Phenoxymethylpenicillin (Penicillin V): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Phenoxymethylpenicillin, commonly known as Penicillin V, is a natural, narrow-spectrum β-lactam antibiotic derived from the fermentation of Penicillium chrysogenum.[1] Its defining characteristic is a remarkable stability in gastric acid, a structural advantage over its predecessor, Benzylpenicillin (Penicillin G), which established Penicillin V as a cornerstone of oral antibiotic therapy for decades.[3] The drug's primary clinical utility is directed against Gram-positive pathogens, particularly Streptococcus pyogenes, making it a first-line agent for common outpatient infections such as pharyngotonsillitis and certain skin infections.[3] In the modern era of antimicrobial stewardship, its narrow spectrum of activity is increasingly valued as a means to minimize collateral damage to the host microbiome and reduce the selective pressure that drives antibiotic resistance. This monograph provides a definitive, evidence-based overview of Phenoxymethylpenicillin, detailing its physicochemical properties, synthesis, comprehensive pharmacology, clinical applications, and regulatory status. It further synthesizes current research that is actively refining its clinical use through optimized dosing strategies and pharmacokinetic enhancement, underscoring its enduring relevance in contemporary medicine.[7]

Drug Identification and Physicochemical Properties

Nomenclature and Identifiers

To ensure unambiguous identification, Phenoxymethylpenicillin is cataloged under a variety of systematic names and registry numbers across global databases.

• Primary Name: Phenoxymethylpenicillin.[3]
• Common Synonyms: The drug is widely referred to as Penicillin V (PcV). The potassium salt is specifically known as Penicillin VK, a common formulation in clinical practice.[3] Other historical and international names include Oracillin, V-Cillin, Pen-Vee, and Fenoximetilpenicilina.[1]
• Systematic (IUPAC) Name: The precise chemical structure and stereochemistry are defined by its IUPAC name: (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.[3]
• Registry Numbers:
• CAS Number: The free acid form is registered under CAS number 87-08-1.[3] Its clinically important salts have distinct identifiers: 132-98-9 (Potassium salt) and 147-48-8 (Calcium salt).[3]
• DrugBank ID: DB00417.[3]
• Other Key Identifiers: For comprehensive cross-referencing, it is also identified by PubChem CID: 6869; ChEMBL ID: ChEMBL615; UNII: Z61I075U2W; and KEGG: D05411.[3]

Chemical Structure, Formulation, and Physical Properties

The pharmacological activity and clinical utility of Phenoxymethylpenicillin are direct consequences of its molecular structure and physical characteristics.

• Molecular Structure: The molecule is built upon the characteristic penam core, which consists of a four-membered β-lactam ring fused to a five-membered thiazolidine ring.[2] Its unique identity comes from the 6β-(phenoxyacetyl)amino side-chain attached to this core, which distinguishes it structurally from its analog Penicillin G (benzylpenicillin).[1]
• Molecular Formula and Mass: The chemical formula for Phenoxymethylpenicillin is $C_{16}H_{18}N_{2}O_{5}S$. It has an average molecular weight of 350.39 g·mol⁻¹.[3]
• Physical Appearance: In its pure form, it is a white to off-white, odorless, crystalline solid.[1]
• Solubility and Melting Point: It is characterized as being very slightly soluble in water but is soluble in polar organic solvents such as ethanol and acetone.[1] The compound melts with decomposition in the range of 120–128 °C.[1]
• Spectroscopic Data: Its chemical identity can be confirmed through analytical techniques, with a predicted Gas Chromatography-Mass Spectrometry (GC-MS) spectrum available for reference.[17]
• Formulations: For clinical use, Phenoxymethylpenicillin is typically formulated as its potassium (Penicillin VK) or calcium salts. These salt forms exhibit improved stability and absorption from the gastrointestinal tract compared to the free acid.[18] Pharmaceutical preparations, including tablets and powders for oral solution, contain various excipients such as microcrystalline cellulose, povidone, and magnesium stearate to ensure proper formulation and delivery.[19]

Stability and Storage

The stability profile of Phenoxymethylpenicillin is its most clinically significant physicochemical property, dictating its route of administration and storage requirements.

• Acid Stability: The defining feature of Phenoxymethylpenicillin is its relative stability in acidic environments. The electron-withdrawing nature of the phenoxy group in its side chain sterically protects the amide bond within the β-lactam ring from acid-catalyzed hydrolysis in the stomach. This property is the primary reason it can be administered orally, unlike the acid-labile Penicillin G.[3]
• Stability in Solution: Once reconstituted from a powder into an oral solution, its stability becomes highly dependent on storage conditions. Studies have shown that the stability of the reconstituted potassium salt can be significantly shorter than the manufacturer's stated expiration date for the bulk container, particularly when repackaged. One critical study found that when stored in plastic oral syringes, the solution's potency dropped below 90% in 11.5 days under refrigeration (4°C) and in less than 37 hours at room temperature (25°C).[22] This finding demonstrates a crucial point in pharmacotherapy: the interaction between a drug and its secondary packaging can directly impact chemical integrity. The increased exposure to air, moisture, or materials from the plastic syringe likely accelerates degradation, creating a risk of patients receiving sub-potent doses if extended expiration dates based on bulk storage are erroneously applied. Other research has shown that most commercially available reconstituted products retain over 90% potency for seven days at 25°C.[23] Further research has explored the use of cyclodextrins to enhance its stability in acidic solutions.[21]
• Storage Recommendations: Based on stability data, solid dosage forms should be stored in a cool, dry place away from light and moisture.[24] Reconstituted oral suspensions must be stored under refrigeration (2-8°C) and are typically discarded after 10 days.[5]

The seemingly minor structural modification of a phenoxymethyl side chain, compared to Penicillin G's benzyl side chain, has a profound impact on the molecule's electronic properties and acid stability. This single chemical change was a landmark discovery that unlocked the potential for reliable oral penicillin therapy, fundamentally altering the landscape of outpatient antibiotic treatment and solidifying the drug's clinical niche.

