Individual Assignment

Tropical Infection Module/2017/1nd Term/3st Grade

By Nabilla Merdika Putri Kusuma, 1406642385

PBL-GD1: Pharmacological Management of Fever

Overview
Body temperature regulation necessitates the balance between heat production and loss, in which it
is mainly mantained by hypothalamus. If the set point within hypothalamus is elevated beyond the
normal range due to diverse underlying mechanisms, fever will be elicited as the body response
towards the alteration. This can be due to the manifestation of inflammations, trauma, and other
origins either individually or together, which induce the release various inflammatory cytokines,
consequently acting as endogenous pyrogen, thus raising the set point of temperature.1

I. Antipyretic and Analgesic Drugs

Various drugs, termed as anti-pyretic, continue to be develop overtime to halt the fever condition.
These drugs are able to alleviate fever due to aforementioned circumstances, yet they are not
capable reduce the normal body temperature or when hyperthermia occurs. They function mainly to
reduce the PGE2 level in thermoregulatory center. Most commonly prescribed antipyretic drugs are
as follows: aspirin, ibuprofen, methampyrone, and acetaminophen (paracetamol). As denoted
previously aspirin and ibuprofen are classified within NSAIDs, which mainly work to inhibit
cyclooxygenase (COX) enzyme, thereby preventing the generation of prostaglandin. Several others
drug classified as NSAIDs, for instances: diclofenac, ketorofen, naproxen, and indomethacin might
also be used as antipyretic agents yet they often yield more side effects compared to those
aforementioned, furthermore they require higher doses to attain the desired clinical response.1

I.1 Aspirin
An over-the-counter (OTC) drug also known as acetyl salicylic acid. Aspirin has anti-inflammatory,
analgesic, and antipyretic properties by inhibiting the synthesis of PGE2. Aspirin is rapidly absorbed
via gastrointestinal tract, from stomach up to upper part of small intestine, and requires 1-2 hours to
reach the plasma maximum level. Hydrolization of aspirin by esterases mostly found in liver tissue
and blood resulting in acetic acid and salicylate, in which the last is bound with albumin within
bloodstreams. Then it would be excreted through urine with plasma half life only 15 minutes.
Adverse effects include gastrointestinal discomfort and ulcers, liver damage, asthma, skin rashes,
prolonged bleeding, and renal impairment. Aspirin is contraindicated in children below 12 years old
due to its probability to induce Reye’s syndrome, manifested as coma, seizures, cerebral edema,
internal organ dysfunctions, and death. The intoxication of this substance is commonly termed as
salicylism, demonstrated by nausea and vomiting, tinnitus, hearing loss, hyperventilation and
vertigo.2

I.2 Ibuprofen
The derivative of phenylproprionic acid which exhibits analgesic and antipyretic properties as
aspirin’s. It non-selectively inhibits COX and rapidly absorbed via gastrointestinal tract with half-
life approximately 2 hours. It needs 30-60 minutes before it exerts the effect on the body with
duration of action of six to eight hour. 90% of this drug is bound with albumin to be distributed
throughout bloodstreams, metabolized by the liver, and excreted via renal. Despite the lower anti-
inflammatory effect compared with aspirin, ibuprofen provokes lesser gastrointestinal problems in
comparison. The usual dose as antipyretic for children is 5-10 mg/kg orally, given 6–8-hourly, to a
maximum of 4 doses/day.2
 I.3 Methampyrone
Methampyrone is a derivative of pyrazolon with relatively low anti-inflammatory effect. Although
some countries had limited or banned the usage of methampyrone in everyday practices, yet the
consumption rate in Indonesia is still quite high due to various reasons. Side effects include
agranulocytosis, aplastic anemia, and thrombocytopenia. The drug is commonly being chosen if
parenteral route of administration is required.2

