vancomycin and other agents with activity against gram-positive aerobes

Question 1

glycopeptides

Answer 1

vancomycin

Question 2

streptogramins

Answer 2

quinupristin-dalfopristin (synercid)

Question 3

oxazolidinones

Answer 3

linezolid, tedizolid

Question 4

lipopeptides

Answer 4

daptomycin

Question 5

lipoglycopeptides

Answer 5

telavancin, dalbavancin, oritavancin

Question 6

vancomycin chemistry

Answer 6

Vancomycin is derived from Streptomyces orientalis and has a unique structure in that it is a complex tricyclic glycopeptide* with a molecular weight of 1500 Daltons.

Question 7

vancomycin MOA

Answer 7

Vancomycin inhibits the synthesis of the bacterial cell wall* by blocking glycopeptide polymerization at a site different from that of the β-lactams.
Vancomycin inhibits synthesis and assembly during the second stage* of cell wall synthesis by firmly binding to the D-alanyl-D-alanine portion of cell wall precursors. Vancomycin prevents cross-linking and further elongation of peptidoglycan, which weakens the cell wall making it susceptible to lysis.
Vancomycin is slowly bactericidal in a time-dependent manner, except against Enterococcus spp. where it displays bacteriostatic activity.

Question 8

vancomycin MOR**

Answer 8

In vancomycin resistant Enterococcus (VRE) and vancomycin resistant Staphylococcus aureus (VRSA), resistance to vancomycin is due to modification of the D-alanyl-D-alanine vancomycin-binding site* of the peptide side chain of peptidoglycan precursors by expression of the vanA (or vanB, vanC, vanD or vanE) gene. The terminal D-alanine is replaced by D-lactate, which results in the loss of a critical hydrogen bond that usually facilitates high-affinity binding of vancomycin to its target. The end result is the loss of antibacterial activity.
In vancomycin intermediate Staphylococcus aureus (VISA), resistance to vancomycin is due to thickening of the peptidoglycan layer of the cell wall, restricting access of vancomycin to its site of activity.

Question 9

vancomycin spectrum of activity

Answer 9

Vancomycin displays activity against many Gram-positive aerobic and anaerobic bacteria
-Groups A, B, C, D, F, and G streptococci
-Viridans streptococci
-Streptococcus pneumoniae (including penicillin-resistant strains, PRSP)
-Enterococcus faecalis and faecium (ONLY BACTERIOSTATIC)
-Staphylococcus aureus and coagulase-negative staphylococci {CNS} (both** methicillin-susceptible {MSSA - not DOC} and methicillin-resistant strains {MRSA - DOC})
-Corynebacterium spp.
-Listeria monocytogenes
-Actinomyces
-Clostridium spp. (INCLUDING C. difficile)
In vitro studies demonstrate synergy between vancomycin and gentamicin or streptomycin against Enterococcus spp., and between vancomycin and gentamicin against viridans streptococci and Staphylococcus spp.
Gram-positive organisms that display resistance to vancomycin include select isolates of Enterococcus faecalis and E. faecium; and most isolates of E. gallinarum, E. casseliflavus, E. durans, Pediococcus spp., and Leuconostoc spp.
Vancomycin is NOT active against Gram-negative aerobes or anaerobes.*

Question 10

vancomycin pharmacology overview

Answer 10

Interpatient variability exists in the pharmacokinetic characteristics of volume of distribution and clearance** of vancomycin. The PD parameter associated with efficacy has not yet been clearly defined (?AUC/MIC of 400).

Question 11

vancomycin absorption

Answer 11

Absorption of vancomycin from the gastrointestinal tract is negligible** after oral administration. Absorption may occur with oral administration in the presence of intense inflammatory colitis, with detectable serum concentrations occasionally observed in patients with renal insufficiency.
**For the treatment of systemic infections, intermittent intravenous infusion is the preferred route of administration (not IM).

Question 12

vancomycin distribution

Answer 12

Vancomycin is widely distributed into body tissues and fluids, including pleural fluid, synovial fluid, ascites, adipose tissue, and bile. Vancomycin displays variable penetration into the CSF, even in the presence of inflamed meninges.
Vancomycin takes approximately ONE HOUR to distribute from the plasma compartment into peripheral tissues and fluids.
Interpatient variability exists in the volume of distribution:
-Vd adults = 0.50 to 0.65 L/kg
-Neonates and infants have a larger Vd than adults. From birth to the first year of life, the Vd declines from an initial value of over 0.7 L/kg to the adult value of 0.5 L/kg.
-Total body weight (TBW) should be used for vancomycin dosing** as it results in a more accurate approximation of the Vd.