Property	Value
Common Name	Phenoxymethylpenicillin, Penicillin V
DrugBank ID	DB00417
CAS Number	87-08-1 (Acid); 132-98-9 (Potassium Salt)
Molecular Formula	$C_{16}H_{18}N_{2}O_{5}S$
Molar Mass	350.39 g·mol⁻¹
Appearance	White to off-white crystalline powder
Melting Point	120–128 °C (with decomposition)
Solubility	Very slightly soluble in water; soluble in ethanol
Key Stability Feature	Relatively stable in gastric acid
Table 1: Key Identifiers and Physicochemical Properties of Phenoxymethylpenicillin

Synthesis and Biosynthesis

Historical Context and Discovery

Phenoxymethylpenicillin was first synthesized in 1948 by researchers at Eli Lilly during a broader investigation into penicillin precursors, although the clinical significance of its acid stability was not appreciated at the time.[3] The pivotal discovery occurred in 1953 at the Austrian company Biochemie, where it was produced in the culture broth of Penicillium chrysogenum following the addition of phenoxyacetic acid to the fermentation medium.[1] This work demonstrated that the biosynthetic machinery of the fungus could be directed to incorporate specific, externally supplied side-chain precursors into the final penicillin molecule.

Biosynthesis

The industrial production of Phenoxymethylpenicillin relies on large-scale fermentation using high-yield strains of the mold Penicillium chrysogenum.[2] The biosynthetic pathway begins with the condensation of the amino acids L-cysteine and D-valine to form the core penam structure, known as 6-aminopenicillanic acid (6-APA).[2] The process that uniquely yields Penicillin V instead of the default Penicillin G is known as "precursor-directed biosynthesis." By supplementing the fermentation medium with phenoxyacetic acid (or a related precursor like phenoxyethanol), the fungal enzyme acyl-CoA:6-APA acyltransferase is induced to attach the phenoxyacetyl side chain to the 6-APA nucleus.[1] This demonstrated that the fungal enzymatic machinery was flexible enough to be manipulated, a foundational concept that predates modern metabolic engineering and enabled the creation of novel penicillin variants.

Chemical and Enzymatic Synthesis

Beyond biosynthesis, Phenoxymethylpenicillin has been produced through various synthetic routes that reflect the evolution of pharmaceutical chemistry.

• Total Synthesis: The first total chemical synthesis of Penicillin V, reported by Sheehan and Henery-Logan in 1959, was a landmark achievement in organic chemistry. This complex, multi-step process, which started from D-penicillamine, served as the definitive proof of the molecule's structure and stereochemistry but was not viable for commercial production.[26]
• Semi-synthesis: More practical and commercially viable methods involve the N-acylation of the 6-APA nucleus. 6-APA is produced efficiently on an industrial scale via fermentation and can then be chemically modified to attach the desired phenoxyacetyl side chain.[25]
• Enzymatic Synthesis: Reflecting a modern emphasis on sustainable "green chemistry," research has focused on using isolated enzymes to catalyze the final synthesis step. For instance, the enzyme α-acylamino-β-lactam acylhydrolase I (ALAHase I) from Erwinia aroideae has been shown to synthesize Penicillin V from 6-APA and phenoxyacetic acid methyl ester.[28] This approach offers potential advantages, including milder reaction conditions and reduced chemical waste, though optimization of yield and reaction kinetics remains an active area of research.

This progression from a monumental academic feat of total synthesis to industrial semi-synthesis and now to sustainable enzymatic methods illustrates how the manufacturing of even a long-established drug is continuously refined by new scientific paradigms and environmental priorities.

Comprehensive Pharmacological Profile

Mechanism of Action

The antibacterial effect of Phenoxymethylpenicillin is bactericidal, meaning it actively kills susceptible bacteria.[3] Its mechanism is identical to that of all other penicillin antibiotics and is most potent when bacteria are in the stage of active multiplication.[3]

The molecular target of the drug is the final stage of bacterial cell wall biosynthesis.[30] Phenoxymethylpenicillin acts by covalently binding to and irreversibly inhibiting a group of bacterial enzymes known as Penicillin-Binding Proteins (PBPs).[11] These enzymes, which include transpeptidases and carboxypeptidases, are located on the inner surface of the bacterial cytoplasmic membrane and are essential for the cross-linking of peptidoglycan polymers.[31] Peptidoglycan provides the rigid structural integrity of the bacterial cell wall. By inhibiting PBPs, the drug prevents the formation of these crucial cross-links, leading to a structurally deficient and weakened cell wall. The compromised wall is unable to withstand the high internal osmotic pressure of the bacterium, resulting in cell swelling, lysis, and death.[31] Specific PBP targets that are inhibited by Phenoxymethylpenicillin include MecA PBP2' (in Staphylococcus aureus), Penicillin-binding protein 1A, and D-alanyl-D-alanine carboxypeptidase DacB.[11]

