Ampicillin/Sulbactam


Article Author:
Basil Peechakara


Article Editor:
Mohit Gupta


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/22/2019 1:05:00 PM

Indications

Ampicillin/sulbactam combination shows synergy to cover strains of bacteria resistant to ampicillin, thus providing broader coverage.[1]

Lower Respiratory Tract Infections

Ampicillin/sulbactam, when compared with various third-generation cephalosporins (cefuroxime and cefotaxime), second-generation cephalosporin (cefoxitin), mezlocillin, ticarcillin/clavulanate, and imipenem/cilastatin had higher efficacy although not clinically significant in the treatment of lower respiratory tract infections.[2][3][4][5][4]

Aspiration Pneumonia

In a study by Kadowaki et al., the efficacy of ampicillin/sulbactam, clindamycin, and imipenem/cilastatin was compared.[6] Cure rates for ampicillin/sulbactam were comparable to imipenem/cilastatin being the highest, although clindamycin was found to be the least expensive.

Gynecological Infections

Pelvic inflammatory disease results from sexually transmitted organisms (Neisseria gonorrhoeae or Chlamydia trachomatis) or anaerobic vaginal flora. First-line treatment includes cefoxitin or cefotetan with doxycycline or clindamycin with gentamycin plus doxycycline. Ampicillin/sulbactam is comparable in efficacy and is an important alternate regimen for gynecological infections.[4]

Intra-abdominal Infections

Ampicillin/sulbactam should be used in mild to moderate community-acquired intra-abdominal infections; however, more serious infections require a broader coverage against facultative and gram-negative aerobic bacteria where the combination of antimicrobials may be necessary (carbapenem in combination with vancomycin).[7]

Diabetic Foot Infections

Ampicillin/sulbactam when compared to imipenem/cilastatin[8] and piperacillin/tazobactam are comparably effective. However, piperacillin/tazobactam has broader coverage, and the most common gram-negative bacterium isolated was Pseudomonas aeruginosa.

Pediatric Infections

In the pediatric population, indications for ampicillin/sulbactam include epiglottitis, periorbital infections, acute fulminant meningococcemia, and sepsis management.[9]

Skin Infections

Ampicillin/sulbactam has an efficacy comparable to third-generation cephalosporins in the treatment of skin infections in patients with or without a history of intravenous drug abuse.[10]

Infection in the Intensive Care Unit (ICU) with Acinetobacter baumannii

It is effective and safe to use ampicillin/sulbactam in multidrug-resistant A. baumannii infections.[11]

Mechanism of Action

Ampicillin is a beta-lactam antibiotic, and sulbactam is a beta-lactamase inhibitor.

Ampicillin

The mode of action of ampicillin, like any other beta-lactam antibiotics, on sensitive organisms, can be considered to be a two-step process. In the first step, the drug binds to primary receptors called membrane-bound penicillin-binding proteins. These proteins perform vital roles in cell cycle-related, the morphogenetic formation of cell wall peptidoglycan. Inactivation of penicillin-binding proteins by bound antibiotic has immediate arresting actions on their function. The second stage comprises the physiological effects caused by this receptor-ligand interaction. Penicillin-binding proteins are involved in the late stages of peptidoglycan synthesis in the cell wall. Because peptidoglycan maintains the integrity of the cell wall, which resides in a hypotonic environment, its disruption causes lysis and cell death.[12]

Sulbactam

It is a beta-lactamase inhibitor and inhibits the action of any bacteria producing the enzyme after binding to it and thereby not allowing its action on the antibiotic.

Administration

Ampicillin/sulbactam is not absorbed adequately after oral absorption. In intravenous formulations, penetration into tissue/fluids includes intraperitoneal fluid (60%), myometrium (64%), sputum (12% to 14%), cerebrospinal fluid (CSF) (11% to 14%). As ampicillin/sulbactam is primarily excreted renally, its half-life increases in patients with impaired renal function.[13] Pharmacokinetics of ampicillin/sulbactam does not change in the pediatric population as compared to adults.[14] Caution must be observed in the administration to neonates with age less than one week and premature infants due to an underdeveloped urinary system.

Adverse Effects

The primary adverse effects of ampicillin-sulbactam include seizure, diarrhea, enterocolitis, pseudomembranous colitis, vomiting, agranulocytosis, hemolytic anemia, eosinophilia, and immune thrombocytopenia.

Common Adverse Effects

Gastrointestinal

Stomatitis, glossitis, black "hairy" tongue, nausea, vomiting, pseudomembranous colitis, enterocolitis, and diarrhea. Mainly seen with oral dose administration.

Hypersensitivity Reactions

There are frequent reports of skin rashes and urticaria. Reports also exist of some cases of erythema multiforme and exfoliative dermatitis. Anaphylaxis is the most serious complication experienced and is usually associated with the parenteral form.

Liver

A moderate elevation of serum glutamic oxaloacetic transaminase (SGOT) is reported, commonly in infants; its significance is unknown. Mild transient elevation occurs with repeated intramuscular administration in individuals receiving larger than usual doses. Evidence indicates that SGOT gets released in the intramuscular injection site, and the increased quantities seen in the blood may not necessarily be from the liver as a source.