Question 13

vancomycin elimination

Answer 13

Intravenous vancomycin is primarily eliminated unchanged by the kidney via glomerular filtration.
In adults with normal renal function, the elimination half-life = 6 to 8 hours. The half-life progressively increases as renal function decreases.** In patients with end-stage renal disease, the elimination half-life of vancomycin approaches 7 to 14 days. *
Vancomycin is NOT appreciably removed by hemodialysis. Vancomycin may be removed during peritoneal dialysis or continuous hemofiltration.

Question 14

vancomycin serum concentration monitoring

Answer 14

There are NO well-controlled clinical trials relating vancomycin serum concentrations to efficacy or toxicity.
Because of interpatient variability in Vd and Cl of vancomycin, serum concentration monitoring may be warranted in some patients to help avoid excessive serum concentrations such as in patients with renal dysfunction, changing renal function, receiving aggressive dosing, or receiving long-term therapy.
“Target” peak concentrations = 30 to 40 μg/ml; “Target” trough concentrations = 10 to 15 μg/ml (some clinicians target higher trough concentrations for the treatment of meningitis, endocarditis, pneumonia, and osteomyelitis due to MRSA with vanco MICs of 2 mg/L)
Peak concentrations should be obtained one hour after the end of infusion* and trough concentrations should be drawn just prior to the dose.

Question 15

dosing of vancomycin

Answer 15

The differences in the vancomycin pharmacokinetic parameters must be considered when determining a vancomycin dose for each patient. Factors that should be considered include the patient’s volume status, renal function, age, gender, weight, concomitant drug therapy, and infection being treated, severity of infection, etc.
Several vancomycin-dosing nomograms are available to assist with dosing based on a patient’s age, weight, and renal function.
Adults with normal renal function: 10 to 15 mg/kg* (typically 1 to 1.5 grams) every 12 hours
Adults with impaired renal function: 10 to 15 mg/kg/dose* (typically 1 to 1.5 grams) with interval based on renal function (every 18, 24, 36, 48 hours)

Vancomycin Dosing Interval Depends on Renal Function:

• CrCl over70 = Every 12 hours
• CrCl 40 - 69 = Every 24 hours
• CrCl 25 - 39 = Every 48 hours
• CrCl under 25 = Every 72 hours or longer
• Neonates and children: 10 to 15 mg/kg/dose every 6 to 24 hours based on gestational age or renal function
• **TBW (up to ∼ 200kg) should be used for dosing in obese patients - maximum initial doses should not exceed 2000mg to 3000 mg

Question 16

vancomycin clinical uses

Answer 16

Infections due to methicillin-resistant staphylococci** (MRSA, CNS) including bacteremia, pneumonia, empyema, endocarditis, peritonitis, osteomyelitis, and skin/soft tissue infections. Intraventricular vancomycin has been rarely used as adjunctive therapy for the treatment of meningitis.
Serious Gram-positive infections in patients allergic to β-lactam antibiotics.
Infections caused by resistant* Gram-positive organisms such as Corynebacterium jeikeium or penicillin-resistant Streptococcus pneumoniae (PRSP).
Perioperative prophylaxis to reduce the risk of infection in patients undergoing cardiac, neurosurgical, orthopedic, or vascular surgical procedures where the local or regional rates of MRSA are high.
**ORAL vancomycin is the drug of choice for the treatment of moderate to severe Clostridium difficile colitis (125 mg PO Q 6 hours)

Question 17

vancomycin AEs

Answer 17

red-man syndrome, nephrotoxicity and ototoxicity, dermatalogic, hematologic, other
the overall incidence of adverse effects decreased with purification of branded vancomycin; however, generic products are now available

Question 18

red-man syndrome with vancomycin**

Answer 18

Characterized by flushing, pruritus, and a maculopapular or erythematous rash on the face, neck, chest, and upper extremities. The reaction may also be accompanied by hypotension.
Begins within 5 to 15 minutes of starting the vancomycin infusion and resolves spontaneously over several hours after the discontinuation of the infusion. The reaction has also been rarely reported after oral and intraperitoneal administration.
Reaction is related to the rate of vancomycin infusion** (faster than 15 mg per minute); rapid infusion causes the release of histamine and other vasodilating substances.
To minimize or prevent this reaction, vancomycin doses of 1 gram should be infused over at least one hour and larger doses should be infused over 90 to 120 minutes. Other measures to alleviate this reaction include further lengthening of the infusion (over 2 or 3 hours) and premedication with antihistamines or corticosteroids.

