, Spinello A, Saha A, Magistrato A |title=Frontiers of metal-coordinating drug design |journal=Expert Opin Drug Discov |volume=16 |issue=5 |pages=497–511 |date=May 2021 |pmid=33874825 |pmc=8058448 |doi=10.1080/17460441.2021.1851188 |url=}}</ref> It can undergo hydrolysis in aqueous solutions, which can reduce its effectiveness.<ref name="pmid36117679">{{cite journal |vauthors=Celis-Llamoca K, Serna-Galvis EA, Torres-Palma RA, Nieto-Juárez JI |title=High-frequency ultrasound processes as alternative methods for degrading meropenem antibiotic in water |journal=MethodsX |volume=9 |issue= |page=101835 |date=2022 |pmid=36117679 |pmc=9471477 |doi=10.1016/j.mex.2022.101835 |url=}}</ref> This means that while meropenem is designed to resist bacterial enzymes, it can still be broken down by water.<ref name="pmid18980308">{{cite journal |vauthors=Tioni MF, Llarrull LI, Poeylaut-Palena AA, Martí MA, Saggu M, Periyannan GR, Mata EG, Bennett B, Murgida DH, Vila AJ |title=Trapping and characterization of a reaction intermediate in carbapenem hydrolysis by B. cereus metallo-beta-lactamase |journal=J Am Chem Soc |volume=130 |issue=47 |pages=15852–63 |date=November 2008 |pmid=18980308 |pmc=2645938 |doi=10.1021/ja801169j |url=}}</ref> That's why meropenem requires frequent or prolonged slow administration to supply new drug to the bloodstream to replace what was hydrolyzed by the water component of blood.<ref>{{Cite web |url=https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/antimicrobial-dosing-protocols/SHC-Extended-Infusion-Meropenem.pdf |title=Medication Administration: Extended-Infusion Meropenem (Merrem) Protocol | publisher = Stanford Hospital and Clinics | work = Pharmacy Department Policies and Procedures |access-date=October 20, 2024 |archive-date=June 3, 2024 |archive-url=https://web.archive.org/web/20240603071455/https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/antimicrobial-dosing-protocols/SHC-Extended-Infusion-Meropenem.pdf |url-status=live }}</ref><ref>{{cite journal|doi=10.1086/590064 |title=Pharmacokinetic and Pharmacodynamic Properties of Meropenem |date=2008 |journal=Clinical Infectious Diseases |volume=47 |pages=S32–S40 |pmid=18713048 | vauthors = Nicolau DP }}</ref>
There is a bit of a paradox with meropenem that the [[amide bond]] in the β-lactam ring of meropenem makes it resistant to many β-lactamases (penicillinases), which are enzymes produced by bacteria that can break down penicillin and related antibiotics such as meropenem.<ref name="pmid39282166">{{cite journal |vauthors=Saikia S, Chetia P |title=Antibiotics: From Mechanism of Action to Resistance and Beyond |journal=Indian J Microbiol |volume=64 |issue=3 |pages=821–845 |date=September 2024 |pmid=39282166 |doi=10.1007/s12088-024-01285-8 |pmc=11399512 |url=}}</ref><ref>{{cite journal|doi=10.1128/microbiolspec.vmbf-0016-2015 |title=Mechanisms of Antibiotic Resistance |date=2016 |journal=Microbiology Spectrum |volume=4 |issue=2 |pmid=27227291 |pmc=4888801 | vauthors = Munita JM, Arias CA |article-number=4.2.15 }}</ref> This resistance is due to the stability of the β-lactam ring in meropenem, which is less susceptible to hydrolysis by these enzymes.<ref name="pmid34129337">{{cite journal |vauthors=Bahr G, González LJ, Vila AJ |title=Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design |journal=Chem Rev |volume=121 |issue=13 |pages=7957–8094 |date=July 2021 |pmid=34129337 |pmc=9062786 |doi=10.1021/acs.chemrev.1c00138 |url=}}</ref> However, meropenem is not stable in the presence of water.<ref name="pmid36450742">{{cite journal |vauthors=Wilamowski M, Sherrell DA, Kim Y, Lavens A, Henning RW, Lazarski K, Shigemoto A, Endres M, Maltseva N, Babnigg G, Burdette SC, Srajer V, Joachimiak A |title=Time-resolved β-lactam cleavage by L1 metallo-β-lactamase |journal=Nat Commun |volume=13 |issue=1 |article-number=7379 |date=November 2022 |pmid=36450742 |pmc=9712583 |doi=10.1038/s41467-022-35029-3 |bibcode=2022NatCo..13.7379W |url=}}</ref><ref name="pmid33874825">{{cite journal |vauthors=Palermo G, Spinello A, Saha A, Magistrato A |title=Frontiers of metal-coordinating drug design |journal=Expert Opin Drug Discov |volume=16 |issue=5 |pages=497–511 |date=May 2021 |pmid=33874825 |pmc=8058448 |doi=10.1080/17460441.2021.1851188 |url=}}</ref> It can undergo hydrolysis in aqueous solutions, which can reduce its effectiveness.<ref name="pmid36117679">{{cite journal |vauthors=Celis-Llamoca K, Serna-Galvis EA, Torres-Palma RA, Nieto-Juárez JI |title=High-frequency ultrasound processes as alternative methods for degrading meropenem antibiotic in water |journal=MethodsX |volume=9 |issue= |article-number=101835 |date=2022 |pmid=36117679 |pmc=9471477 |doi=10.1016/j.mex.2022.101835 |url=}}</ref> This means that while meropenem is designed to resist bacterial enzymes, it can still be broken down by water.<ref name="pmid18980308">{{cite journal |vauthors=Tioni MF, Llarrull LI, Poeylaut-Palena AA, Martí MA, Saggu M, Periyannan GR, Mata EG, Bennett B, Murgida DH, Vila AJ |title=Trapping and characterization of a reaction intermediate in carbapenem hydrolysis by B. cereus metallo-beta-lactamase |journal=J Am Chem Soc |volume=130 |issue=47 |pages=15852–63 |date=November 2008 |pmid=18980308 |pmc=2645938 |doi=10.1021/ja801169j |bibcode=2008JAChS.13015852T |url=}}</ref> That's why meropenem requires frequent or prolonged slow administration to supply new drug to the bloodstream to replace what was hydrolyzed by the water component of blood.<ref>{{Cite web |url=https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/antimicrobial-dosing-protocols/SHC-Extended-Infusion-Meropenem.pdf |title=Medication Administration: Extended-Infusion Meropenem (Merrem) Protocol | publisher = Stanford Hospital and Clinics | work = Pharmacy Department Policies and Procedures |access-date=October 20, 2024 |archive-date=June 3, 2024 |archive-url=https://web.archive.org/web/20240603071455/https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/antimicrobial-dosing-protocols/SHC-Extended-Infusion-Meropenem.pdf |url-status=live }}</ref><ref>{{cite journal|doi=10.1086/590064 |title=Pharmacokinetic and Pharmacodynamic Properties of Meropenem |date=2008 |journal=Clinical Infectious Diseases |volume=47 |pages=S32–S40 |pmid=18713048 | vauthors = Nicolau DP }}</ref>


