Bacterial Infection Flashcards
1
Q
When selecting an antibacterial, the causative organism should be considered in addition to
A
patient factors such as allergy, renal/hepatic impairment, immune function, availability of oral route, severity, age, taking contraceptive pills, pregnancy or breastfeeding.
2
Q
• Viral infections should not be treated with antibacterials unless
A
there is a secondary bacterial infection.
3
Q
- Clostridium difficile can be treated with
A
Metronidazole 1st line or Vancomycin
4
Q
- Endocarditis is treated blind with
A
Amoxicillin then Gentamicin until the causative organism is identified.
5
Q
- Acute exacerbations of Chronic Bronchitis are treated with
A
Amoxicillin or a Tetracycline
6
Q
- Community Acquired Pneumonia is treated with
A
Amoxicillin and Clarithromycin
7
Q
- Hospital Acquired Pneumonia is treated with
A
Co-Amoxiclav or Cefuroxime
8
Q
- UTIs are treated with
A
Trimethoprim or Nitrofurantoin
9
Q
- Chlamydia and Gonorrhoea are treated with
A
Azithromycin
10
Q
- Septicaemia is treated with
A
Tazocycin or Cefuroxime
11
Q
- Gingivitis is treated with
A
Metronidazole
12
Q
- Otitis externa is treated with…
A
Flucloxacillin
13
Q
- Cellulitis is treated with
A
Flucloxacillin
14
Q
- Patients with Asplenia or Sickle-cell disease are prophylactically treated for Pneumococcal infection with
A
Phenoxymethylpenicillin.
15
Q
- Prophylaxis of Meningococcal Meningitis:
A
Ciprofloxacin or Rifampicin
16
Q
Otitis media is treated with
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Amoxicillin
17
Q
Gentamicin should not be given at the same time as
A
Furosemide due to the risk of ototoxicity and nephrotoxicity!
18
Q
Aminoglycosides - Examples include
A
Gentamicin + Neomycin. All are bactericidal and active against some Gram-Positive and many Gram-Negative organisms.
19
Q
Aminoglycosides absorption
A
- They are not absorbed from the gut and therefore must be given by Injection for systemic infections.
20
Q
Aminoglycoside of choice in the UK
A
- Gentamicin is the aminoglycoside of choice in the UK and is used widely for the treatment of serious infections. It has a broad-spectrum but is inactive against anaerobes and has poor activity against haemolytic streptococci and pneumococci.
21
Q
- Aminoglycoside Loading and maintenance doses are calculated based on
A
the patient’s ideal bodyweight and renal function. Dose adjustments are then made based on serum levels; blood levels should be taken 1 hour after a dose and just before the next dose to establish the PEAK and trough concentrations.
22
Q
Aminoglycoside treatment should not exceed
A
7 days and it should be avoided in pregnancy
23
Q
Aminoglycoside dosing regimen
A
- ONCE daily administration of aminoglycosides is more convenient + provides adequate serum concentrations.
- But a ONCE daily, high dose regimen should be avoided in patients with endocarditis due to Gram-positive bacteria, HACEK endocarditis, burns of >20% of body surface area or CrCl less than 20mL/minute.
24
Q
Carbapenems
A
The Carbapenems are beta-lactam antibacterials with a BROAD-SPECTRUM of activity which includes many Gram-Positive and Gram-Negative bacteria and anaerobes.
25
Carbapenems examples
- Examples include Imipenum and Meropenum which have good activity against Pseudomonas Aeruginosa.
26
Carbapenems are used for
the treatment of severe hospital-acquired infections + polymicrobial infections including septicaemia, hospital-acquired pneumonia, intra-abdominal infections, skin + soft tissue infections + complicated UTIs.
27
Ertapenem is licensed for
treating abdominal + gynaecological infections and for CAP. It is also licensed for treating foot infections of the skin and soft tissue in patients with diabetes. However, it is not active against Pseudomonas.
28
Imipenum is partially inactivated in
the kidney by enzymatic activity and is therefore administered with Cilastatin (an enzyme inhibitor) which blocks renal metabolism. Meropenum and Ertapenem are stable to the renal enzyme and therefore can be given without Cilastatin.
29
Cephalosporins
The cephalosporins are broad-spectrum antibiotics which are used to treat many infections.