Question 19

nephrotoxicity and ototoxicity with vancomycin

Answer 19

Occurs rarely with vancomycin monotherapy (under 5%); more common in patients receiving concomitant ototoxins and nephrotoxins (10 to 15%).
Risk factors include the presence of underlying renal insufficiency, the use of prolonged therapy or high doses, ? high serum trough vancomycin concentrations, and concomitant use of other ototoxins or nephrotoxins.
The correlation between serum vancomycin concentrations and toxicity remains to be clarified.
Nephrotoxicity is manifested by transient increases in BUN or serum creatinine, and occasionally the presence of granular casts in the urine. The occurrence of nephrotoxicity is usually transient and reversible.
Vancomycin may cause damage to the auditory branch of the 8th cranial nerve. Tinnitus and high-frequency hearing loss may precede the onset of deafness, and necessitates the discontinuation of therapy. Hearing loss is irreversible.

Question 20

dermatologic AEs with vancomycin

Answer 20

Hypersensitivity skin reactions occur in under 5% of patients who receive vancomycin. Reactions include exfoliative dermatitis, linear IgA bullous dermatosis, macular rashes, vasculitis, and Stevens-Johnson.

Question 21

hematologic AEs with vancomycin

Answer 21

neutropenia, thrombocytopenia, and rarely eosinophilia; especially with prolonged therapy

Question 22

other AEs with vancomycin

Answer 22

thrombophlebitis, muscle spasms in the back and neck; cardiovascular collapse (rapid infusion); drug fever, interstitial nephritis (rare).

Question 23

synercid MOA

Answer 23

Quinupristin and dalfopristin act individually on the 50S ribosomal subunit to inhibit early and late stages of bacterial protein synthesis; each agent alone is bacteriostatic*, but the combination produces an additive or synergistic effect (sometimes bactericidal)

Question 24

synercid MOR

Answer 24

alteration of ribosomal binding site (most common – encoded by erm gene); enzymatic inactivation

Question 25

synercid spectrum of activity

Answer 25

Gram-positive organisms
-Group Streptococci
-Viridans Streptococci
-Streptococcus pneumoniae (including PRSP)
-Enterococcus faecium ONLY** – including VRE (however, NOT ACTIVE vs. E. faecalis**)
-Staphylococcus aureus and CNS (MS and MR*)
-Others – Listeria monocytogenes, Clostridium (not C. difficile), Peptostreptococcus
Gram-negative aerobes – has limited activity against Neisseria and Moraxella; NOT active against Enterobacteriaceae

Question 26

synercid pharmacology

Answer 26

Time-dependent bactericidal activity** (when bactericidal)
Significant PAE** exists for Gram-positive organisms: 2 to 8 hours for S. aureus, 8.5 hours for vancomycin-sensitive E. faecium, 0.2 to 3.2 hours for vancomycin-resistant E. faecium
Absorption – only available parenterally
Distribution – penetrates into extravascular tissue, lung, bile, gallbladder, skin and soft tissue; minimal penetration into CSF; protein binding is 55 to 78% for quinupristin and 11 to 25% for dalfopristin
Elimination – both agents are converted to active metabolites (by CYP enzymes) that are eliminated by hepatic clearance or biliary elimination; urinary elimination accounts for only 15-18 %; half-life ranges 0.6 to 1 hour for quinupristin and 0.3 to 0.4 hours for dalfopristin; dosage adjustments unnecessary* in patients with renal insufficiency, but suggested** in patients with hepatic insufficiency

Question 27

synercid clinical uses and dosing

Answer 27

• **if available, very expensive - $890 to $1335 per day for a 70-kg adult) - only considered when vancomycin, linezolid, AND daptomycin cannot be used
• Vancomycin-resistant Enterococcus faecium** (VRE) bacteremia (7.5 mg/kg every 8 hours)
• Complicated skin and skin structure infections caused by MSSA or S. pyogenes (7.5 mg/kg every 12 hours)
• Other uses: catheter-related bacteremia, infections due to MRSA and community-acquired pneumonia (7.5 mg/kg every 8 hours)

