Ampicillin (ampicillin trihydrate 250 mg) Dailymed

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ampicillin capsules, Ampicillin for Oral Suspension and other antibacterial drugs, Ampicillin Capsules and Ampicillin for Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description

Ampicillin trihydrate is a semisynthetic penicillin derived from the basic penicillin nucleus, 6-aminopenicillanic acid. Ampicillin is designated chemically as (2S, 5R, 6R)-6-[(R)-2-Amino-2-phenylacetamido]-3, 3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate.

It has the following chemical structure:

The molecular formula is C₁₆H₁₉N₃O₄S.3H₂O, and the molecular weight is 403.45.

Ampicillin Capsules, USP for oral administration provide ampicillin trihydrate equivalent to 250 mg and 500 mg ampicillin. Ampicillin Capsules also contain magnesium stearate. The capsule shell contains black iron oxide, D&C red No. 28, FD&C blue No. 1, gelatin, silicon dioxide, sodium lauryl sulfate, and titanium dioxide.

Ampicillin for Oral Suspension, USP provides ampicillin trihydrate equivalent to 125 mg/5 mL and 250 mg/5 mL ampicillin. Ampicillin for Oral Suspension also contains carboxymethylcellulose sodium, colloidal silicon dioxide, flavors, microcrystalline cellulose, sodium citrate, sodium propionate, and sucrose.

Clinical Pharmacology

Ampicillin is bactericidal at low concentrations and is clinically effective not only against the gram-positive organisms usually susceptible to penicillin G but also against a variety of gram-negative organisms. It is stable in the presence of gastric acid and is well absorbed from the gastrointestinal tract. It diffuses readily into most body tissues and fluids; however, penetration into the cerebrospinal fluid and brain occurs only with meningeal inflammation. Ampicillin is excreted largely unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid which inhibits the renal tubular secretion of ampicillin. In blood serum, ampicillin is the least bound of all the penicillins; an average of about 20 percent of the drug is bound to the plasma proteins as compared to 60 to 90 percent of the other penicillins. The administration of a 500 mg dose of ampicillin trihydrate capsules results in an average peak blood serum level of approximately 3.0 mcg/mL; the average peak serum level for a 250 mg dose of ampicillin trihydrate for oral suspension is approximately 2.3 mcg/mL.

Microbiology:

Mechanism of Action

Ampicillin is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria.

Mechanism of Resistance

Resistance to ampicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of ampicillin, rendering it inactive.

Antimicrobial Activity

Ampicillin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

  Gram-Positive Bacteria	  Gram-Negative Bacteria
  Enterococcus spp.	  Escherichia coli
  Staphylococcus spp. (non-penicillinase-producing)	  Haemophilus influenza (non-penicillinase-producing)
  Streptococcus pneumoniae	  Neisseria gonorrhoeae
  Streptococcus pyogenes	  Neisseria meningitidis
  Viridans group streptococci	  Proteus mirabilis
Â	  Salmonella spp.
Â	  Shigella spp.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.12 mcg/mL for ampicillin. However the efficacy of ampicillin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled trials.

  Gram-Positive Bacteria	  Anaerobic Bacteria
  Bacillus anthracis Corynebacterium xerosis	  Clostridium spp.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method^1,3 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. ^2,3 This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of bacteria to ampicillin. The disk diffusion interpretive criteria are provided in Table 1.

Susceptibility to ampicillin of Staphylococcus spp., may be inferred by testing penicillin.³Â  Perform test(s) to detect beta-lactamase production on staphylococci for which the penicillin MICs are ≤ 0.12 mcg/mL or zone diameters are ≥ 29 mm before reporting isolates as penicillin susceptible. Rare isolates of staphylococci that contain genes for beta-lactamase production may appear negative by beta-lactamase tests. Consequently, for serious infections requiring penicillin therapy, laboratories should perform MIC tests and beta-lactamase testing on all subsequent isolates from the same patient. PCR testing of the isolate for the blaZ beta-lactamase gene may be considered.³

Susceptibility to ampicillin of Streptococcus pneumoniae (non-meningitis isolates), may be inferred by testing penicillin or oxacillin. Non-meningitis isolates with a penicillin MIC ≤0.06 mcg/mL or oxacillin zone size ≥20 mm can be considered susceptible to ampicillin.³

Table 1: Susceptibility Test Interpretive Criteria for Ampicillin

Â	  Minimum Inhibitory Concentrations (mcg/mL)			  Disk Diffusion (zone diameters in mm)
  Pathogen	  S	  I	  R	  S	  I	  R
  Enterobacteriaceae	  ≤8	  16	  ≥32	  ≥17	  14-16	  ≤13
  Haemophilus influenzae a	  ≤1	  2	  ≥4	  ≥22	  19-21	  ≤18
  Enterococcus b spp.	  ≤8	  -	  ≥16	  ≥17	  -	  ≤16
  Neisseria meningitidis	  ≤0.12	  0.25-1	  ≥2	  -	  -	  -
  Viridans group streptococci	  ≤0.25	  0.5-4	  ≥8	  -	  -	  -
  Streptococcus pyogenesc	  ≤0.25	  -	  -	  ≥24	  -	  -
  S = Susceptible; I = Intermediate; R = Resistant

^a.          The majority of isolates of H. influenzae that are resistant to ampicillin produce a TEM-type beta-lactamase. In most cases, a direct beta-lactamase test can provide a rapid means of detecting resistance to ampicillin.<sup>3

b.</sup>          Penicillin or ampicillin resistance among enterococci due to beta-lactamase production has been reported very rarely. Penicillin or ampicillin resistance due to beta-lactamase production is not reliably detected with routine disk or dilution methods, but is detected using a direct, nitrocefin-based beta-lactamase test. Because of the rarity of beta-lactamase-positive enterococci, this test need not be performed routinely, but can be used in selected cases. A positive beta-lactamase test predicts resistance to penicillin as well as amino- and ureidopenicillins<sup>.3

c.</sup>          Susceptibility testing of ampicillin need not be performed routinely because nonsusceptible isolates of beta-hemolytic streptococci are extremely rare, and have not been reported for S. pyogenes. If testing is performed, any beta-hemolytic streptococcus isolate that is found to be non-susceptible should be re-identified retested, and if confirmed, reported to the public health laboratory.³

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection.  A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. ^1,2,3 Standard Ampicillin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 10 mcg ampicillin disk, the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Ampicillin ³

  QC strain	  Minimum Inhibitory Concentration(mcg/mL)	  Zone Diameter(mm)
  Escherichia coli ATCC* 25922	  2 – 8	  15 – 22
  Enterococcus faecalis ATCC 29212	  0.5 – 2	  -
  Haemophilus influenzae ATCC 49247	  2 – 8	  13 – 21
  Klebsiella pneumoniae ATCC 700603	>128Â	-
  Staphylococcus aureus ATCC 29213	  0.5 – 2	  -
  Staphylococcus aureus ATCC 25923	  -	  27 - 35
  Streptococcus pneumoniae ATCC 49619	  0.06 – 0.25	  30 – 36
  * ATCC = American Type Culture Collection