I.4 Paracetamol
Serves as an alternative to antipyretic-analgesic purposes with a relatively lower anti-inflammatory
effect compared to aspirin, also known as acetaminophen. It possesses the same pathway of
mechanism as aspirin by inhibiting PGE2 formation in the preoptic region of hyphotalamus.
Commonly consumed daily dose, 1000 mg, is shown to only inhibit both COX-1 and COX-2 in
about 50%, having said that study showed this inhibition applies disproportionate more to the brain,
explaining its effective antipyretic capability. Moreover, it has been suggested that paracetamol also
inhibits COX-3 in the brain. The oral bioavailability for paracetamol is high and requires 30 to 60
minutes to reach maximum plasma level with two hours plasma half-life. Same as previous drugs, it
is metabolized in the liver, minorly bound with plasma protein, and excreted via urine. The minor
metabolite of paracetamol, N-acetyl-p-benzo-quinone imine (NAPQI), is considered hepatotoxic
and nephrotoxic. This drug is preferable for children since it prompts lesser adverse effects
compared with other NSAIDs, also the usage is permitted in pregnancy. It has no deleterious
effects on various systems throughout the body, encompassing gastrointestinal cardiovascular,
respiration, and haemostasis systems, if consumed with proper therapeutic dose (adults: 3-4 x 500
mg/day). Nevertheless, in a very high dose the NAPQI produced surges, therefore causing the
depletion of hepatic gluthatione (GSH), accordingly it induces enzymatic, structural, and metabolic
disarrays of the liver, thereby resulting in liver necrosis. Others severe acetaminophen overdose
effects are renal tubular necrosis and hypoglycemic coma.
Paracetamol must be used cautiously for patients with hepatic problems and alcoholics. This drug is
recommended especially for those who are allergic towards or highly disadvantaged from the side
effects of aspirin. This comprises of patients with gastric acid problems, haemostatic disorders,
virally infected children, infants bronchospasm, also pregnant and lactating mothers. There are
various drug forms of paracetamol such as oral, rectal, and intravenous forms, despite the last two
are selected if the oral route is not possible. The recommended dose of acetaminophen/paracetamol
for children is 15 mg/kg (max 600 mg), orally, no more than every 4 h, to a maximum of 4
doses/day(max 2.4 g/day).1,2

II. Antibiotics in Managing Fever in Children

All infants aged 1-3 months admitted with fever are recommended to be given empirical antibiotic
therapy, although the identification of low-risk infants which may or may not require antibiotic
therapy is still very important if possible. The antibiotic choice will depend on the stage of the
illness, immunization status, and epidemiological factors. For child without focal infection and mild
to moderate disease severity, normal urinalysis, and the absence of meningitis, and there are
indications of infection, below is the list of recommended antibiotics therapy:
• 0–3 months old: amoxi/ampicillin 50 mg/kg IV, 6-hourly PLUS gentamicin 7.5 mg/kg IV,
daily 4 months to 4 years: benzylpenicillin 30 mg (50,000 U)/kg IV, 6-hourly OR
ceftriaxone 50 mg/kg IV or IM, daily
• Over 4 years: the combination of benzylpenicillin 30 mg (50,000 U)/kg (max 1.2 g or 2
million U) IV, 6-hourly PLUS di/flucl/oxa/nafcillin 50 mg/kg (max 2 g) IV, 6-hourly OR, as
single agent, cefotaxime 50 mg/kg IV, 8-hourly OR ceftriaxone 50 mg/kg IV or IM, daily
These recommendations are based on epidemiologic data on the suspected causative agents in
developing countries. Ceftriaxone 50 mg/kg IM as a daily dose has been widely recommended and
often used, especially when hospitalization is not an option or is not preferred.3,4

Figure 1. Pharmacokinetic of Penicillin (1)