Hemato-Lymphatic Systems

There are reports of anemia, thrombocytopenic purpura, thrombocytopenia, eosinophilia, agranulocytosis, and leukopenia during ampicillin-sulbactam therapy. These reactions are reversible on discontinuation of therapy, the etiology being a hypersensitive phenomenon.

Central Nervous System

Seizures

Opportunistic Infections

During therapy, there is a possibility of superinfection with some bacteria or mycotic organisms. Such cases warrant discontinuation of therapy and substitution of appropriate alternative treatment.

Contraindications

Hypersensitivity

There are reports of serious and life-threatening anaphylactoid reactions with ampicillin-sulbactam therapy. Although anaphylaxis is more common following parenteral therapy, it can also occur after oral administration. Anaphylaxis is more likely in a patient with a previous history of penicillin hypersensitivity and/or reaction to multiple allergens. Before initiating therapy, a careful inquiry should be made relating to hypersensitivity reactions to cephalosporins, allergens, or penicillin. If a hypersensitivity reaction occurs, theclinician should discontinue therapy, and alternative therapy initiated. Anaphylactoid reactions require immediate emergency treatment with oxygen, epinephrine, steroids, and airway management, including intubation if indicated.

Clostridium difficile Infection

Antibacterial treatment alters the natural flora of the intestine leading to overgrowth of C. difficile. C. difficile-associated diarrhea (CDAD) occurs with nearly all antibacterial agent use, especially ampicillin. The resulting severity may range from mild diarrhea to fulminant colitis. Hypertoxin producing C. difficile strains cause increased morbidity and mortality, as these strains are refractory to the recommended antimicrobial therapy and may require colectomy. C. difficile-associated diarrhea may be a consideration with all patients after antibacterial use who present with diarrhea. Since it is reported to occur over two months after the administration of antibacterial agents, a careful medical history is necessary in these cases.

If CDAD is confirmed, ongoing antibiotic use not directed against the organism might require therapy discontinuation. Adequate fluid and electrolyte management and protein supplementation along with the antibiotic regimen of C. difficile and surgical evaluation merit consideration if indicated.

Concomitant Infectious Mononucleosis Infection

A high proportion of patients with infectious mononucleosis started on ampicillin-sulbactam to develop a rash. Ideally, the rash appears 7 to 10 days following the initiation of ampicillin-sulbactam therapy and remains for a few days to one week after discontinuing the drug. In the majority of cases, the rash is maculopapular, generalized, and pruritic. Therefore, ampicillin-sulbactam administration is not a recommended agent in these patients. Whether these patients are truly allergic to penicillin remains unknown.

Monitoring

When administering a prolonged therapy, monitor renal, hepatic, and hematologic functions periodically. Monitor also for signs of anaphylaxis during the first dose.

Toxicity

In cases of overdose, discontinuation of the medication, symptomatic treatment, and supportive care institution is necessary. In patients with decreased renal function, the antibiotic is removable via hemodialysis but not peritoneal dialysis.

Enhancing Healthcare Team Outcomes

Ampicillin/sulbactam is a widely prescribed antibiotic by primary care providers, nurse practitioners, internists, surgeons, and other healthcare professionals. While the antibiotic is effective that the drug not be empirically prescribed for all infections. Resistance to this agent is gradually increasing globally. Even when prescribed, the duration of drug use should be limited. Pharmacists should verify dosing and look into the appropriateness of selecting ampicillin-sulbactam base don the infection type and available antibiogram data, as well as checking for drug-drug interactions. Nursing will be administering this drug in most cases and must monitor for adverse events as well as assessing therapeutic effectiveness, informing the clinician of their findings as treatment progresses. An interprofessional team, including the clinician (MD, DO, NP, PA) and pharmacist, should work together to minimize the use of this medication to only those individuals that need the drug and make sure the patient understands the importance of completing the course. This interprofessional team approach to antimicrobial therapy with ampicillin/sulbactam ensures optimal patient outcomes with minimal adverse effects. [Level V]


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Ampicillin/Sulbactam - Questions

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A 72-year-old female is admitted to the hospital with pain in her left leg. She has a history of poorly controlled type 2 diabetes mellitus. Her vitals include a pulse of 99 beats per minute, a blood pressure of 90/70 mmHg, a respiratory rate of 19 cycles per minute and a temperature of 100 degrees Fahrenheit. On examination, the left leg is uniformly swollen, red, and severely tender around the ankle. Pulse is present bilaterally in the dorsalis pedis artery and sensations are intact. Labs are significant for a white blood cell count of 19,000/mm3 and an absolute neutrophil count of 9,800/mm3. Five days later, culture results came back positive for a beta-lactamase-producing staphylococcus infection. Which of the following antibiotics is the best choice to eradicate the infection?



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A retrospective study is studying the sensitivity of organisms to ampicillin and its extended coverage combination ampicillin-sulbactam. Patients with positive blood cultures who were given the antibiotics during hospitalization were followed up with blood cultures to document the eradication of the bacteria. Patients infected with which baceria are most likely to have positive blood cultures after treatment with ampicillin but negative blood culture with ampicillin-sulbactam?



