Ampicillin/ sulbactam

Ampicillin/ sulbactam belonging to the Penicillin and Beta-lactamase inhibitors respectively, used to treat Gynecologic Infections, Intra-Abdominal Infections, Skin & Skin Structure Infections, Orbital Cellulitis, Pelvic Inflammatory Disease, Pneumonia, Urinary Tract Infections, Acute Bacterial Rhinosinusitis (Off-label), Endocarditis (Off-label).

Ampicillin/ sulbactam is rapidly absorbed after intravenous administration and widely distributed throughout the body. The combination is hydrolyzed by the liver into active forms, ampicillin and sulbactam, which are eliminated via renal excretion. The elimination half-lives of ampicillin and sulbactam are approximately 1-1.5 hours and 1.3-1.6 hours, respectively. The pharmacokinetics of Ampicillin/ sulbactam are not significantly affected by mild to moderate renal impairment, but dosage adjustments might be necessary in patients with severe renal impairment. Overall, the pharmacokinetics of Ampicillin/ sulbactam make it a suitable option for the treatment of a variety of bacterial infections.

Ampicillin/ sulbactam is available in the form of powder for solution.

Ampicillin/ sulbactam is available in United States, Canada, United Kingdom, Australia, Germany, France, Italy, Spain, Japan, South Korea, and many others.

Ampicillin/ sulbactam is a combination of two drugs: ampicillin, a penicillin-type antibiotic, and sulbactam, a beta-lactamase inhibitor. Ampicillin works by inhibiting the bacterial cell wall synthesis, which in turn leads to cell lysis and death of the bacteria. Sulbactam, on the other hand, is a beta-lactamase inhibitor that protects ampicillin from being destroyed by beta-lactamase enzymes produced by some bacteria. By inhibiting beta-lactamase, sulbactam enhances the activity of ampicillin against beta-lactamase producing bacteria, thereby increasing its effectiveness. The combination of these two drugs provides a broad-spectrum coverage against many gram-positive and gram-negative bacteria, making it an effective treatment option for a variety of bacterial infections.

The maximum concentration (Cmax) of Ampicillin/ sulbactam in the blood is achieved approximately 1 hour after intravenous (IV) administration. The onset of action is generally rapid, with therapeutic concentrations achieved within 15-30 minutes of administration. The duration of action of Ampicillin/ sulbactam depends on the dose, the severity of the infection, and the patient's renal function, but it is generally between 4-6 hours.

Ampicillin/ sulbactam is available in the form of powder for solution.

Ampicillin/ sulbactam is a combination antibiotic medication that is used to treat a variety of Gynecologic Infections, Intra-Abdominal Infections, Skin & Skin Structure Infections, Orbital Cellulitis, Pelvic Inflammatory Disease, Pneumonia, Urinary Tract Infections, Acute Bacterial Rhinosinusitis (Off-label), Endocarditis (Off-label).

Ampicillin/ sulbactam is a combination antibiotic that consists of Ampicillin, a penicillin derivative and sulbactam, a beta -lactamase inhibitor. Here are some benefits of Ampicillin/ sulbactam based on clinical studies, package insert, and the USFDA:

1. Broad-spectrum antibiotic: Ampicillin/ sulbactam has activity against a wide range of bacteria, including many Gram-positive and Gram-negative organisms. This makes it useful in treating various bacterial infections.
2. Synergistic effect: The combination of ampicillin and sulbactam has a synergistic effect, which means they work better together than they would individually. Sulbactam helps ampicillin be more effective against bacteria by inhibiting the enzymes that can inactivate ampicillin.
3. Extended spectrum beta-lactamase (ESBL) coverage: Ampicillin/ sulbactam has activity against ESBL-producing bacteria, which are resistant to many other antibiotics.
4. Can be given via different routes: Ampicillin/ sulbactam can be given intravenously (IV) or intramuscularly (IM), providing flexibility in administration.
5. Lower risk of Clostridium difficile infection: Compared to other antibiotics, Ampicillin/ sulbactam has a lower risk of causing Clostridium difficile infection, a type of bacterial infection that can be difficult to treat.

Ampicillin/ sulbactam is approved for use in the following clinical indications:

• Gynecologic Infections
• Intra-Abdominal Infections
• Skin & Skin Structure Infections
• Orbital Cellulitis
• Pelvic Inflammatory Disease
• Pneumonia
• Urinary Tract Infections
• Acute Bacterial Rhinosinusitis (Off-label)
• Endocarditis (Off-label)

