Nimedine

Imipenem, cilastatin sodium.

White to almost white or light (pale) yellow powder.
After dilution: Range from colorless to yellow. Variations of color within this range do not affect the potency of the product.
Each vial contains 530 mg of Imipenem monohydrate and 530 mg of Cilastatin sodium corresponding to 500 mg of Imipenem and 500 mg of Cilastatin.

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems. ATC code: J01D H51.
Pharmacodynamics: Mechanism of action: NIMEDINE consists of two components: imipenem and cilastatin sodium in a 1:1 ratio by weight.
Imipenem, also referred to as N-formimidoyl-thienamycin, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya.
Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolizes and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship: Similar to other beta-lactam antibacterial agents, the time that imipenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy.
Mechanism of resistance: Resistance to imipenem may be due to the following: Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins).
Imipenem may be actively removed from the cell with an efflux pump.
Reduced affinity of PBPs to imipenem.
Imipenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do generally express co-resistance to imipenem. There is no target-based cross-resistance between imipenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes.
Breakpoints: EUCAST MIC breakpoints for imipenem to separate susceptible (S) pathogens from resistant (R) pathogens are as follows (v 1,1 2010-04-27): Enterobacteriaceae ¹: S ≤2 mg/l, R >8 mg/l; Pseudomonas spp. ²: S ≤4 mg/l, R >8 mg/l; Acinetobacter spp.: S ≤2 mg/l, R >8 mg/l; Staphylococcus spp. ³: Inferred from cefoxitin susceptibility; Enterococcus spp.: S ≤4 mg/l, R >8 mg/l; Streptococcus A, B, C, G: The beta-lactam susceptibility of beta-haemolytic streptococcus groups A, B, C and G is inferred from the penicillin susceptibility; Streptococcus pneumoniae ⁴: S ≤2 mg/l, R >2 mg/l; Other streptococci ⁴: S ≤2 mg/l, R >2 mg/l; Haemophilus influenzae ⁴: S ≤2 mg/l, R>2 mg/l; Moraxalla catarrhalis ⁴: S ≤2 mg/l, R >2 mg/l; Neisseria gonorrhoeae: There is insufficient evidence that Neisseria gonorrhoeae is a good target for therapy with imipenem; Gram-positive anaerobes: S ≤2 mg/l, R >8 mg/l; Gram-negative anaerobes: S ≤2 mg/l, R >8 mg/l; Non-species related breakpoints ⁵: S ≤2 mg/l, R >8 mg/l.
¹ Proteus and Morganella species are considered poor targets for imipenem.
² The breakpoints for Pseudomonas relate to high dose frequent therapy (1 g every 6 hours).
³ Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.
⁴ Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
⁵ Non-species related breakpoint have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the overview of species-related breakpoints or footnotes.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. (See Table 1.)