III. Antimicrobial Therapy for Specific Disease

III.1 Typhoid
Therapy guideline for typhoid fever is divided to two main classifications: general and specific.
The general one comprises of rehydration, anti-pyretic prescription, nutrition, and blood
transfusion. As for the specific management, antibiotic is used depends on several factors such as
efficacy, availability, and affordability. Based on those parameters, cholaramphenicol is still the
drug of choice to combat the disease in children, especially in developing country. The first line
drug for adults with typhoid fever is fluoroquinolone group, for instances, ofloxacin, ciprofloxacin,
or levofloxacin. Currently, resistance towards several antibiotics which were initially used to
suppress salmonella emerges, a condition termed as Multi Drug Resistance (MDR). The followings
are table depicting the management guideline to treat salmonella based on severity:

Figure 2. Guideline for Typhoid Fever (4)

 • Chloramphenicol
A bacteriostatic broad-spectrum antibiotic works by inhibiting the protein synthesis of bacteria
through the irreversible binding with 50s subunit of microbial ribosomes, thereby hindering the
formation of peptide bond. Ten percent of the administrated dose stays as active compound whereas
90% is conjugated with liver glucoronic acid or reduction to inactive aryl amines. The inactive
metabolites later is excreted via urine, only minor concentration is eliminated through bile and
feces. Usage in patient with hepatic failure must be taken into caution and dosage for neonates must
be lowered to 25 mg/kg/d since they have limited clearance capability. The adverse reactions
include gastrointestinal disturbances, although rare in children and commonly found in adult cases,
also if consumed beyond recommended dosage infants and neonates may develop gray baby
syndrome due to the accumulation of toxic metabolites, indicated by vomiting, flaccidity,
hypothermia, gray color, shock, and vascular collapse. This drug may interact with other drugs by
way of inhibiting liver microsomal enzymes, which in turn prolong the half-lives of several drugs,

Figure 3. Pharmacokinetic of Chloramphenicol (1)

such as phenytoin, tolbutamide, chlorpropamide, and warfarin. Chlorampenicol can also antagonize
bactericidal drugs, for instances penicillin and aminoglycosides.1,2,4
• Fluoroquinolone
A synthetic fluorinated nalixidic acid analogs which is active against gram-positive and gram-
negative bacteria. The mechanism of action is by blocking bacterial DNA synthesis through
impediment of topoisomerase II (DNA gyrase) and topoisomerase IV enzymes. Inhibition of DNA
gyrase prevents the relaxation of positively supercoiled DNA that is required for normal
transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated
chromosomal DNA into the respective daughter cells during cell division. Generally,
fluoroquinolones have more efficacy towards gram-negative bacteria and lesser activity against
gram positive bacteria, however, presently several newer agents have been developed to be more
effective against gram positive cocci. The most active substance for gram-negative is ciprofloxacin,
whereas the L-isomer of the substance, levofloxacin, has superior capability to fight gram-positive
organisms. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache,
dizziness, insomnia, skin rash, or abnormal liver function tests develop. Phototoxicity, elongation of
QT interval, and tendinitis can also develop as adverse effects of this drug. Fluoroquinolones may
damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely
recommended for patients under 18 years of age even though the arthropathy is reversible.
Fluoroquinolones should be avoided during pregnancy in the absence of specific data documenting
their safety.1,2,4

Figure 4. Pharmacokinetic of fluoroquinolone (1)

 • Other Drugs Used in Treating Typhoid Fever
Amoxicillin and ampicillin, both drugs have lower efficacy to treat typhoid fever compared to
chloramphenicol. It is usually indicated for patient with leukopenia. The use of clavulanic acid as
adjuvant is not proven to be beneficial in typhoid fever patients. Usually amoxicillin is given per
oral with pediatric dose 20-40 mg/kg/d in 3 separate dose and 0.25-0.5 g tid for adults in about 14
days and ampicillin is given intravenously in managing patient with typhoid. The resolution of fever
is commonly attained after 5 days of treatment. This drug can also be used as therapy for the carrier
of typhoid infection.