Pharmacodynamics (PD)

• Antimicrobial Spectrum: Phenoxymethylpenicillin is a narrow-spectrum antibiotic, with its activity primarily directed against Gram-positive bacteria.[11] Its spectrum is similar to that of Penicillin G, but it is substantially less active against Gram-negative organisms.[3]
• Susceptible Organisms: Key pathogens effectively targeted by Penicillin V include Streptococcus pyogenes (Group A Streptococcus), Streptococcus pneumoniae (Pneumococcus), and susceptible strains of Staphylococcus that do not produce penicillinase. It also shows activity against Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, and various Clostridia species.[3]
• Mechanisms of Resistance: Bacterial resistance to Phenoxymethylpenicillin occurs primarily through two mechanisms:

1. Enzymatic Inactivation: The production of β-lactamase enzymes (penicillinases) is the most common form of resistance. These enzymes hydrolyze the amide bond in the β-lactam ring, rendering the antibiotic inactive. This is a prevalent mechanism in many strains of Staphylococcus aureus.[30]
2. Target Modification: Alterations in the genetic code for Penicillin-Binding Proteins can change their structure, reducing the binding affinity of the antibiotic for its target. This allows the bacteria to continue cell wall synthesis even in the presence of the drug.[30]

• PK/PD Relationship: For β-lactam antibiotics like Phenoxymethylpenicillin, the primary pharmacodynamic parameter that correlates with efficacy is the cumulative percentage of a dosing interval during which the free (unbound) drug concentration remains above the Minimum Inhibitory Concentration (MIC) of the target pathogen ($fT > MIC$). This time-dependent killing characteristic is the major determinant of its clinical success.[30]

Pharmacokinetics (PK) - ADME

The absorption, distribution, metabolism, and excretion (ADME) profile of Phenoxymethylpenicillin dictates its dosing regimen and clinical limitations.

• Absorption: Following oral administration, the drug is absorbed rapidly but incompletely from the gastrointestinal tract.[18] The oral bioavailability is variable, ranging from 25% to 60%.[3] This variability is a key therapeutic limitation, as it can lead to unpredictable serum concentrations between individuals. For this reason, Phenoxymethylpenicillin is recommended only for mild-to-moderate infections and is considered unreliable for severe or deep-seated infections where consistent, high drug levels are critical.[3] Absorption is significantly increased when the drug is taken on an empty stomach, ideally one hour before or two hours after a meal.[11] Peak plasma concentrations ($C_{max}$) are typically achieved within 30 to 75 minutes post-administration.[18] A standard 500 mg oral dose results in a $C_{max}$ of 3 to 5 µg/mL, while a steady-state study in healthy volunteers reported a mean $C_{max}$ of 5.7 mg/L with a time to peak concentration ($T_{max}$) of 48 minutes.[4]
• Distribution: Phenoxymethylpenicillin is widely distributed throughout the body's tissues and fluids.[30] It exhibits high plasma protein binding, with estimates ranging from 50% to 80%.[3] The drug penetrates into pleural and ascitic fluids, crosses the placenta, and is secreted in small amounts into breast milk.[30] Its penetration into the cerebrospinal fluid (CSF) is generally poor but increases in the presence of meningeal inflammation.[30]
• Metabolism: The extent of metabolism is subject to some conflicting reports. While some sources indicate it is not significantly metabolized and is excreted largely unchanged, others report that a portion of the dose is metabolized in the liver to inactive compounds, such as penicilloic acid.[30] The consensus is that renal excretion, not hepatic metabolism, is the primary pathway for its elimination.
• Excretion: The drug is eliminated rapidly from the body, primarily by the kidneys through a combination of glomerular filtration and active tubular secretion.[33] Reflecting its incomplete absorption, only about 25% to 43% of an oral dose is recovered as active drug in the urine.[18] The elimination half-life ($t_{1/2}$) is very short, averaging 30 to 60 minutes in individuals with normal renal function.[4] This rapid clearance, combined with the need to maintain drug concentrations above the MIC, is the direct cause of the frequent, and often inconvenient, four-times-daily dosing regimen required for treatment. This dosing schedule can be a significant barrier to patient adherence, which in turn risks therapeutic failure. In patients with severe renal impairment, the half-life can be prolonged to approximately 4 hours.[18] The drug is effectively removed by hemodialysis.[30]

Clinical Application and Therapeutic Guidelines

Approved and Off-Label Indications

Phenoxymethylpenicillin is indicated for the treatment of mild to moderately severe infections caused by susceptible organisms, as well as for long-term prophylaxis in specific at-risk populations.