Click on icon to see table/diagram/image

Pharmacokinetics: Imipenem: Plasma concentrations: In normal volunteers, intravenous infusion of NIMEDINE over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 μg/ml for the 250 mg/250 mg dose, from 21 to 58 μg/ml for the 500 mg/500 mg dose, and from 41 to 83 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of imipenem following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 17, 39, and 66 μg/ml, respectively. At these doses, plasma levels of imipenem decline to below 1 μg/ml or less in four to six hours.
Distribution: The binding of imipenem to human serum proteins is approximately 20%.
Biotransformation and elimination: When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies.
Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits metabolism of imipenem so that concomitant administration of imipenem and cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both urine and plasma.
The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10 μg/ml for up to eight hours after a 500 mg/500 mg dose of NIMEDINE. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.
No accumulation of imipenem in plasma or urine has been observed with regimens of NIMEDINE, administered as frequently as every six hours, in patients with normal renal function.
Cilastatin: Plasma concentrations: Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of NIMEDINE, ranged from 21 to 26 μg/ml for the 250 mg/250 mg dose, from 21 to 55 μg/ml for the 500 mg/500 mg dose and from 56 to 88 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of cilastatin following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22, 42, and 72 μg/ml respectively.
Distribution: The binding of cilastatin to human serum proteins is approximately 40%.
Biotransformation and elimination: The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10 hours of administration of NIMEDINE. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Activity of dehydropeptidase-I in the kidney returned to normal levels shortly after the elimination of cilastatin from the blood stream.
Renal insufficiency: Following a single 250 mg/250 mg intravenous dose of NIMEDINE, the area under the curve (AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold in subjects with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m²), moderate (CrCL 30-<50 ml/min/1.73 m²), and severe (CrCL <30 ml/min/1.73 m²) renal impairment, respectively, compared to subjects with normal renal function (CrCL >80 ml/min/1.73 m²), and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Following a single 250 mg/250 mg intravenous dose of NIMEDINE given 24 hours after haemodialysis, AUCs for imipenem and cilastatin were 3.7-fold and 16.4-fold higher, respectively, as compared to subjects with normal renal function. Urinary recovery, renal clearance and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of NIMEDINE. Dose adjustment is necessary for patients with impaired renal function (see Dosage & Administration).
Hepatic insufficiency: The pharmacokinetics of imipenem in patients with hepatic insufficiency have not been established. Due to the limited extent of hepatic metabolism of imipenem, its pharmacokinetics are not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment (see Dosage & Administration).
Paediatric patients: The average clearance (CL) and volume of distribution (Vdss) for imipenem were approximately 45% higher in paediatric patients (3 months to 14 years) as compared to adults. The AUC for imipenem following administration of 15/15 mg/kg per body weight of NIMEDINE to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the exposure following administration of 25/25 mg/kg NIMEDINE to children was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg dose.
Elderly: In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of NIMEDINE 500 mg/500 mg administered intravenously over 20 minutes were consistent with those expected in subjects with slight renal impairment for which no dose alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin were 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of NIMEDINE was observed (see Dosage & Administration).

Treatment: The activity of Nimedine against an unusually broad spectrum of pathogens makes it particularly useful in the treatment of polymicrobic and mixed aerobic/anaerobic infections, as well as initial therapy prior to the identification of the causative organisms. Nimedine is indicated for the treatment of the following infections due to susceptible organisms: Intra-abdominal infections; Lower respiratory tract infections; Gynecological infections; Septicemia; Genitourinary tract infections; Bone and joint infections; Skin and soft tissue infections; Endocarditis.
Nimedine is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. The majority of these mixed infections are associated with contamination by fecal flora or flora originating from the vagina, skin and mouth. In these mixed infections, Bacteroides fragilis is the most commonly encountered anaerobic pathogen and is usually resistant to aminoglycosides, cephalosporins and penicillins. However, Bacteroides fragilis is usually susceptible to Nimedine.
Nimedine has demonstrated efficacy against many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to the cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime and ceftriaxone. Similarly, many infections caused by organisms resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) responded to treatment with Nimedine.
Nimedine is not indicated for the treatment of meningitis.

Nimedine is available as intravenous infusion only.
The dosage recommendations for Nimedine represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present.
The total daily dosage of Nimedine should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s) and renal function.
Dosage in Adults: For Intravenous Injection Only: The dosage of Nimedine in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 2 as follows. The dosage recommendations for Nimedine represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution.
These doses should be used for patients with creatinine clearance of ≥90 mL/min. A reduction in dose must be made for patients with creatinine clearance <90 mL/min as shown in Table 3 (see Dosage in Adult Patients with Renal Impairment as follows).
Recommend that the maximum total daily dosage not exceed 4 g/day.
Administer 500 mg by intravenous infusion over 20 to 30 minutes.
Administer 1000 mg by intravenous infusion over 40 to 60 minutes.
In patients who develop nausea during the infusion, the rate of infusion may be slowed. (See Table 2.)

