Grazieli Maboni and Leticia Trevisan Gressler Lincosamides, pleuromutilins, and streptogramins are structurally distinct classes of antimicrobials, but share many common properties. They are basic compounds characterized by high lipid solubility, high volume of distribution, and capacity to penetrate cellular barriers. In addition, along with macrolides, their mechanism of action shares overlapping binding sites on the 50S subunit of the ribosome. Lincomycin, the parent compound, was isolated in 1962 from the fermentation of Streptomyces spp. lincolnensis ssp. lincolnensis found in a soil sample in Lincoln, Nebraska (Bryskier, 2005). In 1967, lincomycin was licensed in the United States for the treatment of infections caused by Gram‐positive bacteria. Although approved for use in human medicine, lincomycin is rarely used nowadays. In veterinary medicine, lincomycin is approved for use to treat various infections in swine, chickens, dogs, and cats. Many modifications of the lincomycin molecule have been developed in an attempt to produce an improved antimicrobial. Of these, only clindamycin showed distinct advantages over lincomycin, and it is the main lincosamide used in small animal clinical practice. Pirlimycin, a clindamycin analogue, is also approved as an intramammary infusion for the treatment of intramammary infections in cattle. The chemical structures of lincomycin and clindamycin are displayed in Figure 11.1. The lincosamides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and inhibiting peptidyl transferases. The ribosomal binding sites are the same as or closely related to those that bind macrolides, streptogramins, and chloramphenicol. Lincosamides can be bactericidal or bacteriostatic, depending on the drug concentration, bacterial species, and inoculum of bacteria. Lincosamides are moderate‐spectrum antimicrobial drugs. They are active against Gram‐positive bacteria, anaerobic bacteria, and some mycoplasmas. They lack activity against most Gram‐negative bacteria. Clindamycin is several times more active than lincomycin, especially against anaerobes and S. aureus. Clindamycin is used to test for in vitro susceptibility to lincomycin against most staphylococcal strains (CLSI, 2018). Figure 11.1 Chemical structure of lincomycin and clindamycin. Clindamycin has activity against some protozoa such as Toxoplasma gondii and Plasmodium falciparum. It has some activity against Pneumocyctis jiroveci associated with Pneumocystis pneumonia (Li et al., 2016). Clindamycin is a first‐line drug of choice of Capnocytophaga canimorsus infections in humans (Jolivet‐Gougeon et al., 2007). All aerobic Gram‐negative rods, Nocardia spp., Clostridioides difficile, and Mycobacterium spp. Lincosamides are also inactive against Enterococcus spp. Clindamycin may appear active in vitro, but is not effective clinically against Enterococcus faecalis, Enterococcus faecium, and Enterococcus gallinarum/E. casseliflavus (CLSI, 2018). Bacterial resistance to lincosamides can be a result of the acquisition of endogenous mutations or horizontally transmitted resistance genes (Schwarz et al., 2006). The mechanisms of resistance known so far fall into three categories: modification of the antibiotics by specific enzymes, active efflux from the bacterial cell, and methylation of 23S ribosomal RNA. Enzymatic inactivation is often mediated by nucleotidyltransferases encoded by the lnu(A‐F) genes (Schwarz et al., 2016), which show highest activity against lincomycin, moderate activity against pirlimycin, and lowest activity against clindamycin. Resistance by active efflux can occur via both multidrug and specific transporter systems. In most bacterial strains, resistance to lincosamides is by structural ribosomal changes as a result of methylation of adenine residues in the 23S ribosomal RNA of the 50S ribosomal subunit, which prevents drug binding to the target site. The rRNA methylases are encoded by a series of structurally related erythromycin‐resistant methylase (erm) genes. Many of the resistance genes known so far that confer lincosamide resistance are located on mobile genetic elements, which facilitate their rapid dissemination. The erm genes, as an example, are acquired through mobile elements and can be located on the bacterial chromosome or on plasmids (Schwarz et al., 2016). Resistance can develop to the lincosamides alone but more commonly cross‐resistance occurs among macrolides, lincosamides, and streptogramin group B antibiotics (MLSB resistance). This can occur by spontaneous point mutations in the genes coding for the ribosomal peptidyltransferase loop since these antimicrobials have partly overlapped binding