Which adverse effect can result if tetracycline is administered to children younger than 8?

Pre-Clinical Research

Tetracyclines have a broad spectrum of activity against many gram-positive and gram-negative bacteria as well as Mycoplasma, Chlamydia, Rickettsiae, Plasmodia, and amoebae. They are usually bacteriostatic. They are also active against Streptococcus pneumoniae. The tetracyclines are active against most gram-positive bacilli, including Actinomyces israelii, Arachnia, Bacillus anthracis, Listeria monocytogenes, and most clostridia and Nocardia. Many gram-negative bacteria are resistant to tetracyclines. Penicillin-sensitive Neisseria gonorrhoeae and meningococci are sensitive to tetracyclines, whereas penicillin-resistant gonococci tend to be resistant to them. Most community acquired E.coli, Xanthomonas maltophilia, and Pseudomonas pseudomallei are sensitive to tetracyclines, as are most vibrios, Campylobacter, Helicobacter, Pasturella multocida, Brucella, and some Haemophilus spp Klein and Cunha (1995).

1 Introduction

Tetracyclines are natural products derived from Actinomycetes which inhabit the environment. Although first reported in 1948, the consumption of tetracycline goes long back in history. Anthropological research has revealed that bones of Sudanese Nubians dating from 350 to 550 AD excavated near the town of Wadi Halfa along the course of the river Nile were rich in tetracycline. Fluorophore-based analysis revealed that the concentration of tetracycline in bones matched therapeutic level of intake even though the active ingredient was not consumed for medical reasons. Overgrowth of Actinomycetes in bins made of clay used to store grains may have led to consumption of tetracycline in diet. This may have had an effect on the health of the population and their susceptibility to various infections including malaria. It may also have led to adverse effects such as inhibition of spermatogenesis, which over an extended period of time has the potential to determine the fate of a population (Bassett et al., 1980).

Tetracyclines are broad-spectrum bacteriostatic antibiotics. Their low cost and absence of major side effects other than in pregnant adults have contributed to their widespread use. As growth promoters, tetracyclines have been extensively used in animal feed. This has resulted in an increase in the number of tetracycline-resistant pathogens consequently limiting their use in clinical practice. New generation tetracyclines which are effective against a broad range of pathogens including multidrug resistant (MDR) bacteria have been developed and are now widely available.

Chlortetracycline and oxytetracycline are the first-generation tetracyclines developed between 1948 and 1963. Doxycycline and minocycline are the typical second generation tetracyclines of the period 1965–72. The third generation includes tigecycline, which is a glycylcycline (Chopra and Roberts, 2001). The two novel fully synthetic tetracyclines, omadacycline and eravacycline, belong to the fourth generation (Markley and, Wencewicz, 2018). Fig. 1 illustrates the chemistry of tetracycline and doxycycline (Christensen, 2015).

Metabolism

Tetracyclines can increase blood urea nitrogen or serum urea concentrations without a corresponding increase in serum creatinine (that is without accompanying renal damage). The mechanism is an excess nitrogen load of metabolic origin accompanied by negative nitrogen balance. This effect is termed “anti-anabolic” [107,108], but is in fact the result of inhibition of protein synthesis, which affects not only microorganisms but to some degree mammalian cells also. Sodium and water depletion, due to the diuretic effect of some tetracyclines, can further enhance uremia [107].

Tetracyclines have been associated with hypoglycemia [109]. Insulin doses may have to be reduced [110].

Tetracyclines

Tetracyclines are broad spectrum antibiotics obtained from Streptomyces strains or semisynthetically prepared. Use of tetracyclines has resulted in three types of renal effects. First, the use of outdated tetracyclines results in direct proximal tubular toxicity characterized by the increased excretion of amino acids, glucose, and phosphate (Fanconi syndrome). The mechanism of this response is unclear, but appears to be due to the formation of the degradation product anhydro-4-epi-tetracycline. Second, administration of some tetracyclines, particularly demeclocycline, can result in a dose-dependent reversible nephrogenic diabetes insipidus, which appears to result from an inhibition of ADH effects on water reabsorption. Last, in patients with preexisting compromised renal function, tetracyclines can induce increased sodium excretion and azotemia. The mechanism of the natriuresis may be due to an effect of tetracyclines on luminal membrane sodium conductance, while the azotemia appears to result from the antianabolic effects of the tetracyclines.

