Points to Note When Using Antibiotics to Treat Pneumonia in Children

Children < 5 years old: Common causes are pneumococcus and Haemophilus influenzae , antibiotics of choice:

- Amoxicillin 80 mg/kg/day, orally, divided into 2 times. Or

- Amoxicillin - clavulanic 80 mg/kg/day, orally, divided into 2 times. Treatment duration 5 days.

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- If the child is allergic to beta lactams or suspected of having atypical bacterial pneumonia, use macrolides (Azithromycin, clarithomycin or erythromycin) (Hong Ngu Regional General Hospital, 2015).

Severe pneumonia

- Hospitalization.

- Respiratory support if respiratory failure occurs.

- Antibiotics:

Benzyl penicillin: 50,000 units/kg IM or IV/6 hours, at least 3 days. When improved, switch to oral amoxicillin 15 mg/kg/time × 3 times/day, at least 5 days (usually 7-10 days).

If no improvement after 48 hours, switch to chloramphenocol or third-generation cephalosporin until improvement, then maintain oral route for 10 days (Hong Ngu Regional General Hospital, 2015).

Very severe pneumonia

Children with severe pneumonia are hospitalized, the initial antibiotic of choice is a penicillin A drug combined with an aminoglycoside drug. Choice:

- Ampicillin 200 mg/kg/24 hours, divided into 4 times, slow intravenous injection every 6 hours.

- Combined gentamycin 5 - 7.5 mg/kg intramuscular injection once.

- Use cefotaxime 100 - 200 mg/kg/24 hours, divided into 2 - 3 slow intravenous injections, used when the above drugs fail or used from the beginning.

- Use injectable antibiotics for at least 5 days, then switch to oral antibiotics for a full 10 days.

- If there is evidence of staphylococcal pleurisy, use oxacillin or cloxacillin 200 mg/kg/24 hours, divided into 4 doses, slow intravenous injection. Combined with gentamicin

5 - 7.5 mg/kg/24 hours. Aspiration or drainage of pus when there is pleural empyema. Treatment for at least 3 weeks.

- If there is evidence of atypical bacterial pneumonia: Take macrolide if the child does not have respiratory failure. If the child has respiratory failure, use levofloxacin by slow intravenous injection 15 - 20 mg/kg/12 hours, twice a day. Treatment duration is 1 - 2 weeks (Hong Ngu Regional General Hospital, 2015).

2.3.4 Points to note when using antibiotics in the treatment of pneumonia in children

- Choosing the right antibiotics for children: There are not many antibiotics that are contraindicated for children, most of them need to have their dosage adjusted according to age. The most important antibiotics to be noted when using for premature babies and newborns are aminosides (Gentamicin, amikacin...), glycopeptides (Vancomycin), polypeptides (Colistin) because these are antibiotics that can be distributed widely in the water phase, so they diffuse very widely in these age groups. Absolutely do not use antibiotics in the quinolone and tetracycline groups; Do not use chloramphenicol and Sulfamide derivatives for newborns.

- Choosing the appropriate form: For children, choosing the form of the drug is also very important. Each form of drug has its own method of use and route of administration, with different drug release characteristics. Depending on the severity of the disease, the child can be given antibiotics orally, intramuscularly or intravenously.

- Choice of drug form: Oral administration is recommended. Intravenous injection is only used in cases of severe illness. Avoid intramuscular injection because it causes pain and muscle stiffness.

- Antibiotic dosage: Children's dosage should be calculated based on the child's weight, expressed by the following formula (mg/kg):

In addition, it can also be calculated by age and skin area, but calculating by weight is most common.

- Number of times to take the drug per day: The number of times to take the drug per day must be based on the pharmacodynamic and pharmacokinetic properties of the antibiotic, especially the T 1/2 value (Nguyen Thi Ngoc Hoa, 2014).

- According to the study by author Le Thanh Truc et al. (2011) on "Evaluation of the rational use of antibiotics in the treatment of pneumonia in the pediatric department of An Giang hospital from September 2010 to January 2011" showed that: In the group of mild pneumonia, there were still many cases of incorrect use of the route of administration when starting antibiotic treatment and some cases of inappropriate use of antibiotics. Incorrect use of doses occurred in all 3 groups, in the group

Pneumonia, incorrect dose prolongs hospital stay, fever-free time prolongs respiratory failure recovery time.