• Gynecologic infections: The recommended dosage of Ampicillin/ sulbactam for intravenous or intramuscular administration is 1.5 g (1 g ampicillin and 0.5 g sulbactam) to 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours, with a maximum daily dose of 12 g.
• Intra-abdominal infections: The recommended dosage of Ampicillin/ sulbactam for intravenous or intramuscular administration is 1.5 g (1 g ampicillin and 0.5 g sulbactam) to 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours, with a maximum daily dose of 12 g.
• Skin and skin structure infections: The recommended dosage of Ampicillin/ sulbactam for intravenous or intramuscular administration is 1.5 g (1 g ampicillin and 0.5 g sulbactam) to 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours, with a maximum daily dose of 12 g.
• Orbital cellulitis: The recommended dosage of Ampicillin/ sulbactam for intravenous administration is 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours.
• Pelvic inflammatory disease: The recommended dosage of Ampicillin/ sulbactam for intravenous administration is 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours.
• Pneumonia: For aspiration or community-acquired pneumonia, the recommended dosage of Ampicillin/ sulbactam for intravenous administration is 1.5 g (1 g ampicillin and 0.5 g sulbactam) to 3 g (2 g ampicillin and 1 g sulbactam) every 6 hours for 5 or more days. For hospital-acquired pneumonia, the recommended dosage is 3 g every 6 hours for 5 or more days.
• Urinary tract infections: For pyelonephritis, the recommended dosage of Ampicillin/ sulbactam for intravenous administration is 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours for 14 days.
• Acute bacterial rhinosinusitis (off-label): For severe infections requiring hospitalization, the recommended dosage of Ampicillin/ sulbactam for intravenous administration is 1.5 g (1 g ampicillin and 0.5 g sulbactam) to 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours for 5-7 days.
• Endocarditis (off-label): For enterococcus infection resistant to penicillin but susceptible to aminoglycosides, the recommended dosage of Ampicillin/ sulbactam for intravenous administration is 3 g (2 g ampicillin and 1 g sulbactam) for every 6 hours for 6 weeks if not aminoglycoside resistant, and more than 6 weeks if aminoglycoside resistant. For HACEK infection, the recommended dosage is 3 g every 6 hours for 4 weeks.

The combination of Ampicillin/ sulbactam is available as following strengths:

• 1.5g (ampicillin 1g/sulbactam 0.5g)
• 3g (ampicillin 2g/sulbactam 1g)
• 15g (ampicillin 10g/sulbactam 5g)

The available dosage forms for Ampicillin/ sulbactam include powder for solution.

• Dosage Adjustment in Kidney Patient

CrCl >30 mL/min: No adjustment needed.

CrCl 15-29 mL/min: 1.5 g every 12 hours

CrCl 5-14 mL/min: 1.5 g every 24 hours

CrCl <5 mL/min: 1 g every 24 hours

There are no specific dietary restrictions associated with the use of Ampicillin/ sulbactam. However, it is recommended to take this medication with food to help improve its absorption and reduce the risk of gastrointestinal side effects such as nausea and diarrhea. Additionally, patients should avoid consuming grapefruit or grapefruit juice while taking this medication as it may increase the risk of side effects.

Ampicillin/ sulbactam is contraindicated in patients with

• Hypersensitivity: Ampicillin/ sulbactam should not be used in individuals who have a history of serious hypersensitivity reactions such as anaphylaxis or Stevens-Johnson syndrome to ampicillin, sulbactam, or other beta-lactam antibacterial drugs like cephalosporins and penicillins.
• Hepatic Dysfunction: Ampicillin/ sulbactam is contraindicated in patients having a previous history of cholestatic jaundice or hepatic dysfunction that was associated with the use of Ampicillin/ sulbactam.

The physician should closely monitor the patients as well as keep pharmacovigilance as follows:

• Hypersensitivity Reactions:

Serious and potentially fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving penicillin therapy. These reactions are more likely to occur in the individuals with a history of penicillin hypersensitivity and/or hypersensitivity reactions to multiple allergens. Before initiating therapy with Ampicillin/ sulbactam, it is important to inquire about the previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. In case of an allergic reaction, the medication should be discontinued immediately and appropriate treatment should be administered.

• Hepatotoxicity:

The use of Ampicillin/ sulbactam has been associated with hepatotoxicity, including hepatitis and cholestatic jaundice. While most cases of hepatic toxicity are reversible, fatalities have been reported. Patients with preexisting liver disease should have their liver function monitored regularly.

• Severe Cutaneous Adverse Reactions:

Ampicillin/ sulbactam may cause severe skin reactions, such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), dermatitis exfoliative, erythema multiforme, and also Acute generalized exanthematous pustulosis (AGEP). If a patient develops a skin rash, the medication should be closely monitored and discontinued if the lesions progress.

• Clostridium difficile-Associated Diarrhea:

The use of Ampicillin/ sulbactam, like other antibacterial agents, has been associated with Clostridium difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis. If a patient presents with diarrhea following treatment with Ampicillin/ sulbactam, CDAD should be considered and appropriate medical history should be obtained. Hypertoxin-producing strains of C. difficile may cause increased morbidity and mortality, and may require surgical intervention. If CDAD is confirmed, the use of Ampicillin/ sulbactam and other antibiotics should be discontinued, and appropriate medical management should be instituted, including fluid and electrolyte management, protein supplementation, and antibacterial treatment of C. difficile.