Pharmacokinetics

Tetracyclines are incompletely absorbed from the gut, particularly if taken with food. Absorption of oxytetracycline is further impaired by milk, antacids (see Chapter 33), iron and increased intestinal pH. Tetracyclines bind to divalent and trivalent cations, forming inactive chelates (see Chapter 56). The tetracyclines diffuse reasonably well into sputum, urine, and peritoneal and pleural fluid; they cross the placenta but penetrate the CSF poorly.

Tetracyclines are concentrated in the liver and are to some extent excreted via the bile into the small intestine, from where they are partially reabsorbed. Drug concentrations in the bile may be three to five times higher than in the plasma. Tetracyclines are mainly eliminated unchanged in the urine with the exception of doxycycline, which is largely eliminated in the bile. All of the tetracyclines have half-lives within the range 8–22 hours.

Drug interactions

Tetracyclines and all other antimicrobial ribosomal protein synthesis inhibitors may reduce the efficacy of antibiotic cell wall inhibitors, which rely on cell wall division for their action. Polyvalent cations (aluminum, Ca2+, zinc, iron, magnesium, bismuth) may decrease gastric tetracycline absorption by chelation. Na+ bicarbonate alters the gastric pH and reduces absorption of tetracyclines.

Serum levels of tetracyclines may be reduced from increased hepatic metabolism induced by barbiturates, carbamazepine, and hydantoins. The addition of tetracyclines to coumarin anticoagulants (e.g., warfarin) may greatly increase the latter’s effect on the INR and lead to serious bleeding episodes. The effect is partially due to the inhibitory effect of tetracyclines on the intestinal flora that produce vitamin K.

6.4 Tetracycline-Based MMP Inhibitors

Tetracyclines are antibiotics that can chelate Zn2 + ion and thereby inhibit MMP activity.75 Doxycycline is a semisynthetic tetracycline that inhibits MMP-2 and MMP-9.120 Chemically modified tetracyclines have been developed to inhibit MMP activity.120 Chemically modified tetracyclines are preferred overconventional tetracyclines because they reach higher plasma levels for prolonged periods of time and therefore require less frequent administration, and cause less gastrointestinal side effects when administered orally for a chronic disorder. COL-3 or metastat is a chemically modified tetracycline that has a tetracycline scaffold with unsubstituted positions C4-C9, and is a potent MMP inhibitor.121 Although tetracyclines are relatively weak Zn2 + chelators and inhibitors of MMP activity, they could affect MMP expression,121 and their effects on MMP synthesis may contribute to their potential benefits in rheumatoid arthritis.122

7.20.5.2.2 Tetracyclines and malaria

Tetracyclines have clinical utility against malaria parasites caused by Plasmodium species, where tetracycline, minocycline, and doxycycline are active. Doxycycline has been used clinically for malarial prophylaxis in travelers and in geographical areas where resistance to first choice antimalarial agents such as chloroquine is widespread, and is used in conjunction with quinine for malaria treatment.80–82 The tetracyclines show activity against cultured parasites83 and against Plasmodium berghei in murine models,84 while recent reports have described more novel tetracyclines with potent in vitro and in vivo activity.85

Tetracyclines affect the parasite life cycle at the later trophozoite stage, where daughter parasites are found incapable of maturation and further growth is inhibited. During this stage, energy production by malarial mitochondria may be compromised by the tetracyclines,86 where electron-transport proteins related to mitochondrial metabolite biosynthesis are depressed,87 mitochondrial protein synthesis inhibited in a dose-dependent manner,88 and plastid activity decreased.86 Tetracyclines have no effect on mitochondrial membrane potential as compared to other mitochondria inhibitors capable of damaging membrane function.89

Tetracyclines

Mode of Action

Tetracyclines interfere with the initiation step of protein synthesis (Figure 137-10) by inhibiting the binding of aminoacyl tRNA to the A-site of the ribosome.19 The 7S protein and the 16S RNA show the greatest affinity for tetracyclines and are therefore the main targets. This binding inhibits the fixation of a new aminoacyl tRNA on the ribosome. In addition, tetracyclines bind, or at least protrude, in the P-site by alteration in ribosome conformation in the post-translocational state, and may modify the ribosome conformation at the level of the head of the 30S subunit and the interface side of the 50S subunit.