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A 23-year-old female presents to the emergency department with pain in her lower abdomen and abnormal vaginal discharge for a week. Her vitals include a pulse is 87 beats per minute, a blood pressure of 110/82 mm Hg, a respiratory rate of 14 cycles per minute and a temperature of 99.8 degrees Fahrenheit. Her abdomen is not swollen, but there is tenderness in the hypogastrium with no rebound tenderness. There is whitish cervical discharge seen on speculum examination. She appears lethargic. She is started on ampicillin-sulbactam and transferred to the intensive care unit (ICU). In the ICU, her throat starts to swell, and she is intubated. Which of the following is the drug of choice for the management of this acute condition?



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A researcher is studying the effects of different components of drug preparations. While studying ampicillin-sulbactam, it was noticed that when the components were isolated, ampicillin alone was able to offer a narrower antibiotic coverage as compared to the combination drug. While ampicillin was effective against a broad range of gram-positive and gram-negative bacteria, sulbactam seemed to additionally provide coverage to a subset of bacteria many penicillins alone were not able to eradicate. What is the role of sulbactam in the combined ampicillin-sulbactam preparation?



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A 2-year-old unvaccinated child is brought to the emergency department for pain on swallowing for the past two days. Her vitals include a pulse of 88 beats per minute, blood pressure of 100/88 mm Hg, respiratory rate of 14 cycles per minute and a temperature of 100.3 degrees Fahrenheit. On examination, the throat appears erythematous, with a swollen posterior pharynx and significant drooling. A lateral head and neck x-ray shows a swollen structure on the posterior pharynx shaped like a thumbprint. Ampicillin-sulbactam is started. Which of the following organism is the most likely target of this medication?



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Ampicillin/Sulbactam - References

References

Gonz�lez C,Garc�a A,Urrea R,del Solar E,Bello H,Zemelman R, [A combination of ampicillin and sulbactam: effect on aerobic and anaerobic gram-negative bacteria]. Revista medica de Chile. 1990 May     [PubMed]
Ghooi RB,Thatte SM, Inhibition of cell wall synthesis--is this the mechanism of action of penicillins? Medical hypotheses. 1995 Feb     [PubMed]
Geckler RW, A comparison of ampicillin/sulbactam and cefuroxime in the treatment of patients with bacterial infections of the lower respiratory tract. Clinical therapeutics. 1994 Jul-Aug     [PubMed]
Jauregui L,Minns P,Hageage G, A comparison of ampicillin/sulbactam versus cefotaxime in the therapy of lower respiratory tract infections in hospitalized patients. Journal of chemotherapy (Florence, Italy). 1995 Apr     [PubMed]
McKinnon PS,Neuhauser MM, Efficacy and cost of ampicillin-sulbactam and ticarcillin-clavulanate in the treatment of hospitalized patients with bacterial infections. Pharmacotherapy. 1999 Jun     [PubMed]
Yanagihara K,Fukuda Y,Seki M,Izumikawa K,Higashiyama Y,Miyazaki Y,Hirakata Y,Tomono K,Mizuta Y,Tsukamoto K,Kohno S, Clinical comparative study of sulbactam/ampicillin and imipenem/cilastatin in elderly patients with community-acquired pneumonia. Internal medicine (Tokyo, Japan). 2006     [PubMed]
Kadowaki M,Demura Y,Mizuno S,Uesaka D,Ameshima S,Miyamori I,Ishizaki T, Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest. 2005 Apr     [PubMed]
Solomkin JS,Mazuski JE,Baron EJ,Sawyer RG,Nathens AB,DiPiro JT,Buchman T,Dellinger EP,Jernigan J,Gorbach S,Chow AW,Bartlett J, Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003 Oct 15     [PubMed]
Grayson ML,Gibbons GW,Habershaw GM,Freeman DV,Pomposelli FB,Rosenblum BI,Levin E,Karchmer AW, Use of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1994 May     [PubMed]
Talan DA,Summanen PH,Finegold SM, Ampicillin/sulbactam and cefoxitin in the treatment of cutaneous and other soft-tissue abscesses in patients with or without histories of injection drug abuse. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2000 Aug     [PubMed]
Kanra G,Seçmeer G,Gönç EN,Ceyhan M,Ecevit Z, Periorbital cellulitis: a comparison of different treatment regimens. Acta paediatrica Japonica : Overseas edition. 1996 Aug     [PubMed]
Jellison TK,Mckinnon PS,Rybak MJ, Epidemiology, resistance, and outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam. Pharmacotherapy. 2001 Feb     [PubMed]
Campoli-Richards DM,Brogden RN, Sulbactam/ampicillin. A review of its antibacterial activity, pharmacokinetic properties, and therapeutic use. Drugs. 1987 Jun     [PubMed]
Nahata MC,Vashi VI,Swanson RN,Messig MA,Chung M, Pharmacokinetics of ampicillin and sulbactam in pediatric patients. Antimicrobial agents and chemotherapy. 1999 May     [PubMed]

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