Meropenem is administered every 8 hours.<ref name="fda2008"/>
Meropenem is administered every 8 hours.<ref name="fda2008"/>
Line 91: Line 92:
Studies describe application of meropenem [[therapeutic drug monitoring]] (measurements of drug levels in the bloodstream at specific intervals) for optimal application.<ref name="pmid33533509">{{cite journal |vauthors=Steffens NA, Zimmermann ES, Nichelle SM, Brucker N |title=Meropenem use and therapeutic drug monitoring in clinical practice: a literature review |journal=J Clin Pharm Ther |volume=46 |issue=3 |pages=610–621 |date=June 2021 |pmid=33533509 |doi=10.1111/jcpt.13369 |url=|doi-access=free }}</ref><ref name="pmid39166504">{{cite journal |vauthors=Adamiszak A, Bartkowska-Śniatkowska A, Grześkowiak E, Bienert A |title=Interest in antibiotic pharmacokinetic modelling in the context of optimising dosing and reducing resistance: bibliometric analysis |journal=Anaesthesiol Intensive Ther |volume=56 |issue=2 |pages=129–140 |date=2024 |pmid=39166504 |pmc=11284584 |doi=10.5114/ait.2024.141332 |url=}}</ref>
Studies describe application of meropenem [[therapeutic drug monitoring]] (measurements of drug levels in the bloodstream at specific intervals) for optimal application.<ref name="pmid33533509">{{cite journal |vauthors=Steffens NA, Zimmermann ES, Nichelle SM, Brucker N |title=Meropenem use and therapeutic drug monitoring in clinical practice: a literature review |journal=J Clin Pharm Ther |volume=46 |issue=3 |pages=610–621 |date=June 2021 |pmid=33533509 |doi=10.1111/jcpt.13369 |url=|doi-access=free }}</ref><ref name="pmid39166504">{{cite journal |vauthors=Adamiszak A, Bartkowska-Śniatkowska A, Grześkowiak E, Bienert A |title=Interest in antibiotic pharmacokinetic modelling in the context of optimising dosing and reducing resistance: bibliometric analysis |journal=Anaesthesiol Intensive Ther |volume=56 |issue=2 |pages=129–140 |date=2024 |pmid=39166504 |pmc=11284584 |doi=10.5114/ait.2024.141332 |url=}}</ref>