30
Cephalosporins examples
Cefotaxime, Cefuroxime and Cefalexin
- They penetrate the cerebrospinal fluid poorly unless the meninges are inflamed.
31
Suitable drugs for infections of the CNS (e.g. meningitis).
Cefotaxime and Ceftriaxone
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- ‘first generation’ cephalosporins (cefalexin) and the ‘second generation’ cephalosporin, cefaclor, are
useful for UTIs which do not respond to other drugs or which occur in pregnancy.
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- Cefuroxime axetil is
poorly absorbed and needs to be given with food to maximise absorption
34
Ceftriaxone has a
longer half-life and only needs to be given ONCE daily.
35
Cephalosporins - Treatment by mouth usually involves
cefalexin; it can be given in pregnancy and breast-feeding and is taken four times a day
36
Cephalosporins interactions
Cephalosporins possibly increase the anticoagulant effect of Warfarin.
37
Macrolides are
broad-spectrum antibiotics like Penicillin’s but are unrelated. Hence, they can be given as an alternative in penicillin-allergic patients.
38
Macrolides examples
Azithromycin, Clarithromycin and Erythromycin.
39
Erythromycin causes
- Erythromycin causes nausea, vomiting + diarrhoea in some patients. In mild-moderate infections this can be avoided by giving a lower dose, but if a more SERIOUS infection is suspected… HIGHER doses are needed.
40
With Azithromycin...
- With Azithromycin plasma concentrations are very low, but tissue concentrations are much HIGHER. It has a long tissue half-life and ONCE daily dosage is recommended. Do not take indigestion remedies 2 hours before/after taking this medication.
41
Clarithromycin is
an erythromycin derivative with slightly greater activity. Tissue concentrations are HIGHER than with Erythromycin and it is given TWICE daily.
42
Clarithromycin should be avoided in
- pregnancy and breast-feeding
43
Macrolides may interact with
Statins, CCB and Warfarin (increasing their concentration).
44
Azithromycin OTC
Azithromycin can be sold OTC for the treatment of confirmed, asymptomatic chlamydia trachomatis genital infection in those >16 years and for the epidemiological treatment of their sexual partners, subject to max single dose of 1g, max daily dose 1g and a pack size of 1g.
45
Penicillin’s activity
* bactericidal. They diffuse well into body tissues and fluids but penetration into the cerebrospinal fluid is poor except when the meninges are inflamed.
* They are excreted in the urine.
46
Penicillin Hypersensitivity
* Hypersensitivity reactions are the most important side-effect of Penicillin’s, around 1-10% of people are allergic, but only 0.05% of people will have an anaphylactic reaction.
* Patients with penicillin allergy will be allergic to all penicillin’s and possibly to cephalosporins + beta-lactam antibiotics, so they should not receive these.
47
Penicillin side effects
* Another notable side effect is the risk of encephalopathy, the risk is increased with very high doses or in severe renal failure.
* A common side effect of penicillin’s is diarrhoea which can cause colitis.
48
Benzylpenicillin can only be given by
• Benzylpenicillin can only be given by Injection since it is inactivated by gastric acid. Penicillin V is a similar, less active BUT GASTRIC-STABLE drug so suitable for oral administration.
49
Penicillin V should not be given in the treatment of... & can it be used in pregnancy and breastfeeding?
* serious infection because absorption can be unpredictable and plasma concentrations variable. It is indicated principally for respiratory-tract infections in children, for streptococcal tonsillitis and for continuing treatment after injections of Benzylpenicillin.
* Penicillin V can be used in pregnancy and breast-feeding. It is taken 4 times daily on an EMPTY stomach.
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Flucloxacillin
- is a penicillinase-resistant penicillin.
- Bacteria secrete penicillinases. However, Flucloxacillin is not inactivated by these enzymes so is effective in infections caused by penicillin-resistant staphylococci.
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Flucloxacillin is usually only used in the treatment of
* penicillin-resistant Staph infections. It can also be used in the treatment of Cellulitis. Can be given PO or IV as it is acid stable + well absorbed from gut.
* MRSA can be resistant to penicillin’s including Flucloxacillin.
52
Co-Amoxiclav: Cautions
• Cholestatic Jaundice:
Cholestatic jaundice can occur either during or shortly after use of co-amoxiclav. It is more common in >65 + men, but self-limiting. Max 14 days treatment duration.