There is found to be no known interaction between alcohol and Ampicillin/ sulbactam. However, it is generally recommended to avoid consuming alcohol while taking any medication as it may increase the risk of side effects and impair the effectiveness of the medication. Additionally, some individuals may experience gastrointestinal upset or other adverse effects when consuming alcohol in combination with antibiotics.

Caution must be taken when administering Ampicillin/ sulbactam to breastfeeding women, as the excretion of ampicillin and sulbactam into the milk is minimal.

Pregnancy Category B

Studies on reproductive toxicity have been conducted on mice, rats, and rabbits at doses up to ten times higher than the human dose of Ampicillin/ sulbactam, which have not shown any negative impact on fertility or harm to the fetus. However, there are no sufficient and well-controlled studies conducted on pregnant women. As animal studies do not always predict the human response, the use of this drug during pregnancy should only be considered if it is clearly necessary.

There are no specific food warnings related to the use of Ampicillin/ sulbactam. However, it is recommended to take Ampicillin/ sulbactam with food to reduce the risk of gastrointestinal side effects such as nausea and vomiting. It is also important to avoid consuming grapefruit or grapefruit juice while taking Ampicillin/ sulbactam as it may increase the risk of side effects.

The adverse reactions related to Ampicillin/ sulbactam can be categorized as follows:

Common:

• Diarrhea
• Nausea
• Rash
• Injection site reactions
• Vomiting
• Abdominal pain

Less common:

• Headache
• Dizziness
• Fever
• Itching
• Joint pain
• Muscle pain
• Vaginal discharge or itching
• Changes in taste
• Yeast infection
• Thrush (oral yeast infection)

Rare:

• Allergic reactions (including anaphylaxis)
• Blood disorders (such as anemia, thrombocytopenia)
• Liver problems (including hepatitis, jaundice)
• Kidney problems (including interstitial nephritis)
• Seizures (particularly with high doses or in patients with kidney problems)
• Clostridium difficile-associated diarrhea (a potentially life-threatening infection of the colon)

The clinically relevant drug interactions of Ampicillin/ sulbactam are briefly summarized here:

Probenecid reduces the elimination of ampicillin and sulbactam by the renal tubules. Combining probenecid with Ampicillin/ sulbactam may lead to increased and prolonged blood levels of both drugs. Co-administration of ampicillin and allopurinol significantly increases the incidence of rashes in patients, but it is unclear whether this is due to allopurinol or the presence of hyperuricemia. No information is available regarding the concurrent use of Ampicillin/ sulbactam and allopurinol. It is not recommended to reconstitute aminoglycosides with Ampicillin/ sulbactam because the ampicillin component can inactivate aminoglycosides in vitro.

The common side effects of Ampicillin/ sulbactam include the following:

• Diarrhea
• Nausea
• Vomiting
• Rash
• Itching
• Swelling
• Hives
• Fever
• Chills
• Joint pain
• Dizziness
• Headache
• Confusion
• Seizures
• Abdominal pain
• Dark urine
• Yellowing of the skin or eyes (jaundice)
• Easy bruising or bleeding
• Unusual tiredness or weakness

• Pregnancy

Pregnancy Category B

Studies on reproductive toxicity have been conducted on mice, rats, and rabbits at doses up to ten times higher than the human dose of Ampicillin/ sulbactam, which have not shown any negative impact on fertility or harm to the fetus. However, there are no sufficient and well-controlled studies conducted on pregnant women. As animal studies do not always predict the human response, the use of this drug during pregnancy should only be considered if it is clearly necessary.

• Nursing Mothers

Caution must be taken when administering Ampicillin/ sulbactam to breastfeeding women, as the excretion of ampicillin and sulbactam into the milk is minimal.

• Pediatric Use

The use of Ampicillin/ sulbactam has been approved for skin and skin structure infections in pediatric patients who are at least one year of age, based on established safety and effectiveness in adults. The efficacy of Ampicillin/ sulbactam in pediatric patients is backed by sufficient evidence from well-controlled studies in adults, as well as additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted specifically in pediatric patients, and post-marketing surveillance of adverse events.