• Primary Treatment Indications:
• Streptococcal Infections: It is a first-line therapy for pharyngitis and tonsillitis caused by Streptococcus pyogenes (Group A Strep, GAS). It is also used for scarlet fever and streptococcal skin and soft tissue infections such as cellulitis and erysipelas.[3]
• Pneumococcal Infections: Effective for mild community-acquired pneumonia and otitis media caused by susceptible S. pneumoniae.[3]
• Dental Infections: Used as an initial treatment for dental abscesses and, often in combination with metronidazole, for moderate-to-severe gingivitis.[3]
• Other Infections: It is an option for mild, uncomplicated cutaneous anthrax and for early-stage Lyme disease, particularly in pregnant women or young children where tetracyclines are contraindicated.[3]
• Prophylactic Indications:
• Rheumatic Fever: Used for long-term secondary prophylaxis to prevent recurrences in patients with a history of acute rheumatic fever.[3]
• Pneumococcal Infection Prophylaxis: Prescribed for lifelong prophylaxis against invasive pneumococcal disease in patients with functional or anatomical asplenia (e.g., post-splenectomy) and in individuals with sickle cell disease.[3]
• Bacterial Endocarditis: Historically used for prophylaxis in at-risk patients undergoing certain dental or upper respiratory tract procedures, although modern guidelines have significantly restricted this indication.[11]

Dosage and Administration

Correct administration is critical for achieving therapeutic success with Phenoxymethylpenicillin.

• Administration: To ensure maximal absorption, the medication must be administered on an empty stomach, either one hour before or at least two hours after meals.[11] It is imperative that patients complete the entire prescribed course of therapy, even if symptoms improve, to ensure complete eradication of the pathogen and prevent the development of resistance or relapse.[24] The long-standing 10-day treatment course for GAS pharyngitis is not primarily for acute symptom resolution but is a crucial public health measure to fully eradicate the organism and prevent the rare but devastating autoimmune sequela of acute rheumatic fever.[5]
• Dosage Regimens: Dosing varies by indication, age, and weight.
• Available Formulations: Phenoxymethylpenicillin is available as 250 mg and 500 mg tablets and as a powder for reconstitution into an oral suspension, typically in strengths of 125 mg/5 mL and 250 mg/5 mL.[41]

Indication	Adult Dose & Duration	Pediatric Dose & Duration	Key Administration Notes
Streptococcal Pharyngotonsillitis	500 mg PO BID or 250 mg PO QID for 10 days	25-50 mg/kg/day divided BID-TID for 10 days (e.g., 250 mg BID/TID for children)	Take on an empty stomach. Complete full 10-day course to prevent rheumatic fever.
Rheumatic Fever Prophylaxis	250 mg PO BID, long-term	<5 years: 125 mg PO BID; >5 years: 250 mg PO BID, long-term	Adherence is critical for prevention.
Dental Abscess (Initial)	500 mg PO QID for 5-7 days	12.5 mg/kg/dose (max 500 mg) QID for 5 days (often with metronidazole)	Re-evaluation by a dentist is necessary.
Pneumococcal Prophylaxis (Asplenia/Sickle Cell)	250-500 mg PO BID, lifelong	<5 years: 125 mg PO BID; >5 years: 250 mg PO BID, lifelong	Lifelong therapy is required.
Table 2: Summary of Dosing Regimens for Key Indications

Safety, Tolerability, and Toxicology

• Adverse Drug Reactions (ADRs):
• Common: Phenoxymethylpenicillin is generally well-tolerated. The most frequently reported adverse effects are gastrointestinal in nature, including nausea, vomiting, diarrhea, abdominal pain, and epigastric distress.[3] Other common effects include black hairy tongue and oral candidiasis (thrush).[3]
• Hypersensitivity: Allergic reactions are a primary safety concern and are reported in up to 10% of patients receiving a penicillin-class antibiotic.[45] These reactions span a wide spectrum of severity, from mild maculopapular skin rashes and urticaria (hives) to severe, life-threatening systemic reactions such as angioedema and anaphylaxis.[24] Rare but severe reactions include serum sickness-like syndromes and exfoliative dermatoses like Stevens-Johnson syndrome.[5]
• Rare: Infrequent adverse effects include hematologic abnormalities (hemolytic anemia, leukopenia, thrombocytopenia), acute interstitial nephritis, and neurotoxicity (seizures), which are typically associated with extremely high doses or severe renal impairment.[5] As with many antibiotics, Clostridioides difficile-associated diarrhea is a potential complication.[5]
• Contraindications:
• The drug is absolutely contraindicated in individuals with a history of a serious hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any penicillin antibiotic.[3] Caution is also warranted in patients with a history of severe allergy to cephalosporins due to the potential for immunological cross-reactivity.[39] The high rate of self-reported penicillin allergy, much of which is not confirmed upon formal testing, presents a significant clinical challenge, often forcing clinicians to use broader-spectrum, second-line agents unnecessarily. This highlights the importance of careful allergy history-taking and, where appropriate, specialist evaluation.[5]
• Use in Specific Populations:
• Pregnancy: It is considered relatively safe for use during pregnancy (formerly FDA Pregnancy Category B) and is often a drug of choice for susceptible infections in this population.[3]
• Breastfeeding: Phenoxymethylpenicillin is excreted into breast milk in small amounts. While generally considered compatible with breastfeeding, it carries a theoretical risk of causing diarrhea, candidiasis, or allergic sensitization in the nursing infant.[37]
• Renal Impairment: Dosage adjustment is typically not necessary in mild to moderate renal impairment, but caution is advised with high doses. The drug is removed by hemodialysis.[30]
• Drug-Drug Interactions:
• Probenecid: Competitively inhibits the renal tubular secretion of penicillins, leading to decreased excretion and consequently higher and more prolonged plasma concentrations of Phenoxymethylpenicillin. This interaction can be exploited therapeutically to "boost" drug levels.[30]
• Bacteriostatic Antibiotics: Concomitant use with bacteriostatic agents (e.g., tetracyclines, erythromycin) may antagonize the bactericidal activity of penicillins, which require active cell growth to be effective. This combination is generally avoided.[30]
• Methotrexate: Penicillins can decrease the renal clearance of methotrexate, thereby increasing its plasma concentration and the risk of toxicity.[40]
• Anticoagulants: May potentiate the effects of vitamin K antagonists like warfarin.[40]
• Oral Contraceptives: The effectiveness of estrogen-containing oral contraceptives may be reduced, and patients should be advised to use additional contraceptive precautions during therapy.[30]