Click on icon to see table/diagram/image

Dosage in Adult Patients with Renal Impairment: Patients with creatinine clearance less than 90 mL/min require dosage reduction of Nimedine as indicated in Table 3. The serum creatinine should represent a steady state of renal function. Use the Cockroft-Gault method described as follows to calculate the creatinine clearance: (See equation and Table 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In patients with creatinine clearances of 15-30 mL/min, there may be an increased risk of seizures (see Precautions). Patients with creatinine clearance less than 15 mL/min should not receive Nimedine unless haemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of Nimedine for patients undergoing peritoneal dialysis.
Dosage in Hemodialysis Patients: When treating patients with creatinine clearances of less than 15 mL/min who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 15-30 mL/min as previously mentioned in Table 3. Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive Nimedine after hemodialysis and at intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, Nimedine is recommended only when the benefit outweighs the potential risk of seizures (see Dosage in Adult Patients with Renal Impairment as previously mentioned).
Dosage in Paediatric Patients (3 months or older): Nimedine is not recommended in paediatric patients with CNS infections because of the risk of seizures (see Precautions).
Nimedine is not recommended in paediatric patients <30 kg with renal impairment, as no data are available (see Precautions).
Based on studies in adults, the maximum total daily dose in pediatric patients should not exceed 4 g/day (see Dosage in Adults as previously mentioned).
The recommended dosage for pediatric patients with non-CNS infections is shown in Table 4 as follows: (See Table 4.)

Click on icon to see table/diagram/image

Preparation of Nimedine for IV Administration: Nimedine is supplied as a dry powder in a single-dose vial that must be reconstituted and further diluted using aseptic technique prior to IV infusion as outlined as follows.
To prepare the infusion solution, contents of the vial must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial. List of appropriate diluents are as follows: 0.9% Sodium Chloride Injection, 5% Glucose Injection.
The content of the vial is transferred to 100 ml of appropriate infusion solution.
Add approximately 10 ml of the appropriate infusion solution to the vial. Shake well and transfer the resulting mixture to the infusion solution container.
Repeat the previously mentioned procedure with additional 10 ml of infusion solution to ensure complete transfer of vial contents to the infusion solution. Agitate the resulting mixture until clear.
The concentration of the reconstituted solution following the previously mentioned procedure is approximately 5 mg/ml for both Imipenem and Cilastatin.
Reconstituted solutions of Nimedine range from colorless to yellow. Variations of color within this range do not affect the potency of the product.
For patients with renal insufficiency, a reduced dose of Nimedine will be administered according to the patient's CrCl, as determined from Table 5. Prepare 100 mL of infusion solution as directed previously. Select the volume (mL) of the final infusion solution needed for the appropriate dose of Nimedine as shown in Table 5.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed. (See Table 5.)

Click on icon to see table/diagram/image

Route of Administration: Intravenous infusion.

Symptoms of overdose that can occur are consistent with the adverse reaction profile; these may include seizures, confusion, tremors, nausea, vomiting, hypotension, and bradycardia. No specific information is available on treatment of overdose with NIMEDINE. Imipenem-cilastatin sodium is haemodialyzable. However, usefulness of this procedure in the overdose setting is unknown.

Hypersensitivity to the active substances or to any of the excipients.
Hypersensitivity to any other carbapenem antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

