Ampicillin/sulbactam: Difference between revisions

{{Short description|Combination antibiotic drug}}

{{More citations needed|date=December 2014}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 447430143

| image =

| width =

| alt =

| caption =

<!-- Combo data -->

<!-- Clinical data -->

| pronounce = am pi sill' in and sul bak' tam

| tradename = Unasyn

| Drugs.com = {{drugs.com|monograph|ampicillin-sodium-and-sulbactam-sodium}}

| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->

| DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) -->

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU_comment =

| pregnancy_US = B

| pregnancy_US_comment =

| pregnancy_category =

| dependency_liability =

| addiction_liability =

| routes_of_administration = [[Intramuscular]], [[intraveneous]]

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref>{{cite web | title=Unasyn- ampicillin sodium and sulbactam sodium injection, powder, for solution | work = DailyMed | publisher = U.S. National Library of Medicine | date=17 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=155c7ec0-5862-404f-b1d0-f278f8a8bbda | access-date=12 October 2020}}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 69-53-4

| CAS_number2 = 68373-14-8

| CAS_supplemental =

| IUPHAR_ligand =

| DrugBank =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 7C782967RD

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = S4TF6I2330

| KEGG_Ref =

| KEGG = D02065

| ChEBI_Ref =

| ChEBI =

| ChEMBL_Ref =

| ChEMBL =

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

'''Ampicillin/sulbactam''' is a [[fixed-dose combination]] medication of the common [[penicillin]]-derived [[antibiotic]] [[ampicillin]] and [[sulbactam]], an [[Enzyme inhibitor|inhibitor]] of [[bacteria]]l [[beta-lactamase]]. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the brand name '''Unasyn''', generic only outside the United States, is an [[intravenous]] antibiotic. The second, an oral form called [[sultamicillin]], is marketed under the brand name '''Ampictam''' outside the United States, and generic only in the United States. Ampicillin/sulbactam is used to treat [[infection]]s caused by bacteria resistant to [[beta-lactam antibiotic]]s. Sulbactam blocks the [[enzyme]] which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.

== Medical uses ==

Ampicillin/sulbactam has a wide array of medical use for many different types of infectious disease. It is usually reserved as a second-line therapy in cases where bacteria have become beta-lactamase resistant, rendering traditional penicillin-derived antibiotics ineffective. It is effective against certain gram positive bacteria, gram-negative bacteria, and anaerobes.<ref name="pamphlet">{{cite web | url = https://labeling.pfizer.com/showlabeling.aspx?id=617 | publisher = Pfizer | title = Unasyn® (ampicillin sodium/sulbactam sodium) prescribing information | location = New York, NY | date = May 2014 }}</ref>

* [[Gram-positive bacteria|Gram-positive]] bacteria: ''[[Staphylococcus aureus]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Staphylococcus epidermidis]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Staphylococcus saprophyticus]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Enterococcus faecalis]]'', ''[[Streptococcus pneumoniae]]'', ''[[Streptococcus pyogenes]]'', and ''[[Streptococcus viridans]]''.<ref name="pamphlet" /><ref name="CLSI1">{{cite book | title = Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard | edition = Eleventh | volume = 32 | issue = 1 | publisher = Clinical and Laboratory Standard Institute (CLSI) | location = Wayne, PA | date = January 2012 | id = CLSI document M02-A11 | url = }}</ref>

* [[Gram-negative bacteria|Gram-negative]] bacteria: ''[[Haemophilus influenzae]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Moraxella catarrhalis]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Escherichia coli]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Klebsiella]]'' spp. (all known species are beta-lactamase producing), ''[[Proteus mirabilis]]'' (beta-lactamase and non-beta-lactamase producing), ''[[Proteus vulgaris]]'', ''[[Providencia rettgeri]]'', ''[[Providencia stuartii]]'', ''[[Morganella morganii]]'', and ''Neisseria gonorrhoeae'' (beta-lactamase and non-beta-lactamase producing).<ref name="pamphlet" /><ref name="CLSI1" />