53
Broad-spectrum penicillin’s
• Ampicillin is inactivated by penicillinases produced by Staph. Aureus and common Gram-negative bacteria such as E.Coli. As many bacteria are resistant, the use of Ampicillin for ‘blind’ therapy should be considered. Ampicillin is well excreted in the bile + urine.
• Ampicillin is principally indicated for exacerbations of chronic bronchitis, middle ear infections + UTIs
• It can be given by mouth but less than half the dose is absorbed, the absorption is further decreased by the presence of food in the gut.
• Amoxicillin is a derivative of Ampicillin which is better absorbed by mouth producing higher plasma and tissue concentrations.
• Absorption is not affected by the presence of food, so it can be taken with or without food.
- These antibiotics are safe to use in pregnancy and breast-feeding. They are taken 3 times a day.
54
Tetracycline and doxycycline can cause..
• Tetracycline and Doxycycline can cause yellow or grey staining of the teeth
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Tetracyclines
• Tetracyclines are broad-spectrum antibiotics but are rarely used due to resistance.
They have a role in the management of (MRSA) infection
• Tetracyclines may deposit in growing bones + teeth by binding to calcium resulting in staining of teeth, hence they cannot be used in children under 12.
• They should not be given in pregnancy due to effects on skeletal development in the 1st trimester. Administration during the 2nd or 3rd trimester may cause discolouration of the child’s teeth
• They should not be given during breast-feeding as they may cause discolouration of the child’s teeth
• The intestinal absorption of Tetracyclines may be impaired if given with Magnesium, Iron, Calcium, Aluminium, Zinc and antacids.
56
Quinolones should be discontinued
if psychiatric, neurological, tendon disorders or hypersensitivity (Inc. severe rash) reactions occur.
57
• Doxycycline can cause
oesophageal irritation. Avoid exposure to sun. Take with plenty water + food
58
Quinolones are useful against
Gram-positive and Gram-negative bacteria, but not against anaerobes.
59
Quinolones examples include:
Ciprofloxacin, Ofloxacin and Moxifloxacin
60
Quinolones Important safety information:
* they can induce convulsions in patients with or without a history of convulsions, taking NSAIDs at the same time may also increase the chances of having convulsions.
* Quinolones cause ARTHROPATHY (disease) of weight-bearing joints and are therefore not recommended in children and growing adolescents.
* Exposure to sunlight should be kept to a minimum and treatment should be discontinued if Photosensitivity develops.
* The quinolones may also cause tendon damage; hence they are contraindicated in patients with a history of tendon disorders related to quinolone use.
* They should be used with caution in patients over 60 (more prone to tendon damage) and those taking corticosteroids (increased risk of tendon damage).
* Quinolones should be avoided in pregnancy – due to the risk of arthropathy.
61
Ciprofloxacin should be taken
BD & not with milk, indigestion remedies, iron or zinc (leave a 2h gap). May impair skilled tasks (driving)
62
Nebulised Levofloxacin: SE:
Bronchospasm.
63
FLUOROQUINOLONE ANTIBIOTICS MHRA:
- Increased risk of aortic aneurysm and dissection - Report severe abdominal, chest or back pain
- Disabling, long lasting or potentially irreversible ADR affecting MSK and CNS - stop treatment at first signs of tendinitis or tendon rupture, muscle pain/weakness, joint pain/ swelling, peripheral neuropathy + CNS effects
64
Glycopeptide’s are effective against
against aerobic and anaerobic bacteria. They are given by Injection for systemic infections.
65
However, Vancomycin and Teicoplanin can be given
ORALLY for the treatment of C. Difficile infection. They should not be given orally for any other indication as they are not well absorbed.
66
Glycopeptide’s
* Plasma concentration must be monitored throughout therapy.
* Glycopeptide’s should generally be avoided in pregnancy.
* There is a risk of nephrotoxicity and ototoxicity.
67
Tazocin (brand)
* This drug contains Piperacillin and Tazobactam. It is a broad-spectrum antibiotic effective against anaerobes.
* It is given by injection and used for septicaemia, HAP and other complicated infections.
* It should not be used in pregnancy.
68
Metronidazole
• Metronidazole is an antibiotic with high activity against anaerobic bacteria and protozoa
• It cannot be taken with alcohol and should be avoided in pregnancy and breast-feeding
• It can cause nausea, vomiting, taste disturbances and furred tongue.