- According to the study by author Hoang Thi Hue, collaborators (2013) on "Survey of antibiotic use in the treatment of acute respiratory infections in children at Thai Nguyen Central General Hospital 2012" showed that: 71.0% of patients used antibiotics before coming to the hospital, of which 28.0% of families bought antibiotics themselves, beta lactam group was used the most. 100.0% of acute respiratory infections were treated with antibiotics, of which 451 children (33.7%) were treated with one type of antibiotic, 527 children (39.4%) were treated with 2 types of antibiotics from the beginning, 185 children (13.8%) were treated with 3 types of antibiotics, especially 175 children (13.1%) used up to 4 types of antibiotics (Hoang Thi Hue et al. , 2013).

- According to the study by authors Nguyen Thi Van Anh and Nguyen Van Bang (2007) "Survey of antibiotic use in the treatment of pneumonia in children at the Department of Pediatrics, Bach Mai Hospital in 2006" showed that: All 303 children with pneumonia admitted to the hospital were treated with antibiotics for 2 to 32 days, an average of 8.7 ± 4.2 days, of which the majority (68.7%) were treated with one antibiotic, 30.3% were treated with 2 or more antibiotics. The most common initial antibiotic treatment at the hospital was 1st generation cephalosporin (48.5%), the main alternative antibiotic was 3rd generation cephalosporin (31.0%). 15.2% of children were given a combination of antibiotics upon admission, between cephalosporin (1st, 2nd and 3rd generation) and aminoside. The average duration of aminoside use was 6.0 ± 2.4 days, of which 55.8% were used for more than 5 days (Nguyen Thi Van Anh and Nguyen Van Bang, 2007).

- According to author Nguyen Thi Mai Hoa in the study "Survey of antibiotic use in the treatment of pneumonia in children at the Pediatrics Department of Ly Nhan General Hospital, Ha Nam", because there are no conditions to make antibiotic resistance charts, doctors choose to use antibiotics based on experience and treatment regimens in "Pediatrics Treatment Regimen 2006" of the Medical Publishing House. The rate of incorrect antibiotic dosage at the hospital is 40.7%, the main route of administration is injection, over 90.0%. Most of the antibiotics used are third-generation cephalosporin antibiotics widely (Nguyen Thi Ngoc Hoa, 2014).

2.4 SOME COMMONLY USED ANTIBIOTICS IN THE TREATMENT OF PNEUMONIA IN CHILDREN UNDER 5 YEARS OLD

2.4.1 Penicillin group

- Amoxicillin and Clavulanate

Antibacterial properties

Amoxicillin is a semisynthetic antibiotic of the beta-lactam family with a broad spectrum of bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting bacterial cell wall synthesis. However, because amoxicillin is easily destroyed by beta-lactamase, it is ineffective against strains of bacteria that produce these enzymes (many strains of Enterobacteriaceae and Haemophilus influenzae ).

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus , has a beta lactam structure similar to penicillin, and is capable of inhibiting beta lactamase produced by most Gram-negative bacteria and Staphylococcus . In particular, it has a strong inhibitory effect on plasmid-borne beta lactamases that cause resistance to penicillins and cephalosporins.

The antibacterial spectrum of the drug includes: Gram-positive bacteria

Aerobic type: Streptococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Staphylococcus aureus, Corynebacterium, Bacillus anthracis, Listeria monocytogenes.

Anaerobic type: Clostridium species , Peptococcus, Peptostreptococcus . Gram-negative bacteria:

Aerobic type: Haemophilus influenzae, Escherichia coli, Proteus mirabilis, Proteus vulgaris, Klebsiella species , Salmonella, Shigella, Bordetella, Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pasteurella multocida .

Anaerobic type: Bacteroides species including Bacteroides fragilis (Ministry of Health, 2009).

Pharmacokinetics

Amoxicillin and clavulanate are both readily absorbed after oral administration. Peak serum concentrations of both agents occur 1 to 2 hours after oral administration.

With a dose of 250 mg (or 500 mg) there will be 5 micrograms/ml (or 8 – 9 micrograms/ml) of amoxicillin and about 3 micrograms/ml of clavulanic acid in the serum. After 1 hour of taking 20 mg/kg amoxicillin + 5 mg/kg clavulanic acid, there will be an average of

8.7 micrograms/ml amoxicillin and 3.0 micrograms/ml clavulanic acid in serum. Absorption of the drug is not affected by food and is best taken immediately before meals.