sites. In some instances, cross‐resistance may also include ketolides (phenotype referred to as MLSK resistance) and oxazolidinones (MSLKO) antimicrobials. Cross‐resistance is not always present, and its occurrence depends on the mechanism of cross‐resistance. This cross‐resistance is of two types: (1) constitutive resistance (MLSBc), where bacteria show high‐level resistance to all MLSB antimicrobials; and (2) dissociated inducible cross‐resistance (MLSBi), in which bacteria resistant to macrolides but initially fully susceptible to clindamycin rapidly develop resistance to lincosamides when exposed to macrolides. Constitutive resistant mutants are rapidly selected from the inducible strains during treatment with either lincosamides or macrolides. Constitutive resistance may be more common among bacteria isolated from food animals fed tylosin or virginiamycin as growth promoters. MLSBc isolates are readily recognized during in vitro susceptibility testing as being resistant to both macrolides and clindamycin. However, MLSBi resistance is not detected by standard in vitro susceptibility testing methods. Such isolates appear resistant to macrolides but susceptible to clindamycin under standard testing conditions. As a result, isolates that are resistant to macrolides but susceptible to clindamycin should also be tested for methylase‐mediated clindamycin resistance by an additional assay, the D‐zone test (Lewis and Jorgensen, 2005); this includes isolates of Staphylococcus spp., Streptococcus spp. beta‐hemolytic group, and Streptococcus pneumoniae (CLSI, 2018). To perform a D‐test, an agar plate is inoculated with the bacteria in question and two drug‐impregnated disks (one with erythromycin, one with clindamycin) are placed on the plate. If the area of inhibition around the clindamycin disk is “D” shaped, the test result is positive and indicates inducible clindamycin resistance; therefore, it should not be used due to the possibility of resistance and therapy failure. If the area of inhibition around the clindamycin disk is circular, the test result is negative and clindamycin can be used (Woods, 2009). Intrinsic resistance to lincosamides is generally seen in Gram‐negative bacteria because of impermeability and methylation of the ribosomal binding site of lincosamides. E. coli, Haemophilus influenzae, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, and Salmonella are typical representatives of Gram‐negative bacteria intrinsically resistant to lincosamides (Spížek and Řezanka, 2017). Lincosamides are basic compounds with pKa values of about 7.6. They have high lipid solubility and consequently large apparent volumes of distribution. They are well absorbed from the intestine of nonherbivores and eliminated mainly by hepatic metabolism, although about 20% is eliminated in the active form via the urine. Clindamycin is hydrolyzed in the liver to at least seven metabolites. All metabolites but one are devoid of antibacterial activity. Tissue concentrations consistently exceed serum concentrations by several times because of passage across cell membranes. Because of the lincosamide’s basic character, ion trapping also occurs in tissues, such as the udder and prostate where pH is lower than blood. Extensive binding to plasma proteins and relatively rapid elimination prevents concentrations in cerebrospinal fluid (CSF) from exceeding 20% of serum concentrations. Clindamycin achieves therapeutic concentrations in bone, although levels are relatively low, around 10–30% of serum concentrations. Clindamycin is commonly combined with an aminoglycoside or a fluoroquinolone in human medicine to treat or prevent mixed aerobic‐anaerobic bacterial infections, particularly those associated with intestinal spillage into the peritoneum. The combination generally has additive or synergistic effects in vitro against a wide range of bacteria. Combination with spectinomycin appears to give marginally enhanced activity against mycoplasmas in vitro. Clindamycin has synergistic effects with metronidazole against B. fragilis but only additive effects with trimethoprim‐sulfamethoxazole against common Gram‐negative or Gram‐positive aerobes. Lincosamides, macrolides or chloramphenicol/florfenicol should not be used simultaneously given that the similar mechanism of action may cause antagonism and possible cross‐resistance. The major adverse effect of lincosamides is their ability to cause serious and fatal diarrhea in humans, horses, rabbits, and other herbivores. In humans, mild diarrhea follows the use of lincosamides in up to 10% of patients, but in some (0–2.5% of those treated) this may become severe, resulting in pseudomembranous