General: The selection of NIMEDINE to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.
Hypersensitivity: Serious and occasionally fatal hypersensitivity (including anaphylactoid and severe cutaneous adverse reactions) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating therapy with NIMEDINE, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to NIMEDINE occurs, discontinue the therapy immediately. Serious anaphylactic reactions require immediate emergency treatment.
Haematology: A positive direct or indirect Coombs test may develop during treatment with NIMEDINE.
Antibacterial spectrum: The antibacterial spectrum of NIMEDINE should be taken into account especially in life-threatening conditions before embarking on any empiric treatment. Furthermore, due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to NIMEDINE, caution should be exercised. The use of NIMEDINE is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment. Concomitant use of an appropriate anti-MRSA agent may be indicated when MRSA infections are suspected or proven to be involved in the approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications.
Interaction with valproic acid: The concomitant use of NIMEDINE and valproic acid/sodium valproate is not recommended.
Clostridium difficile: Antibiotic-associated colitis and pseudomembranous colitis have been reported with NIMEDINE and with nearly all other anti-bacterial agents and may range from mild to life-threatening in severity. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of NIMEDINE. Discontinuation of therapy with NIMEDINE and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Meningitis: NIMEDINE is not recommended for the therapy of meningitis.
Central nervous system: CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses based on renal function and body weight were exceeded. These experiences have been reported most commonly in patients with CNS disorders (e.g. brain lesions or history of seizures) and/or compromised renal function in whom accumulation of the administered entities could occur. Hence close adherence to recommended dose schedules is urged especially in these patients. Anticonvulsant therapy should be continued in patients with a known seizure disorder.
Special awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold.
If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dose of NIMEDINE should be decreased or discontinued.
Patients with creatinine clearances of ≤5 ml/min/1.73 m² should not receive NIMEDINE unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, NIMEDINE is recommended only when the benefit outweighs the potential risk of seizures.
Effects on Ability to Drive and Use Machine: No studies on the effects on the ability to drive and use machines have been performed. However, there are some side effects (such as hallucination, dizziness, somnolence, and vertigo) associated with this product that may affect some patients' ability to drive or operate machinery.
Hepatic: Hepatic function should be closely monitored during treatment with NIMEDINE due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure and fulminant hepatitis).
Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with NIMEDINE. There is no dose adjustment necessary.
Renal impairment: Imipenem-cilastatin accumulates in patients with reduced kidney function. CNS adverse reactions may occur if the dose is not adjusted to the renal function.
Use in Children: Clinical data are insufficient to recommend the use of NIMEDINE in children under 1 year of age or paediatric patients with impaired renal function (serum creatinine >2 mg/dl). See also Central nervous system as previously mentioned.
NIMEDINE 500 mg/500 mg contains approximately 1.6 mEq (approximately 37.6 mg) of sodium which should be taken into consideration by patients on a controlled sodium diet.

Pregnancy: There are no adequate and well-controlled studies for the use of NIMEDINE in pregnant women.
The potential risk for humans is unknown.
NIMEDINE should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breastfeeding: Imipenem and cilastatin are excreted into the mother's milk in small quantities. Little absorption of either compound occurs following oral administration. Therefore it is unlikely that the suckling infant will be exposed to significant quantities. If the use of NIMEDINE is deemed necessary, the benefit of breastfeeding for the child should be weighed against the possible risk for the child.

All adverse reactions are listed under system organ class and frequency: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 6.)

Click on icon to see table/diagram/image

Paediatric population: Paediatric (≥3 months of age): Studies in paediatric patients ≥3 months of age, the reported adverse reactions were consistent with those reported for adults.

Generalized seizures have been reported in patients who received ganciclovir and NIMEDINE. These medicinal products should not be used concomitantly unless the potential benefit outweighs the risks.
Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anti-convulsant therapies should be considered.
Oral anti-coagulants: Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant agent.
Concomitant administration of NIMEDINE and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolized) imipenem decreased to approximately 60% of the dose when NIMEDINE was administered with probenecid. Concomitant administration of NIMEDINE and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urine recovery of cilastatin.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Instructions for Use as follows.
Instructions for Use: Each vial is for single use only.
Reconstitution: Contents of each vial must be transferred to 100 ml of an appropriate infusion solution: 0.9% sodium chloride. In exceptional circumstances where 0.9% sodium chloride cannot be used for clinical reasons 5% glucose may be used instead.
A suggested procedure is to add approximately 10 ml of the appropriate infusion solution to the vial. Shake well and transfer the resulting mixture to the infusion solution container.
CAUTION: THE MIXTURE IS NOT FOR DIRECT INFUSION.
Repeat with an additional 10 ml of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear.
The concentration of the reconstituted solution following the previously mentioned procedure is approximately 5 mg/ml for both imipenem and cilastatin.
Variations of colour, from colourless to yellow, do not affect the potency of the product.
Any unused product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.
After reconstitution and dilution: The reconstituted solution is stable for 2 hours when stored at 25°C.
Shelf Life: 36 months.
After reconstitution and dilution: The reconstituted solution is stable for 2 hours when stored at 25°C.

Other Beta-Lactams

J01DH51 - imipenem and cilastatin ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

B