• Metronidazole is taken THREE times daily with food and a full glass of water
- Tinidazole has longer duration of action
69
Anthrax
• Anthrax is a bacterial infection of cattle + sheep which can be transmitted to human’s causing skin ulceration or a form of pneumonia
70
Inhalation or Gastrointestinal anthrax should be treated
1. Inhalation or Gastrointestinal anthrax should be treated initially with either Ciprofloxacin OR Doxycycline (>12y) combined with 1-2 other antibacterial (e.g. Amoxicillin, benzylpenicillin, chloramphenicol, clarithromycin, clindamycin, imipenem with cilastatin, rifampicin & vancomycin)
But when the condition improves… treatment can be switched to a SINGLE ANTIBACTERIAL.
Treatment should be continued for 60 days as germination may be delayed
71
Cutaneous anthrax should be treated with
2. either Ciprofloxacin OR Doxycycline for 7 days. Treatment may be switched to Amoxicillin if the infecting strain is susceptible
Treatment may need to be extended to 60 days if exposure is due to aerosol
A combination of antibacterials for 14 days is recommended for cutaneous anthrax with systemic features, extensive oedema or lesions of the head or neck.
For post-exposure prophylaxis… ciprofloxacin or doxycycline may be given for 60 days. Can switch to amoxicillin after 10-14 days if strain of B.anthracis is susceptible. Vaccination against anthrax may shorten prophylaxis duration
72
Leprosy
Leprosy is a contagious disease which affects the skin, mucous membranes and nerves causing discolouration and lumps on the skin.
• A 3-drug-regimen is recommended for multibacillary leprosy and a 2-drug-regimen for paucibacillary leprosy.
• Multibacillary leprosy should be treated with a combination of Rifampicin, Dapsone + Clofazimine for atleast 2 years. Leprosy reactions mostly occur after treatment and treatment should be continued during both Type 1 (reversal) + Type 2 (erythema nodosum leprosum) reactions.
• During type 1 reactions, neuropathic pain or weakness can result in permanent nerve damage. At this point, prednisolone should be given.
• Type 2 reactions involve painful and tender nodules on the skin which may respond to Aspirin. Severe type 2 reactions may require corticosteroids. Thalidomide (unlicensed) is useful for patients who become corticosteroid dependent, but it should be used under specialist supervision. It is teratogenic and thus, contraindicated in pregnancy. Increased doses of Clofazimine are also useful
• Paucibacillary Leprosy should be treated with Rifampicin + Dapsone for 6 months. If treatment is interrupted, the regime should be recommenced where it was left off to complete the full course.
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Multibacillary =
| Paucibacillary =
```
Multibacillary = many bacteria
Paucibacillary = few bacteria
```
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Lyme disease usually presents with
erythema migrans rash which becomes visible 1-4 weeks after tick bite but can appear from 3 days to 3 months + last for several weeks. Other symptoms: fever, swollen glands, malaise, fatigue, neck pain/stiffness, joint/muscle pain, headache, cognitive impairment, parasthesia
75
Lyme disease is a form of
arthritis caused by bacteria B.burgdorferi. It is transmitted by infected tick bites.
Doxycycline (unlicensed) is 1st line for early Lyme disease or Lyme arthritis. If unsuitable give Amoxicillin or if all above unsuitable give Azithromycin (unlicensed). If there is symptoms of CNS involvement IV Ceftriaxone is 1st Line but if it is CI then PO doxycycline should be considered
• I.V. administration of Ceftriaxone, Cefotaxime or Benzylpenicillin is recommended for Lyme disease associated with cardiac or Neurological complications.
The duration of treatment is usually 2-4 weeks. Lyme arthritis may require further treatment.
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Methicillin-resistant Staphylococcus aureus
Infection from Staph. Aureus strains resistant to Meticillin and Flucloxacillin can be difficult to manage.
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skin and soft-tissue infections caused by MRSA.
1. A tetracycline alone or a combination of Rifampicin + Fusidic acid can be used for skin and soft-tissue infections caused by MRSA. Clindamycin alone is an alternative.