colitis. This is caused by the rapid colonic overgrowth of Clostridiodes difficile, which is intrinsically resistant to lincosamides. C. difficile overgrowth may cause destruction of competing anaerobic microflora of the colon, leading to profound shock, dehydration, and death. Less serious adverse effects in humans include depressed neuromuscular transmission and postanesthetic paralysis, depression of cardiac muscle after rapid IV injection, mild liver damage, drug rashes, urticaria, and metallic taste. In cattle, oral administration of lincomycin at concentrations as low as 7.5 parts per million (ppm) in feed resulted in inappetence, diarrhea, ketosis, and decreased milk production (Plenderleith, 1988). Inadvertent contamination of feed with 8–10 ppm of lincomycin and 40 ppm of metronidazole caused some affected cows to develop severe diarrhea and to lose consciousness. Pirlimycin is generally safe and nonirritating to the bovine udder, but extended‐duration therapy with repeated infusions may increase the potential for intramammary infections due to environmental bacteria. Adverse reactions including clinical signs of mastitis (udder swelling and abnormal milk) and increased somatic cell counts following extended therapy with pirlimycin have been reported. Adverse reactions can be associated with failure to thoroughly clean quarters and to use aseptic infusion technique. In ewes, oral administration of lincomycin at a dosage of 225 mg/day resulted in severe enterocolitis leading to death in 2000 of 3000 exposed animals (Bulgin, 1988). In horses, lincosamides administered by parenteral or oral route can cause severe enterocolitis, which may be fatal. In one inadvertent mixing of lincomycin in horse feed, a dose of 0.5 mg/kg caused an outbreak of diarrhea in which one horse died (Raisbeck et al., 1981). In pigs, anal swelling, diarrhea, irritable behavior, and skin reddening have been reported, but these signs are generally self‐limiting within 5–8 days. Lincosamides are highly toxic to rabbits, guinea pigs, and hamsters. Concentrations as low as 8 ppm accidentally added to feed have been followed by severe and fatal cecocolitis in rabbits. In rabbits, the effect is the result of bacterial overgrowth in the large bowel of C. difficile or C. spiroforme (Morris, 1995). Lincomycin is relatively nontoxic to dogs and cats. Anorexia, vomiting, and diarrhea have sometimes occurred, especially with oral use. In cats, clindamycin can be associated with a localized esophagitis and stricture formation if retained in the esophagus after administration; therefore, it is recommended to give food or water after administering the medication (Beatty et al., 2007). Anaphylactic shock has been reported after IM injection. Because of their peripheral neuromuscular blocking and cardiac depressive effects, lincosamides should not be given with anesthetics or by rapid IV injection. Clindamycin given IM is very painful. The use of lincosamides during pregnancy of dogs and cats is reported to be safe (Rebuelto and Loza, 2010). After oral administration to monogastric animals, lincomycin is generally absorbed well and clindamycin is absorbed almost completely. Food significantly reduces absorption of both drugs, especially lincomycin. Complete absorption occurs from IM injection sites. Clindamycin palmitate, available as a syrup for oral administration, is rapidly hydrolyzed in the intestine before absorption. The drug is also available in capsules as the hydrochloride for oral administration and as the phosphate for IM, SC, or IV injection. The SC route is superior to the IM route in terms of local tolerance and serum concentrations. Lincomycin is available as the hydrochloride for PO, IM, and IV administration. The dosage should be reduced in patients with hepatic insufficiency. Lincosamides are used in the treatment of staphylococcal infections (dermatitis, osteomyelitis) caused by penicillin G‐resistant organisms, for other Gram‐positive aerobic infections in penicillin‐sensitive individuals, and in the treatment of anaerobic infections. Lincomycin may have more adverse effects than clindamycin and is therefore no longer used as often. Clindamycin has excellent activity against anaerobes, equivalent to alternatives such as cefoxitin, chloramphenicol, and metronidazole. Clindamycin may be combined with an aminoglycoside or a fluoroquinolone in the treatment of mixed anaerobic infections. Clindamycin may be preferable to penicillin G or ampicillin in the treatment of streptococcal toxic shock syndrome, since it better inhibits superantigen synthesis (Laho et al., 2021). Lincosamides penetrate well into the prostate and eyes. There