As with other β-lactams antibiotics, the effectiveness of treatment depends on the amount of time during the dosing interval that the meropenem concentration is above the minimum inhibitory concentration for the bacteria causing the infection.<ref name="pmid30059536">{{cite journal | vauthors = Yu Z, Pang X, Wu X, Shan C, Jiang S | title = Clinical outcomes of prolonged infusion (extended infusion or continuous infusion) versus intermittent bolus of meropenem in severe infection: A meta-analysis | journal = PLOS ONE | volume = 13 | issue = 7 | pages = e0201667 | date = 2018 | pmid = 30059536 | pmc = 6066326 | doi = 10.1371/journal.pone.0201667 | doi-access = free | bibcode = 2018PLoSO..1301667Y }}</ref> For β-lactams, including meropenem, prolonged intravenous administration is associated with lower mortality compared to bolus intravenous infusion, especially in severe infections or those caused by less sensitive bacteria, such as ''[[Pseudomonas aeruginosa]]''.<ref name="pmid30059536"/><ref>{{cite journal | vauthors = Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME | title = Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials | journal = The Lancet. Infectious Diseases | volume = 18 | issue = 1 | pages = 108–120 | date = January 2018 | pmid = 29102324 | doi = 10.1016/S1473-3099(17)30615-1 }}</ref>
As with other β-lactams antibiotics, the effectiveness of treatment depends on the amount of time during the dosing interval that the meropenem concentration is above the minimum inhibitory concentration for the bacteria causing the infection.<ref name="pmid30059536">{{cite journal | vauthors = Yu Z, Pang X, Wu X, Shan C, Jiang S | title = Clinical outcomes of prolonged infusion (extended infusion or continuous infusion) versus intermittent bolus of meropenem in severe infection: A meta-analysis | journal = PLOS ONE | volume = 13 | issue = 7 | article-number = e0201667 | date = 2018 | pmid = 30059536 | pmc = 6066326 | doi = 10.1371/journal.pone.0201667 | doi-access = free | bibcode = 2018PLoSO..1301667Y }}</ref> For β-lactams, including meropenem, prolonged intravenous administration is associated with lower mortality compared to bolus intravenous infusion, especially in severe infections or those caused by less sensitive bacteria, such as ''[[Pseudomonas aeruginosa]]''.<ref name="pmid30059536"/><ref>{{cite journal | vauthors = Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME | title = Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials | journal = The Lancet. Infectious Diseases | volume = 18 | issue = 1 | pages = 108–120 | date = January 2018 | pmid = 29102324 | doi = 10.1016/S1473-3099(17)30615-1 }}</ref>