Figure 5. Treatment for Typhoid Career(4)

Trimethoprim-sulfomethoxazole is considered to have the same efficacy in typhoid fever treatment,

and indicated for patient with chloramphenicol resistant used together with amoxicillin. Third
generation cephalosporin is designed to be more effective against gram negative bacteria and some
are capable to cross blood-brain-barrier. Ceftriaxon and cefotaxime are commonly selected if the
patient is chloramphenicol resistant, given for approximately 14 days to reduce the proximity of
disease relapse. Cefixime is not commonly used as first-line therapy for typhoid fever without
complications, distinctly it is commonly utilized as second- or third-line therapy for Multiple Drug
Resistance (MDR) bacteria after ceftriaxone. Studies showed that the utilization of third generation
cephalosporin has a low probability of disease relapse. Macrolides serves as first-line therapy for
typhoid fever in patient with resistance towards quinolone and used for a relatively short period (1
week) in uncomplicated typhoid fever.2,4

Figure 6. Pharmacokinetic of 3rd Generation Cephalosporin (1)

III.2 Dengue Hemorrhagic Fever (DHF)

Management of dengue is distinguished into three phases. During fever phase, the requirement of
treatment is only symptomatic and supportive in essence. The antipyretic drug of choice is
paracetamol with dosage of 10mg/kg/dose with interval of 4 hours if the body temperature exceeds
38 degree celcius. Aspirin or NSAIDs usage should be avoided. Critical phase will follow shortly
afterwards, and the treatment concentrates on keeping the balance of body fluid (intravascular
volume, blood pressure, and urine output), which is mainly done through intravenous route. The
chosen solutions are commonly from crystalloid category (isotonic (0.9%) sodium chloride
solution, ringer lactate and acetate) with dosage varies according to several parameters, such as age,
body weight, and the presence of shock. If the critical phase has been resolved, the resolution phase
will take place afterwards. During the last phase, intravenous solution therapy is still necessary and
controlled based on vital signs, clinical condition, laboratory results, and urine production. The
misuses of anti-pyretic and antibiotic are common mistakes during this phase. Intravenous solution
is not required in the absence of plasma leakage. Lastly, blood or thrombocytes transfusion might
be needed if the massive bleeding occurs due to biological shock. There is no specific antiviral
medication for dengue at the present time.4

III.3 Mumps, Measles, Rubella, and Common-cold

There is no current specific antiviral treatment for those diseases. Bed-rest and antipyretic drugs,
commonly paracetamol or ibuprofen, are commonly done to manage patient with aforementioned
disease. Vitamin A had been reported to be associated with reduced mortality rates in children with
measles. Empiric antibiotic therapy may be administered if the children have suspected concomitant
bacterial infection due to immunosuppression and superinfection. Over the counter cough
suppressants or decongestant might be needed in common-cold treatment, yet those substances are
contraindicated for children below four years old.3

IV. Conclusion
For children with fever the use of antipyretics might be beneficial to reduce fever and irritability.
The examples of commonly used drugs are paracetamol and ibuprofen (not recommended for
babies <6 months old), yet it is not advised to consume both drugs more than 3 days without
seeking professional medical advice. Additionally, non-pharmacological method, such as tepid
sponging must be incorporated in fever management.3

References

1. Katzung B, Masters S, Trevor A. Basic & clinical pharmacology. 1st ed. New York: McGraw-
Hill Medical; 2009.
2. Goodman L, Gilman A, Brunton L, Lazo J, Parker K. Goodman & Gilman's the pharmacological
basis of therapeutics. 1st ed. New York: McGraw-Hill; 2006.
3. Isaacs DElliott E. Evidence-based pediatric infectious diseases. 1st ed. Malden, Mass.:
BMJ/Blackwell; 2007.
4. Rezeki Hadinegoor S, Kadim M, Devaera Y, Salamia Idris N, Gita Ambarsari C. Update
Management of Infectious Diseases and Gastrointestinal Disorders. 1st ed. Jakarta:
Departemen Ilmu Kesehatan Anak FKUI-RSCM; 2012.