Question 28

important synercid drug interactions

Answer 28

3A4 inhibitor
statins
immunosuppressive agents - cyclosporin, tacrolimus
carbamazepine

Question 29

synercid AEs

Answer 29

Venous irritation* – significantly greater than comparators (66% vs. 33%); especially with peripheral administration
Gastrointestinal – nausea, vomiting, diarrhea
Myalgias, arthralgias* – 2%
Rash – 2.5%

Question 30

oxazolidinones MOA

Answer 30

Oxazolidinones bind to the 50S ribosomal subunit near the surface interface of the 30S subunit, producing inhibition of the 70S initiation complex for protein synthesis (ultimately, inhibits protein synthesis). This mechanism of action and site of binding of these agents is unique, making cross-resistance with other protein synthesis inhibitors unlikely. For the most part, oxazolidinones are bacteriostatic.

Question 31

oxazolidinones MOR

Answer 31

alteration of the ribosomal subunit target site (chromosomal mutations in genes encoding 23S or ribosomal proteins) has rarely emerged during therapy of infections due to Enterococcus spp. and S. aureus; cross resistance exists between linezolid and tedizolid

Question 32

oxazolidinones spectrum of activity

Answer 32

Gram-positive organisms
-Group Streptococci
-Viridans Streptococci
-Streptococcus pneumoniae (including PRSP)
Enterococcus faecium AND faecalis** (including VRE)
-Staphylococcus aureus and CNS (MS, MR, VI, VR*)
-Others – Listeria monocytogenes, Clostridium (not C difficile), Bacillus, Peptostreptococcus, Propionibacterium acnes
Gram-negative organisms – INACTIVE against Neisseria, Moraxella, Haemophilus and Enterobacteriaceae

Question 33

pharmacology of oxazolidinones

Answer 33

Primarily bacteriostatic; T>MIC is the major predictor of efficacy for linezolid and AUC/MIC correlates with tedizolid activity
PAE exists for Gram-positive organisms: 3 to 4 hours for S. aureus and S. pneumoniae, 1 hour for Enterococcus
***Absorption – linezolid is rapidly and completely absorbed after oral administration with an oral bioavailability of 100%; tedizolid bioavailability = 91%
Distribution – readily distribute into well-perfused tissues; limited data suggest that 30% of simultaneous linezolid serum concentrations are achieved in the CSF; linezolid protein binding = 31%, tedizolid protein binding = 70-90%
Elimination – both agents eliminated by both renal and non-renal routes; linezolid t½ = 4.4 to 5.4 hours and tedizolid t1/2 = 12 hours; linezolid is removed by hemodialysis (but not tedizolid) and neither drug requires dosage adjustment in the presence of renal insufficiency

Question 34

oxazolidinones clinical uses and dosing

Answer 34

very expensive: linezolid $192 (IV) to $366 (PO) per day and tedizolid $282 (IV) to $354 (PO) per day} - reserved for management of serious or complicated infections caused by resistant organisms, especially for infections where vancomycin or β-lactams cannot be used; good oral absorption provides convenient option for “stepdown” therapy
Treatment of VRE infections** (bacteremia, UTI; usually the drug of choice) - Linezolid 600 mg IV or PO every 12 hours
Complicated skin and skin structure infections caused by MSSA or S. pyogenes - Linezolid 600 mg IV or PO every 12 hours or Tedizolid* 200mg PO daily {for 6 days}
Community-acquired pneumonia due to PSSP, MSSA– Linezolid 600 mg IV or PO every 12 hours
Nosocomial pneumonia due to MSSA, MRSA* and PSSP– Linezolid 600 mg IV or PO every 12 hours
Other uses: serious infections due to MSSA, MRSA or VRE (endocarditis, meningitis and osteomyelitis……Linezolid only)

Question 35

oxazolidinones drug interactions

Answer 35

Oxazolidinones are very weak inhibitors of monoamine oxidase* - potential for drug interactions. Although no evidence of MAO inhibition emerged during clinical trials (patients receiving potential interacting drugs were excluded from all tedizolid trials); linezolid may interact with adrenergic and serotonergic agents causing a reversible enhancement of the pressor response to agents such as dopamine or epinephrine and a risk of serotonin syndrome (e.g., hyperpyrexia, cognitive dysfunction, diarrhea, restlessness, clonus) in patients receiving concomitant serotonergic agents** (SSRIs such as fluoxetine, sertraline, citalopram, escitalopram, etc). Use together with caution….