Meropenem exhibits poor permeability across the gut and low oral bioavailability because of its hydrophilic properties, which inhibit its passive diffusion across the intestinal epithelium.<ref name="pmid33197621">{{cite journal |vauthors=Raza A, Ngieng SC, Sime FB, Cabot PJ, Roberts JA, Popat A, Kumeria T, Falconer JR |title=Oral meropenem for superbugs: challenges and opportunities |journal=Drug Discov Today |volume=26 |issue=2 |pages=551–560 |date=February 2021 |pmid=33197621 |doi=10.1016/j.drudis.2020.11.004 |s2cid=226988098 |url=}}</ref> The challenges related to research of oral delivery of meropenem are related to high susceptibility of meropenem to degradation through hydrolysis of the [[amide bond]] in the β-lactam ring, even at relatively low temperatures and humidity.<ref name="pmid33197621"/> This instability can result in the loss of meropenem's antibacterial activity. Besides that, meropenem is unstable in the acidic environment of the stomach, leading to extensive degradation and loss of the drug after oral administration.<ref name="pmid33197621"/> In addition, intestinal efflux (secretory) transport can pump the drug back into the gut: efflux transporters, particularly P-glycoprotein (P-gp), present in the gastrointestinal tract can actively pump meropenem back into the gut lumen, limiting its absorption and reducing oral bioavailability; in the attempts of oral administration bacteria can develop resistance to meropenem by enhancing the active efflux of the antibiotic through efflux transporters, such as the MexAB-OprM tripartite efflux system in Pseudomonas aeruginosa.<ref name="pmid33197621"/> That's why meropenem is administered intravenously.<ref name="pmid33197621"/><ref>{{cite journal|doi=10.1001/jama.2023.10598 |title=Continuous vs Intermittent Meropenem Administration in Critically Ill Patients with Sepsis |date=2023 |journal=JAMA |volume=330 |issue=2 |pages=141–151 |pmid=37326473 |pmc=10276329  | vauthors = Monti G, Bradić N, Marzaroli M, Konkayev A, Fominskiy E, Kotani Y, Likhvantsev VV, Momesso E, Nogtev P, Lobreglio R, Redkin I, Toffoletto F, Bruni A, Baiardo Redaelli M, d'Andrea N, Paternoster G, Scandroglio AM, Gallicchio F, Ballestra M, Calabrò MG, Cotoia A, Perone R, Cuffaro R, Montrucchio G, Pota V, Ananiadou S, Lembo R, Musu M, Rauch S, Galbiati C }}</ref>
Meropenem exhibits poor permeability across the gut and low oral bioavailability because of its hydrophilic properties, which inhibit its passive diffusion across the intestinal epithelium.<ref name="pmid33197621">{{cite journal |vauthors=Raza A, Ngieng SC, Sime FB, Cabot PJ, Roberts JA, Popat A, Kumeria T, Falconer JR |title=Oral meropenem for superbugs: challenges and opportunities |journal=Drug Discov Today |volume=26 |issue=2 |pages=551–560 |date=February 2021 |pmid=33197621 |doi=10.1016/j.drudis.2020.11.004 |s2cid=226988098 |url=}}</ref> The challenges related to research of oral delivery of meropenem are related to high susceptibility of meropenem to degradation through hydrolysis of the [[amide bond]] in the β-lactam ring, even at relatively low temperatures and humidity.<ref name="pmid33197621"/> This instability can result in the loss of meropenem's antibacterial activity. Besides that, meropenem is unstable in the acidic environment of the stomach, leading to extensive degradation and loss of the drug after oral administration.<ref name="pmid33197621"/> In addition, intestinal efflux (secretory) transport can pump the drug back into the gut: efflux transporters, particularly P-glycoprotein (P-gp), present in the gastrointestinal tract can actively pump meropenem back into the gut lumen, limiting its absorption and reducing oral bioavailability; in the attempts of oral administration bacteria can develop resistance to meropenem by enhancing the active efflux of the antibiotic through efflux transporters, such as the MexAB-OprM tripartite efflux system in Pseudomonas aeruginosa.<ref name="pmid33197621"/> That's why meropenem is administered intravenously.<ref name="pmid33197621"/><ref>{{cite journal|doi=10.1001/jama.2023.10598 |title=Continuous vs Intermittent Meropenem Administration in Critically Ill Patients with Sepsis |date=2023 |journal=JAMA |volume=330 |issue=2 |pages=141–151 |pmid=37326473 |pmc=10276329  | vauthors = Monti G, Bradić N, Marzaroli M, Konkayev A, Fominskiy E, Kotani Y, Likhvantsev VV, Momesso E, Nogtev P, Lobreglio R, Redkin I, Toffoletto F, Bruni A, Baiardo Redaelli M, d'Andrea N, Paternoster G, Scandroglio AM, Gallicchio F, Ballestra M, Calabrò MG, Cotoia A, Perone R, Cuffaro R, Montrucchio G, Pota V, Ananiadou S, Lembo R, Musu M, Rauch S, Galbiati C }}</ref>
Line 113: Line 114:


===Protein binding===
===Protein binding===
Meropenem has a low protein binding rate of approximately 2%, in contrast to ertapenem, which is about 90%. This pharmacokinetic difference may impact clinical outcomes, particularly in hypoalbuminemic patients.<ref>{{cite journal | vauthors = Geremia N, Di Bella S, Lovecchio A, Angelini J, D'Avolio A, Luzzati R, Mearelli F, Principe L, Oliva A | title = 'Real-life' approach to applying PK/PD principles in infectious diseases clinical practice without access to prompt TDM | journal = Expert Review of Anti-Infective Therapy | volume = 23 | issue = 2-4 | pages = 119–134 | date = 2025-04-03 | pmid = 39746901 | doi = 10.1080/14787210.2024.2448727 }}</ref> Observational studies have shown that, in this population, treatment with meropenem is associated with a significantly lower 30-day mortality rate compared to ertapenem, with an approximately fourfold reduction in risk.<ref>{{cite journal | vauthors = Zusman O, Farbman L, Tredler Z, Daitch V, Lador A, Leibovici L, Paul M | title = Association between hypoalbuminemia and mortality among subjects treated with ertapenem versus other carbapenems: prospective cohort study | journal = Clinical Microbiology and Infection | volume = 21 | issue = 1 | pages = 54–58 | date = January 2015 | pmid = 25636928 | doi = 10.1016/j.cmi.2014.08.003 }}</ref>
Meropenem has a low protein binding rate of approximately 2%, in contrast to ertapenem, which is about 90%. This pharmacokinetic difference may impact clinical outcomes, particularly in hypoalbuminemic patients.<ref>{{cite journal | vauthors = Geremia N, Di Bella S, Lovecchio A, Angelini J, D'Avolio A, Luzzati R, Mearelli F, Principe L, Oliva A | title = 'Real-life' approach to applying PK/PD principles in infectious diseases clinical practice without access to prompt TDM | journal = Expert Review of Anti-Infective Therapy | volume = 23 | issue = 2–4 | pages = 119–134 | date = 2025-04-03 | pmid = 39746901 | doi = 10.1080/14787210.2024.2448727 }}</ref> Observational studies have shown that, in this population, treatment with meropenem is associated with a significantly lower 30-day mortality rate compared to ertapenem, with an approximately fourfold reduction in risk.<ref>{{cite journal | vauthors = Zusman O, Farbman L, Tredler Z, Daitch V, Lador A, Leibovici L, Paul M | title = Association between hypoalbuminemia and mortality among subjects treated with ertapenem versus other carbapenems: prospective cohort study | journal = Clinical Microbiology and Infection | volume = 21 | issue = 1 | pages = 54–58 | date = January 2015 | pmid = 25636928 | doi = 10.1016/j.cmi.2014.08.003 }}</ref>