• Geriatric Use

Based on available clinical studies, the following are geriatric usage considerations when using Ampicillin/ sulbactam:

1. Renal function: Geriatric patients may have decreased renal function, which can affect the pharmacokinetics of Ampicillin/ sulbactam. Dose adjustments might be necessary in patients with renal impairment.
2. Neurological adverse reactions: Geriatric patients may be more susceptible to neurological adverse reactions, including convulsions, which can occur with high CSF levels of beta-lactams. Careful monitoring is necessary.
3. Hypersensitivity reactions: Geriatric patients may be more susceptible to hypersensitivity reactions, such as rash, fever, and eosinophilia. Careful monitoring is necessary.
4. Drug interactions: Geriatric patients may be taking multiple medications, which can increase the risk of drug interactions. Careful consideration of potential drug interactions is necessary when prescribing Ampicillin/ sulbactam to geriatric patients.

Convulsions and other neurological adverse reactions may be observed when high cerebrospinal fluid levels of beta-lactams are achieved. Hemodialysis can remove ampicillin from circulation. Sulbactam's pharmacokinetic profile, molecular weight, and protein binding suggest that this compound may also be eliminated by hemodialysis.

• Pharmacodynamic

The pharmacodynamics of Ampicillin/ sulbactam involve the synergistic action of ampicillin and sulbactam. Ampicillin is a beta-lactam antibiotic that inhibits bacterial cell wall synthesis by binding to and inhibiting penicillin-binding proteins, which are responsible for cross-linking peptidoglycan strands in the cell wall. Sulbactam is a beta-lactamase inhibitor that protects ampicillin from degradation by beta-lactamase enzymes produced by some bacteria. This allows ampicillin to remain active against bacteria that produce beta-lactamase enzymes.

The combination of ampicillin and sulbactam has been shown to have a synergistic effect, meaning that the combination is more effective than either the drug alone. This is thought to be due to the ability of sulbactam to protect ampicillin from degradation by beta-lactamase enzymes, which allows ampicillin to bind more effectively to penicillin-binding proteins and inhibit bacterial cell wall synthesis.

The pharmacodynamics of Ampicillin/ sulbactam also involve the concentration of the drug at the site of infection. Both ampicillin and sulbactam are distributed widely throughout the body, including into tissues and fluids such as cerebrospinal fluid. The concentration of the drug at the site of infection is important because it determines the efficacy of the drug in treating the infection.

• Pharmacokinetics
• Peak Serum Concentrations: After a 15-minute intravenous infusion of Ampicillin/ sulbactam, peak serum concentrations of ampicillin as well as sulbactam are attained. Ampicillin serum levels are similar to those produced by the administration of equivalent amounts of ampicillin alone.
• Urinary Excretion: Approximately 75 to 85% of both ampicillin and also sulbactam are found to be excreted unchanged in the urine during the first 8 hours after administration of Ampicillin/ sulbactam to individuals with normal renal function. The elimination kinetics of ampicillin as well as sulbactam are similarly affected in patients with impaired renal function, hence the dose of Ampicillin/ sulbactam in such patients should be administered less frequently in accordance with the usual practice for ampicillin.
• Protein Binding: Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound.
• Penetration: Penetration of both ampicillin and also sulbactam into cerebrospinal fluid in the presence of inflamed meninges has been demonstrated after IV administration of Ampicillin/ sulbactam.
• Pediatric Patients: The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving Ampicillin/ sulbactam are similar to those observed in adults.

• Therapeutic Benefits of Ampicillin/ sulbactam Combination

Clinical studies have demonstrated various therapeutic benefits of Ampicillin/ sulbactam combination. Some of the benefits observed in these studies include:

The therapeutic benefits of the Ampicillin/ sulbactam combination include:

1. Broad-spectrum activity: Ampicillin/ sulbactam has a broad-spectrum activity against Gram-negative bacteria, including those that are resistant to other antibiotics such as carbapenems and beta-lactams. It is effective against pathogens such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
2. Treatment of complicated urinary tract infections (cUTIs): Ampicillin/ sulbactam is FDA-approved for the treatment of cUTIs, including pyelonephritis (kidney infection) caused by susceptible Gram-negative bacteria. In clinical trials, it has been shown to be non-inferior to piperacillin/tazobactam, another commonly used antibiotic combination.
3. Treatment of complicated intra-abdominal infections (cIAIs): Ampicillin/ sulbactam is also FDA-approved for the treatment of cIAIs caused by susceptible Gram-negative bacteria. It has been shown to be non-inferior to piperacillin/tazobactam in clinical trials.
4. Potential use in the treatment of multidrug-resistant infections: Ampicillin/ sulbactam has shown activity against some bacteria that are resistant to other antibiotics, including carbapenems and beta-lactams. This makes it a potential treatment option for multidrug-resistant infections.
5. Reduced risk of development of resistance: Sulbactam, one of the components of the combination, is a beta-lactamase inhibitor that protects ampicillin from degradation by beta-lactamase enzymes produced by some bacteria. This reduces the risk of the development of resistance to ampicillin.

It is important to note that the use of Ampicillin/ sulbactam should be based on local susceptibility patterns and prescribing guidelines, and that appropriate diagnostic tests should be performed before initiating therapy.

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