Question 36

oxazolidinones AEs

Answer 36

Gastrointestinal – nausea, diarrhea (6 to 8%), lactic acidosis
CNS – headache (6.5%), peripheral and optic neuropathy (especially with linezolid treatment over 28 days; tedizolid not studied)
Thrombocytopenia and anemia (2 to 4 %)* – especially with treatment > 2 weeks; reversible after discontinuation of therapy

Question 37

daptomycin MOA

Answer 37

Daptomycin binds to bacterial membranes and inserts its lipophilic tail into the cell wall to form a transmembrane channel → leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis, resulting in bacterial cell death. Daptomycin exhibits rapid, concentration-dependent bactericidal activity**.

Question 38

daptomycin MOR

Answer 38

Resistance to daptomycin has been rarely reported in VRE and MRSA due to altered cell membrane binding through loss of a membrane protein.

Question 39

daptomycin spectrum of activity

Answer 39

Gram-positive aerobes – excellent activity
-Group and viridans Streptococci
-Streptococcus pneumoniae (including PRSP)
-Enterococcus faecium AND faecalis** (including VRE* – static)
-Staphylococcus aureus and CNS (MS, MR, VI, VR, LR)
-Corynebacterium jeikeium
Gram-negative aerobes – is INACTIVE against Neisseria, Moraxella, Haemophilus and Enterobacteriaceae

Question 40

daptomycin pharmacology

Answer 40

**Rapid, concentration-dependent bactericidal activity
Distribution – daptomycin distributes fairly well into tissues and is highly protein bound to serum albumin (90 to 93%)
Elimination – daptomycin is excreted primarily by the kidneys, with 78% of the dose being recovered in the urine; half-life ranges from 7.7 to 8.3 hours in healthy volunteers and is prolonged in patients with renal insufficiency; **dosage adjustments of daptomycin are required in the presence of renal insufficiency

Question 41

clinical uses and dosing of daptomycin

Answer 41

very expensive - reserved for treatment of serious/complicated infections caused by resistant Gram-positive bacteria where vancomycin and/or linezolid cannot be used**
Complicated skin and skin structure infections caused by susceptible Gram-positive bacteria (MSSA, MRSA, S. pyogenes, etc) – 4 to 6 mg/kg IV once daily
Staphylococcus aureus bacteremia and endocarditis – 6 mg/kg IV once daily
Other uses: serious infections due to MRSA or VRE (including endocarditis and osteomyelitis); catheter-related bacteremia
****Daptomycin should NOT be used for the treatment of pneumonia since the compound is inactivated by pulmonary surfactant.

Question 42

daptomycin drug interactions

Answer 42

HMG-CoA reductase inhibitors (statins) – may lead to increased incidence of myopathy; use together with caution or temporarily discontinue statin during daptomycin therapy

Question 43

daptomycin AEs

Answer 43

Gastrointestinal – nausea, diarrhea (5%)
Headache – 5.4%
Injection site reactions – 5.8%
Rash – 4.3%
Myopathy and CPK elevation* – 0.9 to 1.5%
Acute eosinophilic pneumonia***

Question 44

lipoglycpeptides MOA

Answer 44

All lipoglycopeptides interfere with the polymerization and cross- linking of peptidoglycan by binding to the D-Ala-D-Ala terminus. The lipid side chain anchors the drugs to the cell membrane and concentrates the drug at the site of action.
Oritavancin and telavancin (not dalbavancin) also appear to bind to bacterial membranes and insert their lipophilic tails into the cell wall to form a transmembrane channel (like daptomycin) - causes leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis, resulting in bacterial cell death.