==Research directions==
==Research directions==

Latest revision as of 14:45, 23 December 2025

Template:Short description Script error: No such module "Unsubst". Template:Cs1 config Template:Drugbox Meropenem, sold under the brand name Merrem among others, is an intravenous carbapenem antibiotic used to treat a variety of bacterial infections.[1] Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.[1]

Common side effects include nausea, diarrhea, constipation, headache, rash, and pain at the site of injection.[1] Serious side effects include Clostridioides difficile infection, seizures, and allergic reactions including anaphylaxis.[1] Those who are allergic to other β-lactam antibiotics are more likely to be allergic to meropenem as well.[1] Use in pregnancy appears to be safe.[1] It is in the carbapenem family of medications.[1] Meropenem usually results in bacterial death through blocking their ability to make a cell wall.[1] It is resistant to breakdown by many kinds of β-lactamase enzymes, produced by bacteria to protect themselves from antibiotics.[2][3][4]

Meropenem was patented in 1983.[5] It was approved for medical use in the United States in 1996.[1] It is on the World Health Organization's List of Essential Medicines.[6][7] The World Health Organization classifies meropenem as critically important for human medicine.[8]

Medical uses

The spectrum of action includes many Gram-positive and Gram-negative bacteria (including Pseudomonas) and anaerobic bacteria. The overall spectrum is similar to that of imipenem, although meropenem is more active against Enterobacteriaceae and less active against Gram-positive bacteria. Meropenem is effective against bacteria producing extended-spectrum β-lactamases but may be more susceptible to hydrolysis by metallo-β-lactamases produced by bacteria.[9] β-lactamases are enzymes that bacteria produce to hydrolyze β-lactam antibiotics, breaking the β-lactam ring and rendering these antibiotics ineffective. This mechanism helps bacteria resist the effects of antibiotics like penicillins, cephalosporins, and carbapenems, making treatment more challenging.[10][11][12] While β-lactam ring in meropenem is more accessible to water molecules than in the other β-lactam antibiotics, that facilitates the hydrolysis process and faster degradation of meropenem's antibacterial properties in aqueous solutions, it is more resistant to degradation by β-lactamase enzymes produced by bacteria than the other β-lactam antibiotics.[13][2]

Meropenem is frequently given in the treatment of febrile neutropenia. This condition frequently occurs in patients with hematological malignancies and cancer patients receiving anticancer drugs that suppress bone marrow formation. It is approved for complicated skin and skin structure infections, complicated intra-abdominal infections and bacterial meningitis.[2][14][15][16]

Meropenem is effective in treating bacterial pneumonia, including hospital-acquired pneumonia.[17]

In 2017, the U.S. Food and Drug Administration (FDA) granted approval for the combination of meropenem and vaborbactam to treat adults with complicated urinary tract infections.[18]

Administration

Meropenem is administered intravenously as an aqueous solution. Meropenem is stored in vials as white crystalline powder (containing meropenem as the trihydrate blended with anhydrous sodium carbonate).[19][20][21] For intravenous administration, if pure meropenem powder is used (rather than the powder blended with sodium carbonate), meropenem is dissolved in 5% monobasic potassium phosphate solution, since meropenem is soluble in 5% monobasic potassium phosphate solution and only sparingly soluble in water[20] (Template:Value).[22][23][24] For intravenous bolus administration, injection vials (that contain meropenem blended with sodium carbonate) are reconstituted with sterile water for injection.[19][20][22]

Reconstituted (dissolved) meropenem degrades over time.[25][26][27][28] The degradation may be associated with color change of the solution, typical for a hydrolysis of the amide bond of the β-lactam ring as seen with most β-lactam antibiotics,[29] while particularly for meropenem the color is changing from colorless or pale yellow to vivid yellowish.[30] Upon reconstitution, the meropenem infusion solution, prepared with 0.9% sodium chloride, exhibits both chemical and physical stability for a duration of 3 hours at a temperature up to Template:Value°C. If refrigerated (Template:Value°C), the stability extends to 24 hours. However, when the product is reconstituted in a 5% dextrose solution, it is used immediately to ensure its efficacy.[25] The degradation of meropenem in a water-based solution is affected by factors such as pH, temperature, initial concentration, and the specific type of infusion solution used.[30] Meropenem solutions should not be frozen.[31][32]