78
severe skin + soft-tissue infections associated with MRSA
2. A Glycopeptide (e.g. Vancomycin) can be used for severe skin + soft-tissue infections associated with MRSA. If a Glycopeptide is unsuitable, Linezolid can be used on expert advice. But as its not active against Gram Negative organism’s, it must be given with other antibacterials if the infection involves Gram Negative organisms. A combination of a Glycopeptide + Fusidic acid or a Glycopeptide and Rifampicin can be considered for skin + soft-tissue infections that have failed to respond to a single antibacterial.
79
Bronchiectasis (widening of the bronchioles) caused by MRSA.
3. A tetracycline or Clindamycin can be used for Bronchiectasis (widening of the bronchioles) caused by MRSA. A Glycopeptide can be used for pneumonia associated with MRSA. If a Glycopeptide is unsuitable, Linezolid can be used on expert advice.
80
UTI caused by MRSA.
4. A tetracycline can be used for UTI caused by MRSA. Trimethoprim or Nitrofurantoin are alternative. A Glycopeptide can be used for UTIs that are severe or resistant to other antibacterials.
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for complicated skin + soft-tissue infections involving MRSA
5. Tigecycline + daptomycin
82
septicaemia associated with MRSA.
6. A Glycopeptide
83
Tuberculosis
Treatment should be started immediately, without waiting for culture results if the patient has clear symptoms of tuberculosis (cough >3 weeks, night sweats, chills, fatigue)
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Tuberculosis is treated in 2 stages:
the initial phase uses 4 drugs and the continuation phase uses just 2.
85
Tuberculosis initial treatment
* 4 drugs are used initially to rapidly clear the bacterial population and prevent resistance. Initial treatment is Rifampicin, Isoniazid, Pyrazinamide and Ethambutol – RIPE which are taken daily.
* The initial phase is continued for 2 months, after which Isoniazid and Rifampicin are continued daily for a further 4 months. Isoniazid is given preferably as a combination preparation with pyridoxine.
* RIP are linked with liver toxicity, so liver function should be checked before treatment begins
* Rifampicin induces hepatic enzymes which accelerates the metabolism of corticosteroids, phenytoin and anticoagulants. Combined oral contraceptive pills will become ineffective (metabolised)
86
A common side effect of Isoniazid is
• peripheral neuropathy – pyridoxine should be given. Vitamin B6 can become deficient during Isoniazid treatment
87
Ethambutol
* Ethambutol is not essential as RI since its main purpose is a backup in case there is isoniazid resistance
* Ethambutol can cause visual problems including blurry vision + colour blindness – patients should be told to stop using ethambutol if this is the case. (Ocular toxicity)
88
Pyrazinamide
• Pyrazinamide is a bactericidal drug which exerts its main effect only in the first 2 or 3 months. It is particularly useful for tuberculous meningitis because of good meningeal penetration.
89
Streptomycin
• is rarely used except for resistant organisms (do not use in pregnancy)
90
TB treatment in patients that cannot comply
A fully supervised treatment plan exists. It is called directly observed therapy and patients are given RIPE 3 times a week. It should be offered to patients who:
- Have a history of non-adherence, are in denial of tuberculosis diagnosis, have multi-drug resistant tuberculosis, have a major psychiatric/cognitive disorder, homeless, drug/alcohol misuse, in prison, too ill to self-administer or request directly observed therapy.
91
Central nervous system Tuberculosis
Patients with active CNS tuberculosis should be offered treatment with Rifampicin, Isoniazid, Pyrazinamide and Ethambutol (with pyridoxine for prophylaxis of isoniazid-induced neuropathy) for 2 months.
After completion of the initial treatment phase, Rifampicin and Isoniazid (with pyridoxine) should be continued for a further 10 months.
• An initial high dose of dexamethasone or prednisolone should be started at the same time as anti-tuberculosis therapy, and then slowly withdrawn over 4-8 weeks.
92
Pericardial tuberculosis
An initial high dose of oral prednisolone should be offered to patients with active pericardial tuberculosis at the same time as initiation of anti-tuberculosis therapy. It should then be slowly withdrawn over 2-3 weeks.
93
Latent tuberculosis
* Some patients with latent tuberculosis are at an increased risk of developing active tuberculosis (e.g. HIV positive, diabetic or receiving treatment with a tumour necrosis alpha inhibitor.)
* When indicated, drug treatment should only be given to patients aged 35-65 if hepatotoxicity is not a concern.