* Anaerobes: ''[[Clostridium]]'' spp., ''[[Peptococcus]]'' spp., ''[[Peptostreptococcus]]'' spp, [[Bacteroides]] spp. including ''[[Bacteroides fragilis|B. fragilis]]''.<ref name="pamphlet" /><ref name="CLSI1" />

;Gynecological Infections: Ampicillin/sulbactam can be used to treat gynecological infections caused by beta-lactamase producing strains of ''E. coli'', and ''Bacteroides'' spp. (including ''B. fragilis'').<ref name="pamphlet" /><ref name="CLSI2">{{cite book | publisher = Clinical and Laboratory Standards Institute (CLSI). | title = Performance Standards for Antimicrobial Susceptibility Testing | edition = 22nd Supplement | id = CLSI document M100-S22, 2012 }}</ref>

;Bone and joint infections: Ampicillin/sulbactam can be used in the treatment of bone and joint infections caused by susceptible beta-lactamase producing bacteria.<ref name="Campoli">{{cite journal | vauthors = Campoli-Richards DM, Brogden RN | title = Sulbactam/ampicillin. A review of its antibacterial activity, pharmacokinetic properties, and therapeutic use | journal = Drugs | volume = 33 | issue = 6 | pages = 577–609 | date = June 1987 | pmid = 3038500 | doi = 10.2165/00003495-198733060-00003 | s2cid = 209140985 }}</ref><ref name="Loffler">{{cite journal | vauthors = Löffler L, Bauernfeind A, Keyl W, Hoffstedt B, Piergies A, Lenz W | title = An open, comparative study of sulbactam plus ampicillin vs. cefotaxime as initial therapy for serious soft tissue and bone and joint infections | journal = Reviews of Infectious Diseases | volume = 8 | issue = Supplement_5 | pages = S593–S598 | date = 1 November 1986 | pmid = 3026009 | doi = 10.1093/clinids/8.supplement_5.s593 }}</ref><ref name="Aronoff2">{{cite journal | vauthors = Aronoff SC, Scoles PV, Makley JT, Jacobs MR, Blumer JL, Kalamchi A | title = Efficacy and safety of sequential treatment with parenteral sulbactam/ampicillin and oral sultamicillin for skeletal infections in children | journal = Reviews of Infectious Diseases | volume = 8 | issue = Supplement_5 | pages = S639–S643 | date = 1 November 1986 | pmid = 3026018 | doi = 10.1093/clinids/8.supplement_5.s639 }}</ref><ref name="Loffler2">{{cite journal | vauthors = Löffler L, Bauernfeind A, Keyl W | title = Sulbactam/ampicillin versus cefotaxime as initial therapy in serious soft tissue, joint and bone infections | journal = Drugs | volume = 35 | issue = Supplement 7 | pages = 46–52 | date = 1988 | pmid = 3265378 | doi = 10.2165/00003495-198800357-00012 | s2cid = 29850810 }}</ref>

;Intra-abdominal infections: Ampicillin/sulbactam can be used to treat intra-abdominal infections caused by beta-lactamase producing strains of ''E. coli'', ''Klebsiella'' spp. (including ''[[Klebsiella pneumoniae|K. pneumonia]]''), ''B. fragilis'', and ''[[Enterobacter]] spp''.<ref name="pamphlet" /><ref name="CLSI2" />