There is a bit of a paradox with meropenem that the amide bond in the β-lactam ring of meropenem makes it resistant to many β-lactamases (penicillinases), which are enzymes produced by bacteria that can break down penicillin and related antibiotics such as meropenem.[33][34] This resistance is due to the stability of the β-lactam ring in meropenem, which is less susceptible to hydrolysis by these enzymes.[35] However, meropenem is not stable in the presence of water.[36][37] It can undergo hydrolysis in aqueous solutions, which can reduce its effectiveness.[38] This means that while meropenem is designed to resist bacterial enzymes, it can still be broken down by water.[39] That's why meropenem requires frequent or prolonged slow administration to supply new drug to the bloodstream to replace what was hydrolyzed by the water component of blood.[40][41]

Meropenem is administered every 8 hours.[22]

Dosing must be adjusted for altered kidney function and for haemofiltration.[42]

Studies describe application of meropenem therapeutic drug monitoring (measurements of drug levels in the bloodstream at specific intervals) for optimal application.[43][44]

As with other β-lactams antibiotics, the effectiveness of treatment depends on the amount of time during the dosing interval that the meropenem concentration is above the minimum inhibitory concentration for the bacteria causing the infection.[45] For β-lactams, including meropenem, prolonged intravenous administration is associated with lower mortality compared to bolus intravenous infusion, especially in severe infections or those caused by less sensitive bacteria, such as Pseudomonas aeruginosa.[45][46]

Meropenem exhibits poor permeability across the gut and low oral bioavailability because of its hydrophilic properties, which inhibit its passive diffusion across the intestinal epithelium.[47] The challenges related to research of oral delivery of meropenem are related to high susceptibility of meropenem to degradation through hydrolysis of the amide bond in the β-lactam ring, even at relatively low temperatures and humidity.[47] This instability can result in the loss of meropenem's antibacterial activity. Besides that, meropenem is unstable in the acidic environment of the stomach, leading to extensive degradation and loss of the drug after oral administration.[47] In addition, intestinal efflux (secretory) transport can pump the drug back into the gut: efflux transporters, particularly P-glycoprotein (P-gp), present in the gastrointestinal tract can actively pump meropenem back into the gut lumen, limiting its absorption and reducing oral bioavailability; in the attempts of oral administration bacteria can develop resistance to meropenem by enhancing the active efflux of the antibiotic through efflux transporters, such as the MexAB-OprM tripartite efflux system in Pseudomonas aeruginosa.[47] That's why meropenem is administered intravenously.[47][48]

There is insufficient data regarding the administration of meropenem during breastfeeding. However, it has been observed that, in general, the concentration of this β-lactam antibiotic in breast milk is relatively low, therefore, β-lactam antibiotics are not anticipated to induce detrimental effects in infants who are breastfed. Nonetheless, there have been sporadic reports of disturbances in the gastrointestinal flora of the infant, manifesting as diarrhea or oral candidiasis (thrush), associated with the use of β-lactam antibiotics, however, these potential side effects have not been thoroughly investigated specifically in the context of meropenem use, therefore, the safety profile of meropenem in breastfeeding mothers and their infants is unknown.[49]

Although meropenem is not approved for intramuscular or subcutaneous routes of administration in humans, there were studies that evaluated the drug bioavailability in cats and reported bioavailability of 99.69% for intramuscular route and 96.52 % for subcutaneous route of administration; these studies also compared elimination half-lives for intravenous, intramuscular or subcutaneous routes of administration in cats and reported duration of 1.35, 2.10 and 2.26 hours, respectively.[50] There was also a small study on local tolerance of meropenem intramuscular administration in humans, and it was reported as generally good.[50][51][52]