Comparative Assessment: Phenoxymethylpenicillin in the Penicillin Class

The clinical role of Phenoxymethylpenicillin is best understood by comparing it to Penicillin G and Amoxicillin. This progression from a natural, parenteral-only product to an orally stable form, and finally to a broader-spectrum, pharmacokinetically superior agent, illustrates the targeted evolution of antibiotic development driven by clinical need.

Phenoxymethylpenicillin (Penicillin V) vs. Penicillin G

• Key Difference: The fundamental distinction lies in their stability in gastric acid. Penicillin V's phenoxymethyl side chain confers acid stability, permitting reliable oral administration.[3] Penicillin G's benzyl side chain does not, rendering it acid-labile and restricting its use to parenteral (IV/IM) routes.[2]
• Spectrum and Potency: Their antimicrobial spectra are nearly identical, with potent activity against a narrow range of Gram-positive bacteria, particularly streptococci.[3]
• Clinical Niche: This chemical difference creates a clear divergence in their clinical roles. Penicillin V is the workhorse for mild-to-moderate outpatient infections (e.g., strep throat) where oral therapy is convenient and appropriate.[2] Penicillin G is reserved for severe, inpatient infections (e.g., sepsis, endocarditis, meningitis) where high, guaranteed systemic drug concentrations are essential for a successful outcome.[36]

Phenoxymethylpenicillin (Penicillin V) vs. Amoxicillin

• Key Differences: Amoxicillin, a semi-synthetic aminopenicillin, was developed to overcome some of Penicillin V's limitations.
• Spectrum: Amoxicillin possesses a broader spectrum of activity. While both are highly effective against streptococci, Amoxicillin's amino group enhances its ability to penetrate the outer membrane of some Gram-negative bacteria, giving it activity against pathogens like Haemophilus influenzae and Escherichia coli.[36]
• Pharmacokinetics: Amoxicillin has a superior pharmacokinetic profile. It is more completely absorbed from the gut (higher bioavailability) and its absorption is not significantly affected by food, unlike Penicillin V.[24]
• Dosing: The better PK profile allows for less frequent dosing (typically twice or three times daily) compared to Penicillin V's typical four-times-daily treatment regimen, which can significantly improve patient adherence.[24]
• Clinical Niche: For strep throat, both are considered effective first-line options.[52] However, Amoxicillin is often preferred for infections like otitis media and sinusitis where H. influenzae is a common co-pathogen.[48] Despite Amoxicillin's advantages, Penicillin V's very narrow spectrum has secured its role in modern antimicrobial stewardship. In an era focused on minimizing resistance, using the narrowest effective agent is paramount. For a confirmed S. pyogenes infection, the additional Gram-negative coverage of Amoxicillin is unnecessary and exerts unwanted selective pressure on the microbiome. This principle is exemplified by the preference for Penicillin V for this indication in Scandinavian countries, demonstrating that "newer and broader" is not always "better".[9]

Parameter	Phenoxymethylpenicillin (V)	Penicillin G	Amoxicillin
Core Structure	Natural	Natural	Semi-synthetic (Aminopenicillin)
Key Side Chain	Phenoxymethyl	Benzyl	p-hydroxy-phenylglycyl
Acid Stability	Stable	Labile	Stable
Oral Bioavailability	Moderate (~60%), food-dependent	None	High (>80%), food-independent
Spectrum	Narrow (Gram-positive)	Narrow (Gram-positive)	Broad (Gram-positive and some Gram-negative)
Typical Oral Dosing Frequency	4 times daily	N/A	2-3 times daily
Primary Clinical Niche	Mild-moderate oral therapy for Gram-positive infections	Severe parenteral therapy for Gram-positive infections	Broad oral therapy for Gram-positive and some Gram-negative infections
Table 3: Comparative Profile of Phenoxymethylpenicillin, Penicillin G, and Amoxicillin

Regulatory Status and Brand Information

Regulatory Approvals

Phenoxymethylpenicillin's long history of use is reflected in its global regulatory approvals and its designation as an essential medicine.

