Clindamycin Resistance

Clindamycin has been used for the treatment of anaerobic infection since the 1960s. Resistance to clindamycin among anaerobes has slowly increased over time. The frequencies of resistance among anaerobes in the B. fragilis group in the U.S.A. was 3% in 1987, and increased to 16%, 26%, and 43% in 1996, 2000, and 2003, respectively (15-18). However, resistance at some locations reached 44% (19). Results from one medical center cannot predict those at other centers as resistance to clindamycin in individual site varies. Surveillance of local resistance is essential in assessing the utility of clindamycin at a certain location. Resistance to clindamycin among Prevotella Porphyromonas, Fusobacterium, and Peptostreptococcus spp. is generally lower and is often less than 10% (20). The anaerobe, most resistant to clindamycin is Clostridium difficile with up to 67% of isolates resistant (21).

These are three mechanisms of resistance: inactivation of the drug, altered permeability, and changed ribosomal target site (22,23). Several genetic clindamycin resistance determinants were identified in the B. fragilis group (ermF, ermG, and ermS), C. perfringens (ermQ and ermP), C. difficile (ermZ, ermB, and ermBZ), and Porphyromonas, Prevotella, Peptostreptococcus, and Eubac-terium spp. (ermF) (24). These determinants are located on the chromosome, plasmids, or transposons and are transferable by conjugation for both B. fragilis and C. difficile. Resistance is mediated by a macrolide-lincosamide-streptogramin (MLS) type 23S RNA methylase at one of two adenine residues (25,26), which prevents binding of clindamycin to the ribosomes and makes them resistant. The same mechanism of resistance was detected in Bacteroides spp. Ribosomes isolated from a clindamycin resistance Bacteroides vulgatus strain, induced with either clindamycin or erythromycin, decreased susceptibility to clindamycin compared with ribosomes isolated from a clindamycin-susceptible strain or a strain with clindamycin resistance that was not induced (25,27). These data illustrate that resistance to clindamycin is at the ribosomal level and probably occurs via methylation of the rRNA.

Three different, but closely related, MLS resistance genes were cloned from various Bacteroides strains. These genes exist within a transposon or on a conjugal element: ermF is encoded on Tn4351, ermFS is encoded on Tn4551, and ermFU is encoded on a B. vulgatus conjugal element (28-30). Their encoded proteins have sequence identities similar to those of the MLS resistance genes from gram-positive organisms (28-30). Most clindamycin-resistant Bacteroides harbor an erm gene related to one these genes. However, not all clindamycin-resistant Bacteroides contain DNA sequences that crosshybridize with the ermF gene (31-33), suggesting that another unrelated MLS resistance gene or another mechanism of resistance also exists.

Clindamycin resistance can be inducible and also constitutive. Conjugal transfer of clindamycin resistance is plasmid-mediated with a frequent cotransfer of tetracycline resistance (34-36). These plasmids are mostly self-transmissible and vary in size from 14.6 kilobases (kb; pBFTM 10) to 41 kb (pIP411 and pBF4; 35) to -82 kb (pBI136) (37). These clindamycin resistance genes are carried on transposons Tn4400 and Tn4351 (38,39). Chromosomal resistance to clindamycin has identified and was also linked with resistance to tetracycline; and the clindamycin resistance gene was found to exist within the tetracycline resistance transfer element (39-41).

Because of the rapid increase in the prevalence of clindamycin resistance, especially among the B. fragilis group, it is no longer considered to be a first-line agent for anaerobic infections

TABLE 2 Susceptibility of Gram-Negative Anaerobic Bacteria

Percentage susceptible toa

TABLE 2 Susceptibility of Gram-Negative Anaerobic Bacteria

Percentage susceptible toa

Anaerobe

Less than 50

50-69

70 84

85-95

More than 95

Peptostreptococcus spp.

LOM

FLE

CIP

LVX

PEN

CTT

MEM

TET

OFX

CLI

PIP

FOX

CHL

ROX

AZM

MIN

AMC

CAZ

CLX

CLR

SAM

ZOX

SIT

ERY

TZP

CRO

SPX

TIM

BIA

TVA

CFP

IPM

MND

CPS

Clostridium difficilef

FOX

CLI

CRO

AMP

TZP

CLX

ZOX

MIN

BIA

PIP

TIM

SIT

CIP

TET

CHL

TIC

CTT

TVA

FLE

AZM

AMC

IPM

MND

LOM

CLR

SAM

MEM

SPX

ERY

ROX

Clostridium ramosum

CIP

SPX

FOX

AMP

AMC

ZOX

SIT

FLE

MIN

PIP

TZP

IPM

MND

LOM

TET

SAM

TIM

CLX

AZM

CHL

CLR

TVA

ERY

CLI

ROX

Clostridium perfringens

TET

MIN

LOM

AMP

ZOX

SPX

CLI

PIP

BIA

TVA

TIC

IPM

MND

SAM

CHL

AZM

AMC

CIP

CLR

TZP

CLX

ERY

TIM

SIT

ROX

CTT

FLE

Other Clostridium spp.

CAZ

CFP

LVZ

MOX

AMX

TIC

CLX

FLE

CTX

OFX

AMP

SAM

SIT

LOM

FOX

SPX

CAR

AMC

TVA

ZOX

CLI

PEN

BIA

MND

CRO

TET

PIP

IPM

MIN

CIP

CHL

AZM

CLR

ERY

ROX

Non-spore-forming gram-positive rod

FLE

CIP

CFP

CTT

PEN

FTX

CLI

LOM

OFX

MOX

FOX

PIP

ZOX

CLX

MND

SPX

CRO

AMC

BIA

SIT

TET

CPS

SAM

IPM

LVX

TVA

TZP

MEM

MIN

AZM

TIM

CHL

CLR

ERY

ROX

a The order of listing of drugs within percent susceptible categories is not significant. According to the national committee for clinical laboratory standards -approved breakpoints (M11-A3), using the intermediate category as susceptible. b Breakpoint is used only as a reference point. Clostridium difficile is primarily of interest in relation to antimicrobial induced pseudomembranous colitis. These data must be interpreted in the context of level of drug achieved in the colon and impact of agent on indigenous colonic flora.

Abbreviations: AMC, amoxicilin/clavulanate; AMP, ampicillin; AMX, amoxicillin; AZM, azithromycin; BIA, biapenem; CAZ, ceftazidime; CFP, cefoperazone; CHL, chloramphenicol; CIP, ciprofloxacin; CLI, clindamycin; CLR, clarithromycin; ClX, clinafloxacin; CPS, cefoperazone/-sulbactam; CRO, ceftriaxone; CTT, cefotetan; CTX, cefotaxime; ERY, erythromycin; FLE, fleroxacin; FOX, cefoxitin; IPM, imipenem; LOM, lomefloxacin; LVX, levofloxacin; MEM, meropenem; MIN, minocycline; MND, metronidazole; mOx, moxalactam, OfX, ofloxacin; PEN, penicillin; PIP, piperacillin; ROX, roxithromycin; SAM, ampicillin/sulbactam; SIT, sitafloxacin; SpX, sparfloxacin; TEM, temafloxacin; TET, tetracycline; TIC, ticarcillin; TIM, ticarcillin/clavulanate; TVA, trovafloxacin; TZP, piperacillin/tazobactam; ZOX, ceftizoxime. Source: From Ref. 13

due to these organisms (42). Clindamycin can still be considered when treating AGNB with known susceptibilities or other mixed infections that do not harbor or are not likely to harbor these bacteria, such as oral, upper and lower respiratory tract infections (URTIs) and lower.

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