are some doubts about the in vivo efficacy of clindamycin in the treatment of toxoplasmosis, although combination with pyrimethamine may enhance efficacy (Caney, 2021). Clindamycin in combination with primaquine may be useful in treating pneumonia associated with Pneumocystis jiroveci infection (Koga, 2021). There are no formulations of lincosamides labeled for systemic use in ruminants. Pirlimycin is exclusively approved for veterinary applications as an intramammary infusion for the control of bovine clinical and subclinical intramammary infections. Intramammary pirlimycin has been proven effective against Staphylococcus species such as S. aureus, and Streptococcus dysgalactiae, S. agalactiae, and S. uberis (Tomazi et al., 2018; McDougall et al., 2021). Prepartum treatment of dairy heifers with pirlimycin reduces the prevalence of early lactation intramammary infections caused by coagulase‐negative staphylococci (Middleton et al., 2005). There are few, if any, indications for the other lincosamides in ruminants because of the availability of approved alternatives. Subconjunctival injection of clindamycin was effective in the treatment of naturally occurring infectious bovine keratoconjunctivitis (Senturk et al., 2007). A single IM injection of the combination (5 mg/kg lincomycin, 10 mg/kg spectinomycin) cured over 90% of sheep with infectious pododermatitis and was almost as effective as the same dose given on each of three days (Venning et al., 1990). The combination has also been used in the treatment of rams to prevent Ureaplasma spp. contamination of semen (Marcus et al., 1994). Lincomycin (8 g/l) administered as a spray once daily for five days was effective in the control of papillomatous digital dermatitis in cattle (Shearer and Elliott, 1998). Topical lincomycin under a bandage was effective for treatment of bovine digital dermatitis, but recurrence may be observed in animals from farms with irregular claw trimming and no treatment program for digital dermatitis (Berry et al., 2012). Lincomycin can be used in pigs to control dysentery caused by Brachyspira hyodysenteriae, B. hampsonii, and B. suanatina, although its use against swine dysentery has decreased over the past years due to the development of resistance. Lincomycin is also used to control porcine proliferative enteropathies caused by Lawsonia intracellularis and mycoplasma infections. Lincomycin is used in feed or water (33 mg/l) to treat (100 ppm feed) or prevent (40 ppm feed) swine dysentery. It can also be administered at 11 mg/kg IM for 3–7 days. A drawback has been failure to completely eliminate B. hyodysenteriae, so that drug withdrawal is followed by recrudescence of infection. Lincomycin delivered in drinking water has also been shown to be effective for the treatment of proliferative enteropathy both in a field study and following experimental infection (Bradford et al., 2004; Alexopoulos et al., 2006). Control of erysipelas and streptococcal infections may be incidental benefits to incorporating the drug in feed for the principal purposes. Lincomycin is also used to reduce the severity of the effects of swine respiratory disease associated with Mycoplasma hyopneumoniae. The combination of lincomycin‐spectinomycin every 24 hours for three days resulted in a temporary clinical recovery of pigs presenting arthritis associated with Mycoplasma hyosynoviae; however, relapses of disease may occur (Moronato et al., 2017). Pleuromutilins are considerably more effective than lincomycin in control of swine dysentery and mycoplasma infections in swine. Lincomycin and clindamycin have been used experimentally to induce enterocolitis in horses (Prescott et al., 1988). These drugs should not be used in horses, although there are rare reports of apparently successful use in the treatment of osteomyelitis by IM injection without apparent adverse effects. Lincosamides are used in the treatment of abscesses, osteomyelitis, periodontal disease, and soft tissue or wound infections that involve Gram‐positive cocci or anaerobic bacteria. In dogs, they demonstrate excellent efficacy in the treatment of upper respiratory infections and dermal infections, particularly those caused by staphylococci and streptococci. Lincosamides have demonstrated efficacy even in some chronic conditions and infections which have resisted treatment with other antimicrobials. In cats, lincosamides are used in the treatment of localized infections, pneumonitis, and feline rhinotracheitis. Clindamycin is a first‐line antimicrobial in the treatment of canine deep pyoderma because of its antistaphylococcal activity. It is considered an appropriate drug for empirical treatment