The oral bioavailability of amoxicillin is 90.0% and that of clavulanic acid is 75.0%. The serum half-life of amoxicillin is 1 - 2 hours and that of clavulanic acid is about 1 hour.

55.0 – 70.0 % of amoxicillin and 30.0 – 40.0 % of clavulanic acid are excreted in the urine in active form. Probenecid prolongs the excretion time of amoxicillin but does not affect the excretion of clavulanic acid (Ministry of Health, 2009).

Dosage and administration

Oral form

Children 40 kg and over , 1 tablet of 250 mg every 8 hours.

For severe infections and respiratory tract infections: 1 tablet of 500 mg every 8 hours for 5 days.

Children under 40 kg weight : Usual dose: 20 mg/kg amoxicillin/day, divided into several doses 8 hours apart.

For the treatment of severe infections, the usual dose is 40 mg amoxicillin/kg/day divided into several doses every 8 hours for 5 days. Children under 40 kg in weight should not use the 250 mg film-coated tablet (Ministry of Health, 2009).

Injection form

Children, infants, newborns:

Use 500 mg injection vial. Do not exceed 5 mg/kg body weight of Clavulanic Acid per injection.

Children from 3 months to 12 years: 100 mg/kg/day, divided into 4 times, injected very slowly intravenously or by infusion. In severe infections, up to 200 mg/kg/day can be used, divided into 4 infusions. The maximum dose of clavulanic acid is 20 mg/day.

Newborns over 8 days old and children under 3 months old: From 100 mg to

150 mg/kg/day divided into 3 infusions. The maximum dose of clavulanic acid is 15 mg/kg/day.

Treatment should not exceed 14 days without re-examination (Ministry of Health, 2009).

Undesirable effects

At normal doses, adverse reactions occur in over 5.0% of patients, most commonly gastrointestinal reactions: diarrhea, nausea, vomiting. Skin: rash, itching. The rate of these reactions increases with higher doses and is more common than with amoxicillin alone (Ministry of Health, 2009).

2.4.2 Cephalosporin Group Classification

Although cephalosporins can be classified according to chemical structure, clinical pharmacology, beta-lactamase resistance, or antibacterial spectrum, the “generation”-based classification has been the most widely accepted and used.

Generational classification based on antibacterial activity of Cephalosporins

Generation 1 (including cephalothin, cefazolin, cephalexin...) has good effect on Gram (+) bacteria and some Gram (-) bacteria. Most Gram (+) cocci are sensitive except Enterococci and Methicillin- resistant Staphylococcus aureus , Staphylococcus epidermidis. Most anaerobic bacteria in the oral cavity (except Bacteroides fragilis ) are also sensitive. Good effect on Moraxella catarrhalis, E.coli, Klebsiella pneumoniae, Proteus miabilis.

Second-generation cephalosporins have a broader spectrum of activity against Gram (-) bacteria than first-generation cephalosporins, but are less active than third-generation cephalosporins. These drugs are also more resistant to beta-lactamase. Some antibiotics (Cefoxitin, cefotetan, cefmetazol) have good activity against the Bacteroides fragilis group .

Third-generation cephalosporins are less effective against Gram (+) cocci than first-generation cephalosporins, but are more active against Enterobacteriaceae, including beta-lactamase-producing species. Some antibiotics such as ceftazidime and cefoperazone are effective against P.aeruginosa .

Fourth-generation cephalosporins (Cefepime) have an extended spectrum of activity like third-generation cephalosporins but are more effective against aerobic Gram (-) bacteria that are resistant to third-generation cephalosporins.

General pharmacokinetic characteristics of cephalosporins

Cephalosporins can be administered intramuscularly, intravenously, or orally, depending on the preparation. Cephalosporins are excreted mainly in active form by the kidneys. Dosage may be modified in patients with renal failure, except for cefoperazone and cefpiramid (which are mainly excreted in the bile). Third-generation cephalosporins can penetrate the blood-brain barrier in concentrations sufficient to treat meningitis. Cephalosporins can also be

Penetrates into the placenta, synovial membrane and pericardium. Penetration into the ocular fluid of third-generation cephalosporins is quite good, but penetration through the lens is poor. Concentrations in bile are quite high, especially when using cefoperazone and cefpiramid (Ministry of Health, 2009).