* Chemoprophylaxis involves the use of either Isoniazid (with pyridoxine) alone for 6 months or Rifampicin + Isoniazid for 3 months (recommended when hepatotoxicity is a concern).
* Testing for HIV, hepatitis B and C should be offered before therapy as this may affect choice of therapy.
94
A break in anti-tuberculosis treatment
of at least 2 weeks (during the initial phase) or missing >20% of prescribed doses is classified as treatment interruption. Treatment should be re-established as soon as possible to avoid relapse, drug resistance or further adverse events.
95
Following treatment interruption due to drug-induced hepatotoxicity
Following treatment interruption due to drug-induced hepatotoxicity… once hepatic function has recovered; anti-tuberculosis therapy should be re-introduced at the same dose (within 10 days) with ethambutol and either isoniazid (with pyridoxine) or rifampicin.
• In patients with severe or highly infectious tuberculosis who need to interrupt the standard regimen, consider continuing treatment with atleast 2 drugs with a low risk of hepatoxicity e.g. ethambutol and streptomycin.
• If a patient with severe or highly infectious tuberculosis has a cutaneous reaction, continue treatment with a combination of atleast 2 drugs with a low risk for causing cutaneous reactions e.g. ethambutol and streptomycin.
96
Resistance to Isoniazid:
First 2 months: rifampicin, pyrazinamide + ethambutol and continue with rifampicin + ethambutol for 7-10 months.
97
Resistance to Pyrazinamide:
First 2 months: rifampicin, isoniazid (pyridoxine) and ethambutol and continue with rifampicin + isoniazid for 7 months
98
Resistance to Ethambutol:
First 2 months: rifampicin, isoniazid (with pyridoxine) and pyrazinamide and continue with rifampicin and isoniazid for 4 months
99
Resistance to Rifampicin:
atleast SIX anti-tuberculosis drugs to which mycobacterium is likely to be sensitive.
100
Urinary Tract Infections
Urinary tract infections are more common in women than in men. Recurrent disease in men may indicate a renal tract problem.
E. coli is the most common cause of UTIs. Staphylococcus Saprophyticus is a common cause in sexually active young women.
101
UTI - A urine sample should be collected for culture and sensitivity testing before starting treatment in:
- Men
- Pregnant women
- Children under 3
- Suspected upper UTI
- If resistant organisms are suspected
102
UTI - Once a sample has been taken… treatment can begin immediately while waiting for test results.
* Uncomplicated lower urinary tract infections often respond to Trimethoprim, Nitrofurantoin (colours urine but harmless) or alternatively Amoxicillin, ampicillin or oral cephalosporin.
* Suggested duration of treatment is 7 days but a short course (3 days) is adequate for uncomplicated UTIs in women. Alternatives for resistant organisms include Co-Amoxiclav, quinolone or Fosfomycin.
* Long-term low dose prophylaxis can be used to prevent recurrence of infection with Trimethoprim, Nitrofurantoin and Cefalexin
103
Upper urinary tract infections
* Acute Pyelonephritis can lead to septicaemia and is treated initially by injection of a broad-spectrum antibacterial e.g. cephalosporin, quinolone (if severely ill) or gentamicin. Suggested duration of treatment is 10-14 days (longer treatment may be required if complicated)
* Prostatitis can be difficult to cure and requires treatment for several weeks with an antibacterial that penetrates the prostatic tissue e.g. quinolones (ciprofloxacin or ofloxacin) or alternatively trimethoprim. Suggested duration of treatment is 28 days.
104
In pregnancy - UTI
Penicillin’s and Cephalosporins can be used but avoid Nitrofurantoin during 3rd Trimester and Trimethoprim during 1st Trimester. Do NOT give sulfonamides and quinolones.
105
In renal impairment - UTI
antibacterials which are normally cleared by the kidneys accumulate resulting in toxicity. Hence aminoglycosides should be used with caution. Tetracyclines, Methenamine Hippurate (Hipprex) + Nitrofurantoin should be avoided.
106
Flucloxacillin can cause
• cholestatic jaundice and hepatitis (even up to two months after stopping). It should be used in caution with hepatically-impaired patients. Elderly + treatment >2w at increased risk.
107
Flucloxacillin in pregnancy and breast-feeding.
Flucloxacillin can be used in pregnancy and breast-feeding. It is taken 4 times daily on an EMPTY stomach