of superficial bacterial folliculitis. Field trials have demonstrated the 94–100% efficacy of single‐daily dosing with 11 mg/kg orally (average duration 45 days) in the treatment of deep pyoderma (Harvey et al., 1993; Scott et al., 1998). The advantages of this protocol would include the once‐daily dosing and low or absent side‐effects or toxicities (Bloom and Rosser, 2001). Lincomycin (22 mg/kg, q 12 h) orally is equally effective in the treatment of staphylococcal skin disease in dogs (Harvey et al., 1993). In a study of experimental anaerobic infections in dogs, clindamycin (5.5 or 11 mg/kg twice daily IM) was highly efficacious against Bacteroides fragilis, Prevotella melaninogenica, Fusobacterium necrophorum, and C. perfringens. In the same study, clindamycin gave better results than lincomycin (22 mg/kg twice daily) (Berg et al., 1984). Clindamycin is used effectively in the treatment of periodontal infections in dogs, when combined with dental surgery or cleaning (Johnson et al., 1992). Anecdotally, its routine use in periodontal surgery has been associated with problems of salmonellosis in veterinary hospitals. This is likely associated with the marked disruption of the colonic anaerobic microflora by oral clindamycin, which reduces the number of Salmonella organisms required to establish infection to very few (Prescott, 2005). Clindamycin is also useful for prostatic infections caused by Gram‐positive bacteria. Dosing of 11 mg/kg once daily orally appears to be appropriate, but the same dose could be administered twice daily in serious infections (e.g., osteomyelitis). In experimentally induced Staphylococcus aureus osteomyelitis in dogs, a dosage of 11 mg/kg clindamycin administered q 12 h for 28 days effectively resolved the infection. Dosage of 5.5 mg/kg q 12 h was less effective (Braden et al., 1988). Clindamycin has been used successfully in the treatment of toxoplasmosis in cats, although the treatment success rate for chorioretinitis or anterior uveitis is variable (Ali et al., 2021). Some clinicians use higher doses in cats with CNS involvement (e.g., 20–50 mg/kg orally q 12 h for four weeks). Pyrimethamine has been used in combination with clindamycin in refractory cases (Caney, 2021). Clindamycin administered to cats experimentally infected with toxoplasmosis did not prevent ocular lesions and was associated with increased morbidity and mortality from hepatitis and interstitial pneumonia (Davidson et al., 1996). In contrast, clindamycin completely prevented shedding of T. gondii in experimentally infected cats even after severe immunosuppression (Malmasi et al., 2009). Clindamycin is also the drug of choice for treating clinical toxoplasmosis in dogs. It was successful in resolving clinical signs caused by Neosporum caninum in dogs, although the pathogen was not necessarily eradicated (Dubey et al., 1995, 2007). Clindamycin was also successful for the treatment of dogs experimentally infected with Babesia gibsoni (Wulansari et al., 2003). Clindamycin in combination with diminazene and imidocarb was more effective at eradicating B. gibsoni in naturally infected dogs than a combination of atovaquone and azithromycin (Lin et al., 2012). Clindamycin (2 mg/kg PO q 12 h) combined with metronidazole (15 mg/kg PO q 12 h) and doxycycline (5 mg/kg PO q 12 h) for five weeks is reported as a successful protocol to treat B. gibsoni infection in dogs (Almendros et al., 2020; Strobl et al., 2021). Lincomycin‐spectinomycin combination is administered orally to young chickens for the control of mycoplasma air sacculitis and complicated chronic respiratory disease caused by Mycoplasma gallisepticum and E. coli. Lincomycin‐spectinomycin has also been proven effective in the treatment of Enterococcus cecorum associated with skeletal disease in broilers when administered in the first week of life; however, the combination was shown to have a negative impact on the development of the cecal microbiota (Schreier et al., 2022). Lincomycin has also been used in the control of necrotic enteritis caused by susceptible pathogens such as C. perfringens in broilers (Lanckriet et al., 2010).
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Lincosamides, Pleuromutilins, and Streptogramins
Lincosamides: Lincomycin, Clindamycin, and Pirlimycin
Mechanism of Action
Antimicrobial Activity
Good Susceptibility (MIC ≤2.0 mg/ml)
Resistant (MIC ≥4 mg/ml)
Antimicrobial Resistance
Pharmacokinetic Properties
Drug Interactions
Toxicity and Adverse Effects
Administration
Clinical Use
Cattle, Sheep, and Goats
Swine
Horses
Dogs and Cats
Poultry
Pleuromutilins: Tiamulin and Valnemulin
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