Question 45

lipoglycopeptides MOR

Answer 45

Alteration in the peptidoglycan terminus (in VRE) - especially vanA resistance where D-Ala-D-Ala is changed to D-Ala-D-Lac affects the activity of telavancin and dalbavancin (MICs are 2 to 4 fold higher); however, oritavancin still maintains activity

Question 46

lipoglycopeptides spectrum of activity

Answer 46

Gram-positive aerobes – all have excellent activity
-Group streptococci
-viridans streptococci
-Streptococcus pneumoniae
-Enterococcus faecium AND faecalis* - some strains of VRE display resistance to telavancin and dalbavancin
-Staphylococcus aureus and CNS (MS, MR, VI; oritavancin also displays activity against VRSA)
Gram-negative aerobes – INACTIVE

Question 47

lipoglycopeptides pharmacology

Answer 47

Concentration-dependent bactericidal activity, where the AUC/MIC is the best predictor of efficacy
Distribution – all agents distribute fairly well into tissues including skin and lung tissue; all display poor CSF penetration and are ∼90% protein bound
Elimination - none are appreciably removed by HD
-Telavancin is excreted primarily by the kidneys, with 70% of the dose being recovered unchanged in the urine; t½ = 6.1 to 9.1 hours in healthy volunteers and is prolonged in patients with renal insufficiency; dosage adjustments are suggested in the presence of renal insufficiency*
-Dalbavancin is excreted in the feces (20%), with 33% of the dose recovered unchanged in the urine; t½ = 346 hours* in healthy volunteers; dosage adjustments of dalbavancin are suggested in patients with severe renal insufficiency who are not receiving HD** (750mg x one, 375mg one week later)
-Oritavancin is excreted primarily by ?? (less than 5% recovered unchanged in the urine, less than 1% in the feces, and not appreciably metabolized); t½ = 245 hours; no dosage adjustments are required in renal or hepatic insufficiency***

Question 48

lipoglycopeptides clinical uses and dosing

Answer 48

use should only be considered in adults* with infections due to resistant Gram-positive organisms where vancomycin, linezolid/tedizolid, AND daptomycin cannot be used**

• Telavancin (very expensive $472 per day in 70kg adult) has been approved for the treatment of complicated skin/soft tissue infections or hospital-acquired (including ventilator-associated) pneumonia at a dose of 10 mg/kg IV once daily
• Dalbavancin (very expensive $5,364 per course) has been approved for the treatment of acute bacterial skin and skin structure infections at a dose of 1 gram IV followed by 500mg IV one week later
• Oritavancin (very expensive $3,480 per course) has been approved used for the treatment of acute bacterial skin and skin structure infections as a single 1200mg IV dose infused over 3 hours

Question 49

lipoglycoepetides drug interactions

Answer 49

no clinically relevant drug interactions have been noted with telavancin; drug interactions studies have not been performed with dalbavancin; oritavancin is a weak inducer of CYP3A4 and a non-selective inhibitor of CYP2C9 and CYP2C19 (no interactions noted in limited studies performed); telavancin and oritavancin interfere with results of coagulation tests such as the prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) because they bind to and prevent the action of phospholipid reagents, which activate coagulation in many coagulation tests

Question 50

lipglycopeptides AEs

Answer 50

Infusion-related reactions (Red Man Syndrome, all)* - doses must be infused over at least 30 minutes (dalbavancin), 60 minutes (telavancin), or 3 hours (oritavancin)
Nephrotoxicity (telavancin, 3.1%)* - incidence higher in patients with comorbidities predisposing to renal dysfunction (preexisting renal disease, diabetes, congestive heart failure, or hypertension); patients receiving other nephrotoxins (NSAIDs, loop diuretics, ACE inhibitors), and patients over 65 years of age
QTc prolongation* - telavancin should be avoided in patients with congenital long QT syndrome, patients with known prolongation of the QT interval, and patients taking drugs that prolong the QT interval.
Other - taste disturbances* (telavancin - metallic or soapy), nausea, vomiting, diarrhea, headache (all), foamy urine (telavancin), ? macrophage dysfunction (oritavancin)

Question 51

lipoglycopeptide use during pregnancy

Answer 51

Telavancin is Pregnancy Category C* - adverse developmental outcomes were observed in 3 animal species at clinically relevant doses, which has raised concerns about potential adverse developmental outcomes in humans. Therefore, ***a black box warning exists warning against use during pregnancy; pregnancy test needed before use in women of childbearing potential.
Dalbavancin and Oritavancin are also Pregnancy Category C due to lack of adverse developmental outcomes in animal studies and lack of safety data in humans; use only during pregnancy if potential benefit justifies the potential risk to the fetus.