What is the next antibiotic if amoxicillin doesn't work?

October 12, 2025 •

4 min read

In the U.S., more than 2.8 million antimicrobial-resistant infections occur each year [1.11.1, 1.11.2]. This growing problem often leads patients to ask: what is the next antibiotic if amoxicillin doesn't work? Understanding the alternatives requires a look at why the first-line treatment may have failed.

Quick Summary

When amoxicillin therapy is not effective, a physician may prescribe an alternative based on the specific infection and potential for resistance. Common next-step antibiotics include amoxicillin-clavulanate, cephalosporins, and macrolides.

Key Points

Treatment Failure Reasons: Amoxicillin may not work due to antibiotic resistance, a non-bacterial (e.g., viral) cause, or the patient not taking the medication as prescribed [1.5.1, 1.5.2, 1.5.5].
Doctor's Visit is Essential: A healthcare provider must determine the cause of failure and the correct next antibiotic; self-prescribing is dangerous [1.2.3].
Common First Alternative: Amoxicillin-clavulanate (Augmentin) is often the next choice as it overcomes a common resistance mechanism [1.6.3, 1.6.4].
Options for Penicillin Allergy: Cephalosporins (like cefdinir) or macrolides (like azithromycin) are common alternatives for patients with penicillin allergies [1.2.2, 1.2.3].
Infection-Specific Choices: The best second-line antibiotic for a sinus infection (e.g., doxycycline) may differ from one for strep throat (e.g., cephalexin) [1.2.3, 1.4.2].
Reserved Antibiotics: Powerful drugs like fluoroquinolones are reserved for severe infections where other options have failed due to significant side effect risks [1.9.2, 1.9.3].
Antibiotic Stewardship: Using antibiotics correctly is crucial to combat the global threat of antimicrobial resistance and preserve the effectiveness of these life-saving drugs [1.10.2, 1.10.3].

Amoxicillin is a widely prescribed penicillin-class antibiotic, often serving as the first line of defense against common bacterial infections like strep throat, ear infections, and sinusitis [1.2.2, 1.3.2]. However, there are times when it doesn't resolve an infection, leading to persistent symptoms and concern. Understanding the next steps involves exploring why it might have failed and what alternatives a healthcare provider might consider.

Key Reasons Why Amoxicillin Might Not Work

When an antibiotic like amoxicillin fails, it's not always a simple matter. Several factors could be at play, and a physician must evaluate them before choosing a new treatment path.

The Infection Is Not Bacterial

Many common illnesses, such as colds, the flu, and most cases of bronchitis, are caused by viruses, not bacteria [1.5.2, 1.5.4]. Antibiotics have no effect on viruses [1.5.1]. If your symptoms are due to a viral infection, amoxicillin will not help, and a different approach focusing on symptom relief is needed [1.2.5]. Many sinus and ear infections are also viral, which highlights the importance of an accurate diagnosis before antibiotics are prescribed [1.2.3].

Antibiotic Resistance

The overuse and misuse of antibiotics have contributed to the rise of antibiotic-resistant bacteria [1.5.5]. Some bacteria develop mechanisms to protect themselves from antibiotics. For example, some produce an enzyme called beta-lactamase, which destroys amoxicillin, rendering it ineffective [1.6.3, 1.6.4]. The CDC reports that more than 2.8 million antibiotic-resistant infections occur annually in the United States alone [1.11.1].

Incorrect Dosing or Non-Adherence

For an antibiotic to work, it must be taken exactly as prescribed. Stopping a course of antibiotics too early, even if you feel better, can allow the more resilient bacteria to survive and multiply [1.5.2]. This can lead to a relapse of the infection, which may then be harder to treat. Skipping doses can have a similar effect.

The Crucial Role of Medical Consultation

It is vital to consult a healthcare professional if you believe your amoxicillin prescription is not working. Self-diagnosing and taking leftover antibiotics from a previous illness is dangerous. A doctor will evaluate your symptoms, consider your medical history, and determine the cause of treatment failure. In some cases, a bacterial culture may be performed to identify the specific bacteria causing the infection and test its susceptibility to various antibiotics [1.5.2]. This ensures the next antibiotic chosen is the most effective one.

Common Second-Line Antibiotics

The choice of the next antibiotic depends heavily on the type of infection, local resistance patterns, and patient-specific factors like allergies [1.2.3].

Amoxicillin-Clavulanate (Augmentin)

For many infections where amoxicillin resistance is suspected, amoxicillin-clavulanate (brand name: Augmentin) is a common next step [1.2.3, 1.6.1]. It combines amoxicillin with clavulanate, a beta-lactamase inhibitor [1.6.3]. The clavulanate protects amoxicillin from being broken down by beta-lactamase-producing bacteria, allowing it to kill the bacteria effectively [1.6.4, 1.6.5]. It's frequently used for ear infections, sinus infections, and some lung infections [1.6.3].