;Skin and skin structure Infections: This medication can be used to treat skin and skin structure infections caused from beta-lactamase-producing strains of ''S. aureus'', ''Enterobacter'' spp., ''E. coli'', ''Klebsiella'' spp. (including ''K. pneumoniae''), ''P. mirabilis'', ''B. fragilis'', and ''[[Acinetobacter calcoaceticus]]''.<ref name="pamphlet" /><ref name="CLSI2" /> Examples of skin conditions treated with ampicillin-sulbactam are moderate to severe diabetic foot infections and type 1 Necrotizing fasciitis, commonly referred to as "flesh-eating bacteria".<ref name="Dipiro">{{cite book | vauthors = Fish DN |chapter=Skin and Soft-Tissue Infections |chapter-url=https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=224360905 |title=Pharmacotherapy: A Pathophysiologic Approach |isbn=978-1-260-11681-6 |year=2020 |publisher=McGraw-Hill Education }}</ref>

== Contraindications ==

Ampicillin/sulbactam is contraindicated in individuals who have a history of a penicillin allergy. Symptoms of allergic reactions may range from rash to potentially life-threatening conditions, such as anaphylaxis. Patients who have asthma, eczema, hives, or hay fever are more likely to develop undesirable reactions to any of the penicillins.<ref name = "Peechakara_2022">{{cite book | vauthors = Peechakara BV, Gupta M | chapter = Ampicillin/Sulbactam | date = 12 October 2022 | title = StatPearls [Internet] | location = Treasure Island (FL) | publisher = StatPearls Publishing | url = https://www.ncbi.nlm.nih.gov/books/NBK526117/ | pmid = 30252373 }}</ref>

== Adverse effects ==

Reported adverse events include both local and systemic reactions. Local adverse reactions are characterized by redness, tenderness, and soreness of the skin at the injection site. The most common local reaction is injection site pain. It has been reported to occur in 16% of patients receiving intramuscular injections, and 3% of patients receiving intravenous injections. Less frequently reported side effects include inflammation of veins (1.2%), sometimes associated with a blood clot (3%). The most commonly reported systemic reactions are diarrhea (3%) and rash (2%).<ref name="Peechakara_2022" /><ref name="insert">{{cite web | title = UNASYN [package insert] | publisher = Pifzer Inc. | location = New York, NY | date = April 2007 | url = http://labeling.pfizer.com/ShowLabeling.aspx?id=617| access-date = 21 November 2014 }}</ref> Less frequent systemic reactions to ampicillin/sulbactam include chest pain, fatigue, seizure, headache, painful urination, urinary retention, intestinal gas, nausea, vomiting, itching, hairy tongue, tightness in throat, reddening of the skin, nose bleeding, and facial swelling. These are reported to occur in less than 1% of patients.<ref name="Peechakara_2022" /><ref name="insert" /><ref name="lexicomp">{{cite web | title = Unasyn | work = Lexi-Drugs Online | url = http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6354#f_adverse-reactions | access-date = 21 November 2014 }}</ref>

== Pharmacology ==

===Pharmacodynamics and pharmacokinetics===

The addition of sulbactam to ampicillin enhances the effects of ampicillin. This increases the antimicrobial activity by 4- to 32-fold when compared to ampicillin alone.<ref name="Rafailidis">{{cite journal | vauthors = Rafailidis PI, Ioannidou EN, Falagas ME | title = Ampicillin/sulbactam: current status in severe bacterial infections | journal = Drugs | volume = 67 | issue = 13 | pages = 1829–1849 | date = 2007 | pmid = 17722953 | doi = 10.2165/00003495-200767130-00003 | s2cid = 209145407 | doi-access = free }}</ref> Ampicillin is a time-dependent antibiotic. Its bacterial killing is largely related to the time that drug concentrations in the body remain above the minimum inhibitory concentration (MIC). The duration of exposure will thus correspond to how much bacterial killing will occur. Various studies have shown that, for maximum bacterial killing, drug concentrations must be above the MIC for 50-60% of the time for the penicillin group of antibiotics. This means that longer durations of adequate concentrations are more likely to produce therapeutic success. However, when ampicillin is given in combination with sulbactam, regrowth of bacteria has been seen when sulbactam levels fall below certain concentrations. As with many other antibiotics, under-dosing of ampicillin/sulbactam may lead to resistance.<ref name="Adnan">{{cite journal | vauthors = Adnan S, Paterson DL, Lipman J, Roberts JA | title = Ampicillin/sulbactam: its potential use in treating infections in critically ill patients | journal = International Journal of Antimicrobial Agents | volume = 42 | issue = 5 | pages = 384–389 | date = November 2013 | pmid = 24041466 | doi = 10.1016/j.ijantimicag.2013.07.012 }}</ref>

