Sulfamethoxazole and Trimethoprim (sulfamethoxazole 800 mg trimethoprim 160 mg) Dailymed

Clinical Pharmacology Section

Sulfamethoxazole and trimethoprim is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N

₄

-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3’- and 4’-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

 

Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see

DOSAGE AND ADMINISTRATION

section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68 mcg/mL, respectively. These steady-state levels were achieved after three days of drug administration.

¹

Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5%  for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N

₄

-acetylated metabolite.

²

When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.

 

Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk.

 

The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-U.S. approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.

³

 

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.

In vitro

studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.

 

Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both

in vitro

and in clinical infections as described in the

INDICATIONS AND USAGE

section.

 

Streptococcus pneumoniae

 

Escherichia coli

(including susceptible enterotoxigenic strains implicated in traveler's diarrhea)

Klebsiella

species

Enterobacter

species

Haemophilus influenzae

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Shigella flexneri

Shigella sonnei

 

Pneumocystis jiroveci

 

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 procedure. Standardized procedures are based on a dilution method

⁴

(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sulfamethoxazole and trimethoprim powder. The MIC values should be interpreted according to the following criteria:

 

For testing

Enterobacteriaceae:

      MIC (mcg/mL)                         Interpretation

      ≤2/38                                       Susceptible (S)

      ≥4/76                                       Resistant (R)

When testing either

Haemophilus influenzae

^a

or

Streptococcus pneumoniae

^b

:

      MIC (mcg/mL)                         Interpretation

^b

      ≤0.5/9.5                                   Susceptible (S) 

      1/19-2/38                                 Intermediate (I)

      ≥4/76                                       Resistant (R)

^a.

These interpretative standards are applicable only to broth microdilution susceptibility tests with

Haemophilus influenzae

using

Haemophilus

Test Medium (HTM).

<sup>4

b.</sup>

These interpretative standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.

⁴

 

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

 

Quality Control

 

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard sulfamethoxazole and trimethoprim powder should provide the following range of values:

 

      Microorganism                                                                 MIC (mcg/mL)

      Escherichia coli                      

ATCC  25922                      ≤0.5/9.5

      Haemophilus influenzae

^c           

ATCC 49247               0.03/0.59 – 0.25/4.75

      Streptococcus pneumoniae

^d   

ATCC 49619                 0.12/2.4 – 1/19

^c.

 This quality control range is applicable only to

Haemophilus influenzae

ATCC 49247 tested by broth microdilution procedure using

Haemophilus

Test Medium (HTM).

<sup>4

d.</sup>

 This quality control range is applicable to tests performed by the broth microdilution method only using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.

⁴

 

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure

⁵

requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 1.25/23.75 mcg of sulfamethoxazole and trimethoprim to test the susceptibility of microorganisms to sulfamethoxazole and trimethoprim.

 

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 1.25/23.75 mcg of sulfamethoxazole and trimethoprim disk should be interpreted according to the following criteria:

 

For testing either

Enterobacteriaceae

or

Haemophilus

influenzae

^e

:

      Zone Diameter (mm)                    Interpretation

               ≥16                                    Susceptible (S)

           11 – 15                                  Intermediate (I)

               ≤10                                    Resistant (R)

^e.

These zone diameter standards are applicable only for disk diffusion testing with

Haemophilus influenzae

and

Haemophilus

Test Medium (HTM).

⁵

 

When testing

Streptococcus pneumoniae

^f

:

      Zone Diameter (mm)                 Interpretation

               ≥19                                 Susceptible (S)

           16 – 18                               Intermediate (I) 

               ≤15                                Resistant (R)

^f.

These zone diameter interpretative standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated in 5% CO

_2.

⁵

 

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for sulfamethoxazole and trimethoprim.

 

Quality Control

 

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 1.25/23.75 mcg sulfamethoxazole and trimethoprim disk* should provide the following zone diameters in these laboratory test quality control strains:

 

      Microorganism                                                             Zone Diameter Ranges (mm)

      Escherichia coli                        

ATCC 25922                         23–29

      Haemophilus influenzae

^g         

    

ATCC 49247                         24–32

      Streptococcus pneumoniae

^h  

   

ATCC 49619                         20–28

* Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an

Enterococcus

faecalis

(ATCC 29212 or ATCC 33186) may be tested with sulfamethoxazole and trimethoprimdisks. A zone of inhibition ≥20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

^g.

This quality control range is applicable only to

Haemophilus influenzae

ATCC 49247 tested by a disk diffusionprocedure using

Haemophilus

Test Medium (HTM).

<sup>5

h.</sup>

This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated in 5% CO

_2.

⁵