Why Do Antibiotics Raise Body Temperature and Trigger Fevers?

Antibiotics are essential for treating bacterial infections, but they can sometimes cause unexpected side effects, including fever. This rise in body temperature is often mistaken for worsening illness, leading to confusion about whether the infection or the medication is responsible.

Understanding why antibiotics might trigger a fever requires examining their interaction with the body’s immune system and metabolism.

Mechanisms Influencing Body Temperature

The human body maintains a stable internal temperature through complex physiological processes regulated by the hypothalamus. This brain region acts as a thermostat, responding to signals from the nervous system and circulating molecules to adjust heat production and dissipation. Antibiotics can disrupt this balance, leading to an increase in body temperature.

One way antibiotics influence thermoregulation is by altering mitochondrial function. Mitochondria generate energy through oxidative phosphorylation, a process that also produces heat. Certain antibiotics, particularly those that interfere with bacterial protein synthesis, can inadvertently affect human mitochondrial ribosomes due to their evolutionary similarity to bacterial counterparts. This disruption increases metabolic activity and heat production. Studies have shown that tetracyclines and chloramphenicol can impair mitochondrial function, leading to metabolic stress and subsequent thermogenic effects.

Antibiotics also impact the gut microbiome, which plays a role in systemic inflammation and metabolism. Broad-spectrum antibiotics can cause dysbiosis, an imbalance in microbial populations, which has been linked to altered energy metabolism and changes in body temperature. Research published in Cell Metabolism has demonstrated that shifts in gut microbiota composition can influence thermogenic pathways, particularly through interactions with brown adipose tissue, a specialized fat type involved in heat production.

Additionally, some antibiotics interfere with neurotransmitter signaling that affects temperature regulation. Certain beta-lactam antibiotics, for example, modulate glutamate activity in the central nervous system. Since glutamate plays a role in hypothalamic control of body temperature, alterations in its signaling can lead to transient hyperthermia. Animal studies have observed increased neuronal excitability and elevated core temperature following administration of specific antibiotics.

Common Classes Linked To Fever

Certain antibiotic classes are more frequently associated with fever. Beta-lactams, including penicillins and cephalosporins, are among the most commonly implicated. Reports indicate that up to 10% of drug-induced fevers are linked to these antibiotics, with cephalosporins such as ceftriaxone and cefepime being notable offenders. Some studies suggest that beta-lactams interfere with enzymatic pathways involved in cellular metabolism, leading to transient elevations in body temperature. Additionally, these antibiotics may accumulate in tissues at higher concentrations in certain individuals, prolonging thermogenic effects.

Fluoroquinolones, including ciprofloxacin and levofloxacin, have also been associated with febrile responses. One proposed explanation is their interaction with the central nervous system, as fluoroquinolones can cross the blood-brain barrier and influence neurotransmitter activity. Research published in The Journal of Antimicrobial Chemotherapy has highlighted fluoroquinolone-induced alterations in gamma-aminobutyric acid (GABA) receptor function, which may contribute to increased neuronal excitability and hyperthermia. These antibiotics have also been linked to oxidative stress, which can raise metabolic heat production.

Tetracyclines, such as doxycycline and minocycline, are another group frequently linked to fever. These antibiotics interfere with mitochondrial protein synthesis, leading to metabolic disturbances that may manifest as elevated body temperature. A study in Molecular Microbiology demonstrated that tetracyclines disrupt mitochondrial translation in mammalian cells, triggering compensatory energy production pathways that generate excess heat. Minocycline, in particular, has been associated with drug-induced fever more frequently than other tetracyclines, possibly due to its higher lipophilicity and prolonged systemic effects.

Macrolides, such as erythromycin and clarithromycin, have also been reported to induce fever, though less commonly than beta-lactams or fluoroquinolones. These antibiotics influence gastrointestinal motility by acting as motilin receptor agonists, which may lead to metabolic changes affecting body temperature. Additionally, macrolides modulate ion channel activity in cardiac and neural tissues, potentially disrupting thermoregulatory processes. Case reports in Clinical Infectious Diseases have documented fever following macrolide administration, particularly in patients receiving high doses or prolonged treatment.

Distinguishing Drug Fever From Other Causes

Determining whether a fever is caused by antibiotics or an underlying condition requires evaluating symptom patterns, timing, and response to discontinuation. Drug-induced fevers often occur without typical infection signs, such as localized pain, swelling, or elevated white blood cell counts. Instead, they appear unpredictably, sometimes days after starting treatment, and may persist despite clinical improvement in the primary illness. Fever that resolves after stopping the antibiotic strongly suggests a drug-related reaction.

Unlike infection-related fevers, which often follow a pattern of morning lows and evening spikes, drug fevers tend to be erratic, with fluctuations unrelated to bacterial illness. Some antibiotics, such as beta-lactams and sulfonamides, have been linked to febrile episodes accompanied by eosinophilia or mild liver enzyme elevations, indicating a systemic reaction rather than an ongoing infection. Blood cultures taken during antibiotic-induced fever episodes frequently return negative, reinforcing the absence of an active bacterial source.

Clinical history is crucial in distinguishing drug fever from other causes. Patients with prior febrile reactions to the same or related antibiotics are more likely to experience recurrence. Individuals with autoimmune conditions or hypersensitivity syndromes are also at increased risk. Reviewing the sequence of events—when the fever began relative to antibiotic initiation, whether it worsened despite appropriate antimicrobial coverage, and how it responded to medication cessation—can help clinicians determine the most likely cause.