Ampicillin/sulbactam has poor absorption when given orally.<ref name="Rafailidis" /> The two drugs have similar pharmacokinetic profiles that appear unchanged when given together. Ampicillin and sulbactam are both hydrophilic antibiotics and have a volume of distribution (Vd) similar to the volume of extra-cellular body water. The volume that the drug distributes throughout in healthy patients is approximately 0.2 liters per kilogram of body weight. Patients on hemodialysis, elderly patients, and pediatric patients have shown a slightly increased volume of distribution.

Using typical doses, ampicillin/sulbactam has been shown to reach desired levels to treat infections in the brain, lungs, and abdominal tissues.<ref name="Adnan" />

Both agents have moderate protein binding, reported at 38% for sulbactam and 28% for ampicillin.15,16 The half-life of ampicillin is approximately 1 hour, when used alone or in combination with sulbactam; therefore it will be eliminated from a healthy person in around 5 hours. It is eliminated primarily by the urinary system, with 75% excreted unchanged in the urine. Only small amounts of each drug were found to be excreted in the bile.<ref name="Adnan" /> Ampicillin/sulbactam should be given with caution in infants less than a week old and premature neonates. This is due to the underdeveloped urinary system in these patients, which can cause a significantly increased half-life for both drugs.16 Based on its elimination, ampicillin/sulbactam is typically given every 6 to 8 hours. Slowed clearance of both drugs has been seen in the elderly, renal disease patients, and critically ill patients on renal replacement therapy. Reduced clearance has been seen in both pediatric and post-operative patients. Adjustments in dosing frequency may be required in these patients due to these changes.<ref name="Adnan" />

===Mechanism of action===

Ampicillin/sulbactam is a combination of a β-lactam antibiotic and a β-lactamase inhibitor. Ampicillin works by binding to penicillin-binding proteins (PBPs) to inhibit bacterial cell wall synthesis.<ref name="Rafailidis" /><ref name="Adnan" /> This causes disruption of the bacterial cell wall and leads to bacterial cell death. However, resistant pathogens may produce β-lactamase enzymes that can inactivate ampicillin through hydrolysis.<ref name="Adnan" /> This is prevented by the addition of sulbactam, which binds and inhibits the β-lactamase enzymes.<ref name="Rafailidis" /><ref name="Adnan" /> It is also capable of binding to the PBP of ''[[Bacteroides fragilis]]'' and ''[[Acinetobacter]]'' spp., even when it is given alone. The activity of sulbactam against ''Acinetobacter'' spp. seen in in-vitro studies makes it distinctive compared to other β-lactamase inhibitors, such as tazobactam and clavulanic acid.<ref name="Adnan" />

== Chemistry ==

Ampicillin sodium is derived from the basic penicillin nucleus, 6-aminopenicillanic acid. Its chemical name is monosodium (2S, 5R, 6R)-6-[(R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. It has a molecular weight of 371.39 grams and its chemical formula is C16H18N3NaO4S.<ref name="pamphlet" />

Sulbactam sodium is also a derivative of 6-aminopenicillanic acid. Chemically, it is known as either sodium penicillinate sulfone or sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide. It has a molecular weight of 255.22 grams and its chemical formula is C8H10NNaO5S.<ref name="pamphlet" />

| [[Skeletal formula]] of [[ampicillin]] || Skeletal formula of [[sulbactam]] || Skeletal formula of [[sultamicillin]], highlighting ampicillin in blue and sulbactam in red

Ampicillin/sulbactam is also used when the cause of an infection is not known ([[empiric therapy]]), such as [[peritonitis|intra-abdominal infections]], skin infections, [[pneumonia]], and [[gynecology|gynecologic infections]]. It is active against a wide range of bacterial groups, including ''[[Staphylococcus aureus]]'', [[Enterobacteriaceae]], and [[anaerobic bacteria]]. Importantly, it is not active against ''[[Pseudomonas aeruginosa]]'' and should not be used alone when infection with this organism is suspected or known.