• United States (FDA): First approved in 1958, it is available by prescription only (℞-only).[3] It is marketed under the generic name Penicillin V.[53]
• United Kingdom (MHRA): Approved in 1998.[12]
• Australia (TGA): Approved and subsidized under the Pharmaceutical Benefits Scheme (PBS).[54] The TGA has issued medicine shortage information for certain formulations, indicating periodic supply chain challenges.[56]
• World Health Organization (WHO): It is included on the WHO's List of Essential Medicines, signifying its role as a core antibiotic that should be consistently and globally available at an appropriate quality and price.[3]

Brand Names and Formulations

The drug is widely available as a generic medication.[3] In 2023, it was the 248th most commonly prescribed medication in the United States.[3] Common brand names include:

• Global/US: Veetids, Pen-Vee K, V-Cillin.[1]
• Australia: Cilicaine VK, LPV, Phenoxymethylpenicillin-AFT.[54]

Patent Status

As a drug discovered in the mid-20th century, all primary patents for Phenoxymethylpenicillin have long since expired. There are no significant patent barriers to the manufacturing of generic versions in the United States and other major markets.[53] This off-patent status contributes to its low cost but also makes it susceptible to market pressures. Its position as an old, low-cost generic with high clinical value but low commercial incentive for manufacturers can lead to fragility in the supply chain, a common paradox for older essential medicines that is evidenced by the periodic shortage notifications.[56]

Review of Current Research and Future Perspectives

Despite its long history, Phenoxymethylpenicillin is the subject of active clinical and pharmacological research aimed at optimizing its use in the context of modern medical challenges, particularly antimicrobial resistance. This demonstrates that the therapeutic lifecycle of an essential drug can be cyclical, with new research extending its utility in response to new challenges.

Synopsis of Recent Clinical Trials

• Optimizing Dosing for Pharyngotonsillitis: A primary focus of recent research has been to challenge the long-standing 10-day treatment course for GAS pharyngotonsillitis. A pivotal open-label, randomized, non-inferiority trial concluded that a shorter, 5-day course with a higher daily dose (800 mg four times daily) was clinically non-inferior to the standard 10-day regimen (1000 mg three times daily).[7] The 5-day regimen was associated with faster symptom relief and a lower incidence of adverse events, although bacteriological eradication rates were slightly lower.[7] A subsequent prospective study confirmed this clinical benefit in patients with both moderate (Centor Score 3) and severe (Centor Score 4) presentations, strengthening the case for the 5-day regimen as a future standard of care.[58]
• Ongoing and Other Trials: A Phase 4 clinical trial (NCT04083417) is currently recruiting to compare Penicillin V against no antibiotic treatment for patients with sore throat who test negative for GAS. This study aims to clarify the role of other potential bacterial pathogens, such as Fusobacterium necrophorum, and to promote more judicious antibiotic use.[59] Other completed trials have investigated its use in early Lyme disease (NCT01368341) and compared it to amoxicillin for community-acquired pneumonia (NCT03208361).[61]

Emerging Research Areas

• Pharmacokinetic Boosting: A recent randomized, crossover study in healthy volunteers confirmed that co-administration with probenecid significantly increases the serum concentrations of Penicillin V by inhibiting its renal excretion.[8] The analysis showed that this "boosting" effect could allow for a fourfold increase in MIC coverage. This finding has significant implications, suggesting the combination could be used to treat infections caused by less susceptible organisms, optimize dosing in complex outpatient settings, or potentially mitigate the impact of drug shortages by allowing lower doses to be effective.[8]
• Ecological Impact on Gut Microbiota: Traditionally viewed as having a limited impact on the gut flora due to its narrow spectrum, a recent study challenged this perception. It found that modern, higher-dose regimens of Penicillin V led to a significant increase in the proportion of ampicillin-resistant Enterobacterales and organisms with decreased susceptibility to third-generation cephalosporins in the fecal microbiota of treated patients.[65] This research highlights that even narrow-spectrum antibiotics exert considerable selective pressure and contribute to the reservoir of antimicrobial resistance genes. This expands the definition of drug safety beyond patient-centric adverse effects to include the broader ecological impact on the microbiome, a profound shift in clinical pharmacology.
• Novel Applications (Drug Repurposing): Pre-clinical research has explored new uses for Phenoxymethylpenicillin beyond its antimicrobial activity. One study identified it as a potential inhibitor of mushroom tyrosinase, an enzyme responsible for browning in fruits and vegetables. This suggests a novel application in the food industry as a food preservation agent.[53]

Future Perspectives and Concluding Remarks

Phenoxymethylpenicillin, a foundational antibiotic, is far from obsolete. Its value is being re-contextualized in the modern era of antimicrobial stewardship, where its narrow spectrum of activity is a distinct therapeutic advantage. Future research will likely continue to focus on refining its use by validating shorter, more potent dosing regimens to improve patient adherence and reduce total antibiotic exposure. Furthermore, the clinical potential of pharmacokinetic boosting with probenecid to overcome emerging resistance and manage supply issues warrants further investigation. Finally, a deeper understanding of its ecological effects on the microbiome will be crucial for guiding its judicious use. Phenoxymethylpenicillin remains a vital, essential medicine whose optimal role in therapy is still being actively defined, ensuring its relevance for the foreseeable future.