- Some specific antibiotics

Cefalexin is a first-generation cephalosporin antibiotic for oral use, with good activity against penicillinase-producing and non-penicillinase-producing Staphylococcus aureus . The drug is almost completely absorbed in the gastrointestinal tract and reaches peak plasma concentrations of about 9 and 18 micrograms/ml after one hour with oral doses of 250 and 500 mg, respectively; a double dose doubles the peak concentration. The drug is excreted in 20.0

– 50.0% by hemodialysis and peritoneal dialysis.

Cefaclor is a semisynthetic, second-generation oral cephalosporin antibiotic. Cefaclor is active against Gram (+) cocci and is resistant to many beta-lactamase enzymes of Gram (-) bacteria. The drug reaches mean peak plasma concentrations of approximately 7 and 13 micrograms/ml, respectively, after 30 to 60 minutes, with doses of 250 mg and 500 mg taken in the fasting state. Cefaclor is 85.0% excreted unchanged by the kidneys within 8 hours.

Cefotaxime is the first antibiotic of the third generation. The drug is effective against aerobic Gram (+) and Gram (-) bacteria, and has poor effect against Bacteroides fragilis . The drug's half-life is 1 hour. The drug is metabolized into deacetyl-cefotaxime, a less active form. Cefotaxime is used effectively in the treatment of meningitis caused by Haemophilus influenzae , penicillin-sensitive pneumococci and Neisseria meningitidis (Ministry of Health, 2009).

2.4.3 Aminoside group

- Gentamicin

Antibacterial properties

The drug is effective against most Gram (-) intestinal bacilli such as: E.coli, Enterobacter, Klebsiella, Proteus, Citrobacter, Serratia and Yersinia. Other Gram (-) bacteria are also sensitive, however, the serious resistance of aerobic Gram (-) bacteria to getamicin may limit the use of this drug in the future. For Gram (+) bacteria, only Staphylococcus aureus and Staphylococcus epidermidis are sensitive to the drug (Ministry of Health, 2009).

Pharmacokinetics

To achieve serum drug concentrations similar to those in adults, children require higher doses due to their larger volume of distribution. Intramuscular injection with a dose

2 - 2.5 mg/kg body weight/time in children under 5 years old, the maximum drug concentration achieved in serum is 7 mg/ml after 1 hour. The drug's half-life is about 4 hours and after 8 hours the drug concentration decreases to 1 mg/ml. The drug is excreted in active form mostly through the kidneys through glomerular filtration (Ministry of Health, 2009).

Dosage and administration

Children under 5 years old are given 2 - 2.5 mg/kg body weight intramuscularly or intravenously every 8 hours. Children under 7 days old are given a reduced dose of 2.5 mg/kg body weight every 12 hours. Experimental studies have shown that using a total daily dose in a single injection is equally effective and less toxic than when divided into multiple doses. Currently, Gentamicin as well as other Aminosides are indicated for injection once a day, intramuscularly or slowly intravenously or by short-term infusion (Ministry of Health, 2009).

Undesirable effects

Like other drugs in the Aminosid group, the drug is toxic to the ears (causing vestibular disorders or deafness) and toxic to the kidneys (Ministry of Health, 2009).

2.4.4 Macrolide group

Including drugs erythromycin, azithromycin, spiramycin...

- Erythromycin

Antibacterial properties

Effective against pneumococci, streptococci, Mycoplasma pneumoniae, Haemophilus influenzae , and effective against staphylococci and Gram (-) bacilli (Ministry of Health, 2009).

Pharmacokinetics

The drug is widely distributed in fluids and tissues. 70.0 - 90.0% of the drug binds to plasma proteins. More than 90.0% of the drug is metabolized in the liver and excreted mainly in the bile, a small part is excreted in the urine (Ministry of Health, 2009).

Dosage and administration

Adults: 1 - 2 g/day divided into 2 - 4 times. In severe infections, the dose may increase.

4 g/day divided into several times. Children about 30 - 50 mg/kg body weight/day, in case of severe infection, the dose can be doubled. Children from 2 - 8 years old use 1 g/day divided into several times. Children under 2 years old use 500 mg/day divided into several times (Ministry of Health, 2009).

Undesirable effects

Can cause digestive disorders, liver toxicity... (Ministry of Health, 2009).

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