== History ==

The introduction and use of ampicillin alone started in 1961.<ref name =Acred>{{cite journal | vauthors = Acred P, Brown DM, Turner DH, Wilson MJ | title = Pharmacology and chemotherapy of ampicillin--a new broad-spectrum penicillin | journal = British Journal of Pharmacology and Chemotherapy | volume = 18 | issue = 2 | pages = 356–369 | date = April 1962 | pmid = 13859205 | pmc = 1482127 | doi = 10.1111/j.1476-5381.1962.tb01416.x }}</ref> The development and introduction of this drug allowed the use of targeted therapies against gram-negative bacteria. With the rise of beta-lactamase producing bacteria, ampicillin and the other penicillin-derivatives became ineffective to these resistant organisms. With the introduction of beta-lactamase inhibitors such as sulbactam, combined with ampicillin made beta-lactamase producing bacteria susceptible.<ref name =Aronoff>{{cite journal | vauthors = Aronoff SC, Jacobs MR, Johenning S, Yamabe S | title = Comparative activities of the beta-lactamase inhibitors YTR 830, sodium clavulanate, and sulbactam combined with amoxicillin or ampicillin | journal = Antimicrobial Agents and Chemotherapy | volume = 26 | issue = 4 | pages = 580–582 | date = October 1984 | pmid = 6097169 | pmc = 179968 | doi = 10.1128/aac.26.4.580 }}</ref>

==Formulation==

Ampicillin-sulbactam only comes in a parenteral formulation to be either used as intravenous or intramuscular injections, and can be formulated for intravenous infusion.<ref name="pamphlet"/><ref name=Dynamed>{{cite web | title = Ampicillin/Sulbactam Drug Monograph | url = https://www.dynamed.com/drug-monograph/ampicillin-sulbactam | work = DynaMed | publisher = EBSCO Industries, Inc. }}</ref> It is formulated in a 2:1 ratio of ampicillin:sulbactam. The commercial preparations available include:<ref name="Dynamed"/>

* 1.5 grams (1 gram ampicillin and 0.5 gram sulbactam)

→Brand names: Unasyn, Unasyn ADD-Vantage, Unasyn Piggyback

* 3 grams (2 grams ampicillin and 1 gram sulbactam)

→Brand names: Unasyn, Unasyn ADD-Vantage, Unasyn Piggyback

* 15 grams (10 grams ampicillin and 5 grams sulbactam)

→Brand name: Unasyn

== Society and culture ==

=== Names ===

* Unasyn (US)

* Subacillin (Taiwan)

* Unictam (Egypt)

* Ultracillin (Egypt)

* Fortibiotic

* Sulbin (Egypt)

* Novactam (Egypt)

* Devasid (Turkey)

* Sulbacin (Kenya<ref>{{Cite web |url=https://www.dawa.kenyapharmtech.com/drugs/ampicillin-sulbactam/ | title=Ampicillin/Sulbactam | quote = Sulbacin, Unichem Laboratories Ltd. | work = Druglist Kenya }}</ref>)

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ampicillin%20mixture%20with%20sulbactam | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ampicillin mixture with Sulbactam }}

{{PenicillinAntiBiotics|state=collapsed}}

{{Portal bar | Medicine}}

{{DEFAULTSORT:Ampicillin Sulbactam}}

[[Category:Penicillins]]

[[Category:Combination antibiotics]]

[[Category:Drugs developed by Pfizer]]