Works cited

1. PENICILLIN V | 87-08-1 - ChemicalBook, accessed October 17, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5351620.htm
2. Penicillin - Wikipedia, accessed October 17, 2025, https://en.wikipedia.org/wiki/Penicillin
3. Phenoxymethylpenicillin - Wikipedia, accessed October 17, 2025, https://en.wikipedia.org/wiki/Phenoxymethylpenicillin
4. Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study - PMC - PubMed Central, accessed October 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8684501/
5. Phenoxymethylpenicillin (penicillin V) Monograph - Paediatric - Perth Children's Hospital, accessed October 17, 2025, https://pch.health.wa.gov.au/~/media/Files/Hospitals/PCH/General-documents/Health-professionals/ChAMP-Monographs/Phenoxymethylpenicillin.pdf
6. What is the dosing regimen for Penicillin V (Phenoxymethylpenicillin) for the treatment of Pharyngitis (Throat Infection)? - Dr.Oracle, accessed October 17, 2025, https://www.droracle.ai/articles/34024/what-is-the-dosing-regimen-for-penicillin-v-phenoxymethylpenicillin-for-the-treatment-of-pharyngitis-throat-infection
7. Penicillin V four times daily for five days versus three times daily for ..., accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/31585944/
8. Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections - PubMed Central, accessed October 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11271292/
9. Phenoxymethylpenicillin Versus Amoxicillin for Infections in Ambulatory Care: A Systematic Review. | DrugBank Online, accessed October 17, 2025, https://go.drugbank.com/articles/A178609
10. Identity - ECHA CHEM, accessed October 17, 2025, https://chem.echa.europa.eu/100.001.566/identity
11. Phenoxymethylpenicillin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 17, 2025, https://go.drugbank.com/drugs/DB00417
12. phenoxymethylpenicillin | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed October 17, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10920
13. CAS No : 87-08-1 | Product Name : Phenoxymethylpenicillin - API Standards - Pharmaffiliates, accessed October 17, 2025, https://www.pharmaffiliates.com/en/87-08-1-phenoxymethylpenicillin-api-pa6932000.html
14. Penicillin V | CAS 87-08-1 | SCBT - Santa Cruz Biotechnology, accessed October 17, 2025, https://www.scbt.com/p/penicillin-v-87-08-1
15. Penicillin V - CAS Common Chemistry, accessed October 17, 2025, https://commonchemistry.cas.org/detail?cas_rn=87-08-1
16. Penicillin V | C16H18N2O5S | CID 6869 - PubChem, accessed October 17, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Penicillin-V
17. Predicted GC-MS Spectrum - GC-MS (DB00417) | DrugBank Online, accessed October 17, 2025, https://go.drugbank.com/spectra/c_ms/11310
18. phenoxymethylpenicillin (PD010039, BPLBGHOLXOTWMN-MBNYWOFBSA-N), accessed October 17, 2025, https://www.probes-drugs.org/compound/PD010039/
19. Phenoxymethyl Penicillin | Drug Information, Uses, Side Effects, Chemistry, accessed October 17, 2025, https://www.pharmacompass.com/chemistry-chemical-name/phenoxymethyl-penicillin
20. CN104622834A - Preparation method of phenoxymethylpenicillin potassium tablet - Google Patents, accessed October 17, 2025, https://patents.google.com/patent/CN104622834A/en
21. Possibilities to Improve Benzylpenicillin and Phenoxymethylpenicillin Stability in Acidic Environment | The Journal of Critical Care Medicine - Acta medica marisiensis, accessed October 17, 2025, https://actamedicamarisiensis.ro/possibilities-to-improve-benzylpenicillin-and-phenoxymethylpenicillin-stability-in-acidic-environment/
22. (PDF) Stability of Penicillin V Potassium in Unit Dose Oral Syringes, accessed October 17, 2025, https://www.researchgate.net/publication/23028562_Stability_of_Penicillin_V_Potassium_in_Unit_Dose_Oral_Syringes
23. Stability of oral reconstituted penicillins - Sabinet African Journals, accessed October 17, 2025, https://journals.co.za/doi/pdf/10.10520/AJA00089176_824
24. About your medication PHENOXYMETHYLPENICILLIN O R AMOXYCILLIN - The Royal Children's Hospital, accessed October 17, 2025, https://www.rch.org.au/uploadedFiles/Main/Content/pharmacy/Amoxycillin_and_Phenoxymethylpenicillin.pdf
25. Biosynthesis of benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K) from glutathione S-derivatives - PubMed, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/2166024/
26. The Total Synthesis of Penicillin V, accessed October 17, 2025, https://pubs.acs.org/doi/pdf/10.1021/ja01521a044
27. pubmed.ncbi.nlm.nih.gov, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/2166024/#:~:text=%22In%20vitro%22%20synthesis%20of%20benzylpenicillin,(S%2Dphenoxyacetyl)glutathione.
28. Enzymatic synthesis of phenoxymethylpenicillin using Erwinia ..., accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/6438038/
29. en.wikipedia.org, accessed October 17, 2025, https://en.wikipedia.org/wiki/Phenoxymethylpenicillin#:~:text=Mechanism%20of%20action,-Further%20information%3A%20Penicillin&text=The%20mechanism%20of%20phenoxymethylpenicillin%20is,biosynthesis%20of%20cell%2Dwall%20peptidoglycan.
