Clindamycin Hydrochloride

CLINDAMYCIN HYDROCHLORIDE- clindamycin hydrochloride capsule
Mylan Institutional Inc.

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

WARNING

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin hydrochloride and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.
Because clindamycin hydrochloride therapy has been asso‑ciated with severe colitis which may end fatally, it should be reserved for serious infec‑tions where less toxic antimicrobial agents are inappropriate, as described in the INDICA‑TIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections.
C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

DESCRIPTION

Clindamycin hydrochloride is the hydrated hydrochlo‑ride salt of clindamycin. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin.
The chemical name for clindamycin hydrochloride is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl- trans -4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L- threo -α-D- galacto -octopyranoside monohydrochloride. The structural formula is represented below:

Chemical Structure
(click image for full-size original)

Clindamycin hydrochloride capsules, USP contain clindamycin hydro‑chloride USP equivalent to 150 mg or 300 mg of clindamycin. Each capsule also contains the following inactive ingredients: lactose monohydrate, corn starch, talc, and magnesium stearate. The empty hard gelatin capsule shell consists of FD&C Blue #1, titanium dioxide, gelatin, and sodium lauryl sulphate. In addition 150 mg also contains yellow iron oxide. The capsules are printed with edible ink containing black iron oxide and shellac.

CLINICAL PHARMACOLOGY

Human Pharmacology

Absorption

Serum level studies with a 150 mg oral dose of clindamycin hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.5 mcg/mL was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.7 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and the concomitant admin‑istration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum level studies following multiple doses of clindamycin hydrochloride for up to 14 days show no evidence of accumulation or altered metabolism of drug. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses.

Distribution

Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indi‑cated organisms for at least six hours following adminis‑tration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges.
Metabolism
In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly metabolized by Cytochrome P450 3A4 (CYP3A4), with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin. Excretion

The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bioinactive metabolites.

Special Populations

Renal Impairment

Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Use in Elderly

Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimi‑nation half-life is increased to approximately 4 hours (range 3.4 to 5.1 h) in the elderly compared to 3.2 hours (range 2.1 to 4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function 1.

Microbiology

Mechanism of Action

Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic.

Resistance

Resistance to clindamycin is most often caused by modification of specific bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete. Because the binding sites for these antibacterial drugs overlap, cross-resistance is sometimes observed among lincosamides, macrolides and streptogramin B. Macrolide-inducible resistance to clindamycin occurs in some isolates of macrolide-resistant bacteria. Macrolide-resistant isolates of staphylococci and beta-hemolytic streptococci should be screened for induction of clindamycin resistance using the D-zone test.

Antimicrobial Activity

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

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains)

Streptococcus pneumoniae (penicillin-susceptible strains)

Streptococcus pyogenes

Anaerobic Bacteria

Clostridium perfringens

Fusobacterium necrophorum

Fusobacterium nucleatum

Peptostreptococcus anaerobius

Prevotella melaninogenica

At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 1. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible strains)

Streptococcus agalactiae

Streptococcus anginosus

Streptococcus mitis

Streptococcus oralis

Anaerobic Bacteria

Actinomyces israelii

Clostridium clostridioforme

Eggerthella lenta

Finegoldia (Peptostreptococcus) magna

Micromonas (Peptostreptococcus) micros

Prevotella bivia

Prevotella intermedia

Propionibacterium acnes

Susceptibility Testing Methods

When available, the clinical microbiology laboratory should provide cumulative 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 antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentra‑tions (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 2,3 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require the measurement of zone diameters can also provide reproducible estimates of the susceptibility of bac‑teria to antimicrobial compounds. The zone size should be determined using a standardized method 2,5. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of bacteria to clindamycin. The disk diffusion breakpoints are provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to clindamycin can be determined by a standardized test method 2,4. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table 1. Susceptibility Test Interpretive Criteria for Clindamycin
NA=not applicable

Pathogen

Susceptibility Interpretive Criteria

Minimal Inhibitory Concentrations (MIC in mcg/mL)

Disk Diffusion (Zone Diameters in mm)

S

I

R

S

I

R

Staphylococcus spp.

≤0.5

1 to 2

≥4

≥21

15 to 20

≤14

Streptococcus pneumoniae and other Streptococcus spp.

≤0.25

0.5

≥1

≥19

16 to 18

≤15

Anaerobic Bacteria

≤2

4

≥8

NA

NA

NA

A report of Susceptible (S) indicates that the antimicrobial drug 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 (I) indicates that the result should be considered equivocal, and, if the microorgan‑ism is not fully susceptible to alternative, clinically feasi‑ble 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 that prevents small, uncon‑trolled technical factors from causing major discrepan‑cies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. 2,3,4,5 Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved.

Table 2. Acceptable Quality Control Ranges for Clindamycin
1. Enterococcus faecalis has been included in this table for quality control purposes only. 2. Quality control for C. difficile is performed using the agar dilution method only, all other obligate anaerobes may be tested by either broth microdilution or agar dilution methods. NA=Not applicable ATCC ® is a registered trademark of the American Type Culture Collection

QC Strain

Acceptable Quality Control Ranges

Minimum Inhibitory Concentration Range (mcg/mL)

Disk Diffusion Range (Zone Diameters in mm)

Enterococcus faecalis 1 ATCC 29212

4 to 16

NA

Staphylococcus aureus ATCC 29213

0.06 to 0.25

NA

Staphylococcus aureus ATCC 25923

NA

24 to 30

Streptococcus pneumoniae ATCC 49619

0.03 to 0.12

19 to 25

Bacteroides fragilis ATCC 25285

0.5 to 2

NA

Bacteroides thetaiotaomicron ATCC 29741

2 to 8

NA

Clostridium difficile 2 ATCC 700057

2 to 8

NA

Eggerthella lenta ATCC 43055

0.06 to 0.25

NA

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