Side effects

Among antibiotic drugs, meropenem is relatively safe.[2][44] The most common adverse effects are diarrhea (4.8%), nausea and vomiting (3.6%), injection-site inflammation (2.4%), headache (2.3%), rash (1.9%) and thrombophlebitis (0.9%).[53] Many of these adverse effects were observed in severely ill individuals already taking many medications including vancomycin.[54][55] Meropenem has a reduced potential for seizures in comparison with imipenem. Several cases of severe hypokalemia have been reported.[56][57]

Interactions

Meropenem rapidly reduces serum concentrations of valproic acid. As a result, people who use valproic acid for epilepsy are at increased risk of seizures during treatment with meropenem. In situations where the use of meropenem cannot be avoided, prescription of an additional anticonvulsant should be considered.[58]

Pharmacology

Mechanism of action

Meropenem is bactericidal except against Listeria monocytogenes, where it is bacteriostatic. It inhibits bacterial cell wall synthesis like other β-lactam antibiotics. In contrast to other β-lactams, it is highly resistant to degradation by β-lactamases or cephalosporinases. In general, resistance arises due to mutations in penicillin-binding proteins, production of metallo-β-lactamases, or resistance to diffusion across the bacterial outer membrane.[53] Unlike imipenem, it is stable to dehydropeptidase-1, so can be given without cilastatin.[59]

In 2016, a synthetic peptide-conjugated PMO (PPMO) was found to inhibit the expression of New Delhi metallo-beta-lactamase 1, an enzyme that many drug-resistant bacteria use to destroy carbapenems.[60][61]

Protein binding

Meropenem has a low protein binding rate of approximately 2%, in contrast to ertapenem, which is about 90%. This pharmacokinetic difference may impact clinical outcomes, particularly in hypoalbuminemic patients.[62] Observational studies have shown that, in this population, treatment with meropenem is associated with a significantly lower 30-day mortality rate compared to ertapenem, with an approximately fourfold reduction in risk.[63]

Research directions

Nebulized meropenem (inhaled route) is researched, but is not approved, for prevention of bronchiectasis exacerbation.[64]

Society and culture

File:Meropenem 1.jpg
Meropenem vial

Trade names

Trade names
Country Name Maker
India UNOMERO Scutonix Lifesciences, Bombay
India Inzapenum Dream India
Aurobindo Pharma
Penmer Biocon
Meronir Nirlife
Merowin Strides Acrolab
Aktimer Aktimas Biopharmaceuticals
Neopenem Neomed
Mexopen Samarth life sciences
Meropenia SYZA Health Sciences LLP
Ivpenem Medicorp Pharmaceuticals
Merofit
Lykapiper Lyka Labs
Winmero Parabolic Drugs
Bangladesh
I-Penam Incepta Pharmaceuticals Ltd.
Meroject Eskayef Pharmaceuticals Ltd.
Merocon Beacon Pharmaceuticals
Indonesia Merofen Kalbe Farma
Brazil Zylpen Aspen Pharma
Japan, Korea Meropen
Australia Merem
Taiwan Mepem
Germany Meronem
Nigeria Zironem Lyn-Edge Pharmaceuticals
Ukraine[65] Meropenem Lekhim-Kharkiv
Panlaktam (Panlaktam) "Darnytsia"
Mepenam Kyivmedpreparat
Merobicide Borshchahiv HFZ
US Meronem AstraZeneca
Indonesia Merosan Sanbe Farma
Indonesia Merobat Interbat
Zwipen
Carbonem
Ronem Opsonin Pharma, BD
Neopenem
Merocon Continental
Carnem Laderly Biotech
Penro Bosch
Meroza German Remedies
Merotrol Lupin)
Meromer Orchid Chemicals
Mepenox BioChimico
Meromax Eurofarma
Ropen Macter
mirage adwic
Meropex Apex Pharma Ltd.
Merostarkyl Hefny Pharma Group[66]

References

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