Cephalosporins

This class of antibiotics is another option, especially for patients with a mild (non-anaphylactic) penicillin allergy [1.2.3].

Cephalexin (Keflex): Often used for strep throat and skin infections [1.2.3, 1.2.4].
Cefdinir: A broader-spectrum, third-generation cephalosporin used for ear infections, pneumonia, and sinusitis, especially when amoxicillin has been ineffective [1.2.3, 1.3.5].
Cefuroxime (Ceftin): Another option for respiratory and ear infections [1.2.2, 1.3.5].

Macrolides

For patients with a significant penicillin allergy, macrolides are often prescribed [1.2.2]. However, resistance to this class is growing, so they may not be a first choice in all areas [1.2.3].

Azithromycin (Zithromax, Z-Pak): Popular for its convenient dosing schedule, it is used for respiratory infections, strep throat, and ear infections [1.2.3, 1.8.4].
Clarithromycin (Biaxin): Another macrolide used for similar infections [1.2.2, 1.8.1].

Other Antibiotic Classes

For more persistent infections or specific types of bacteria, a doctor might turn to other classes.

Tetracyclines (e.g., Doxycycline): Used for sinusitis, some types of pneumonia, and skin infections [1.2.3]. Doxycycline is a common second-line choice for respiratory infections [1.4.2].
Fluoroquinolones (e.g., Levofloxacin): These are powerful, broad-spectrum antibiotics generally reserved for more serious infections or when other treatments have failed. This is due to a risk of significant side effects, including tendon rupture and nerve damage [1.2.3, 1.9.1, 1.9.3]. The FDA advises against using them for uncomplicated infections like sinusitis or UTIs if other options are available [1.9.2].

Comparison of Common Second-Line Antibiotics


Antibiotic	Class	Common Uses After Amoxicillin Failure	Key Considerations
Amoxicillin-Clavulanate	Penicillin + Inhibitor	Ear infections, sinus infections, resistant respiratory infections [1.6.3]	More effective against beta-lactamase producing bacteria [1.6.4]. Higher rate of GI side effects like diarrhea [1.6.2].
Cefdinir	Cephalosporin	Ear, sinus, and lung infections [1.2.3]	Good option for those with a mild penicillin allergy. Broad-spectrum action [1.2.3].
Azithromycin	Macrolide	Respiratory infections, strep throat (for penicillin allergy) [1.2.2, 1.8.3]	Convenient dosing [1.2.3]. Growing bacterial resistance is a concern [1.2.3].
Doxycycline	Tetracycline	Sinusitis, atypical pneumonia, some skin infections [1.2.3]	Can cause sun sensitivity. Not typically used in young children or pregnant women [1.2.3].
Levofloxacin	Fluoroquinolone	Complicated UTIs, severe respiratory infections [1.4.3]	Reserved for cases where other options are not suitable due to risks of serious side effects [1.9.1, 1.9.2].

Conclusion: The Importance of Antibiotic Stewardship

Figuring out the next antibiotic when amoxicillin fails is a clinical decision that balances the nature of the infection with the risks of increasing antibiotic resistance. This is the core of antibiotic stewardship: the effort to use antibiotics wisely to ensure they remain effective for future generations [1.10.2]. As a patient, you can contribute by taking medications exactly as prescribed, not pressuring your doctor for antibiotics for viral illnesses, and asking questions to understand your treatment plan [1.10.3]. The right next step is always determined in partnership with your healthcare provider.

For more information on antibiotic resistance, you can visit the CDC's page on Antimicrobial Resistance. [1.11.2]

Frequently Asked Questions

The two most common reasons are that the infection is caused by a virus (which antibiotics don't treat) or the bacteria causing the infection has become resistant to amoxicillin [1.5.1, 1.5.3, 1.5.5].

No. This is dangerous because different antibiotics treat different types of bacteria, and your leftover medication may not be appropriate for your current infection. Always consult a doctor for a new prescription [1.2.3, 1.10.3].

Augmentin contains amoxicillin plus clavulanate. The clavulanate helps amoxicillin work against certain bacteria that have become resistant [1.6.3]. So, it's not 'stronger' but has a broader range of activity against specific resistant bacteria [1.6.4].

For patients with a penicillin allergy, doctors often prescribe antibiotics from the cephalosporin class (like cephalexin) or the macrolide class (like azithromycin or clindamycin) [1.2.2, 1.2.4].

You should generally see some improvement within 48 to 72 hours of starting an antibiotic [1.3.2]. If your symptoms are not improving or are getting worse after this period, you should contact your doctor.

Fluoroquinolones are reserved for more serious infections because they carry FDA warnings about an increased risk of severe, and potentially permanent, side effects involving tendons, muscles, joints, and nerves [1.9.1, 1.9.3].

Antibiotic stewardship is the effort to improve how antibiotics are prescribed and used to ensure they are only used when needed [1.10.2]. The goal is to improve patient outcomes and combat the rise of antibiotic resistance [1.10.3].