30. Phenoxymethylpenicillin 250mg Film-coated Tablets - Summary of Product Characteristics (SmPC) - (emc) | 10628, accessed October 17, 2025, https://www.medicines.org.uk/emc/product/10628/smpc
31. What is the mechanism of Penicillin V? - Patsnap Synapse, accessed October 17, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-penicillin-v
32. Phenoxymethylpenicillin Action Pathway (New) - PathWhiz, accessed October 17, 2025, https://pathbank.org/pathwhiz/pathways/PW126772
33. Pharmacology of Penicillin V (Phenoxymethylpenicillin) ; Pharmacokinetics, Mechanism of action, Uses - YouTube, accessed October 17, 2025, https://www.youtube.com/watch?v=DGFwhfEu0Fs
34. A Pharmacokinetic and Pharmacodynamic Study of Phenoxymethylpenicillin for Children, accessed October 17, 2025, https://ctv.veeva.com/study/a-pharmacokinetic-and-pharmacodynamic-study-of-phenoxymethylpenicillin-for-children
35. Pharmacokinetics of Phenoxymethylpenicillin in Volunteers, accessed October 17, 2025, https://karger.com/che/article-pdf/28/4/241/2390819/000238084.pdf
36. Penicillin - StatPearls - NCBI Bookshelf, accessed October 17, 2025, https://www.ncbi.nlm.nih.gov/books/NBK554560/
37. Phenoxymethylpenicillin : Indications, Uses, Dosage, Drugs Interactions, Side effects, accessed October 17, 2025, https://medicaldialogues.in/generics/phenoxymethylpenicillin-2723497
38. Pharmacokinetics of Penicillins ; Absorption, Distribution, Metabolism, Excretion - YouTube, accessed October 17, 2025, https://www.youtube.com/watch?v=3xGJywECOTg
39. PHENOXYMETHYLPENICILLIN = PENICILLIN V oral - MSF Medical Guidelines, accessed October 17, 2025, https://medicalguidelines.msf.org/en/viewport/EssDr/english/phenoxymethylpenicillin-penicillin-v-oral-16684434.html
40. Phenoxymethylpenicillin 250 mg/5ml Powder for Oral Solution - Summary of Product Characteristics (SmPC) - (emc) | 13526, accessed October 17, 2025, https://www.medicines.org.uk/emc/product/13526/smpc
41. Pen Vee K, Penicillin V (penicillin VK) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed October 17, 2025, https://reference.medscape.com/drug/pen-vee-k-penicillin-v-penicillin-vk-342483
42. How and when to take phenoxymethylpenicillin - NHS, accessed October 17, 2025, https://www.nhs.uk/medicines/phenoxymethylpenicillin/how-and-when-to-take-phenoxymethylpenicillin/
43. Side effects of phenoxymethylpenicillin - NHS, accessed October 17, 2025, https://www.nhs.uk/medicines/phenoxymethylpenicillin/side-effects-of-phenoxymethylpenicillin/
44. Penicillin-v - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Renal Dose, Hepatic Dose | Drug Index, accessed October 17, 2025, https://www.pediatriconcall.com/drugs/penicillin-v/859
45. Phenoxymethylpenicillin – Knowledge and References - Taylor & Francis, accessed October 17, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Phenoxymethylpenicillin/
46. Penicillin VK (Penicillin V Potassium): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed October 17, 2025, https://www.rxlist.com/penicillin-vk-drug.htm
47. Taking phenoxymethylpenicillin with other medicines and herbal supplements - NHS, accessed October 17, 2025, https://www.nhs.uk/medicines/phenoxymethylpenicillin/taking-phenoxymethylpenicillin-with-other-medicines-and-herbal-supplements/
48. Amoxicillin vs. Penicillin: Similarities, Differences & Prices - K Health, accessed October 17, 2025, https://www.khealth.com/learn/antibiotics/amoxicillin-vs-penicillin/
49. What is the difference between penicillin and amoxicillin? - Dr.Oracle, accessed October 17, 2025, https://www.droracle.ai/articles/8063/please-explain-the-difference-between-penicillin-and-amoxycillin
50. Amoxicillin vs. penicillin: Differences, similarities, and which is better for you - SingleCare, accessed October 17, 2025, https://www.singlecare.com/blog/amoxicillin-vs-penicillin/
51. Amoxicillin vs. Penicillin for Treating Infections - Verywell Health, accessed October 17, 2025, https://www.verywellhealth.com/amoxicillin-vs-penicillin-uses-efficacy-storage-safety-7564147
52. Penicillin vs. Amoxicillin for Strep Throat: Which Is Better? - GoodRx, accessed October 17, 2025, https://www.goodrx.com/classes/penicillin-antibiotics/penicillin-vs-amoxicillin
53. Market Analysis of Phenoxymethylpenicillin (Penicillin V) in the ..., accessed October 17, 2025, https://synapse.patsnap.com/blog/market-analysis-phenoxymethylpenicillin-penicillin-v
54. PHENOXYMETHYLPENICILLIN - Pharmaceutical Benefits Scheme (PBS), accessed October 17, 2025, https://www.pbs.gov.au/medicine/item/1705R-1789E-2965C-3363B-3364C-5012T-9143F
55. Phenoxymethylpenicillin (AFT) - Healthdirect, accessed October 17, 2025, https://www.healthdirect.gov.au/medicines/brand/amt,929833011000036109/phenoxymethylpenicillin-aft
56. phenoxymethylpenicillin potassium - medicine shortage information, accessed October 17, 2025, http://apps.tga.gov.au/Prod/msi/Search/Details/phenoxymethylpenicillin%20potassium?sort=date
57. A randomized controlled study of 5 and 10 days treatment with phenoxymethylpenicillin for pharyngotonsillitis caused by streptococcus group A - PubMed, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/27618925/
58. Clinical course of pharyngotonsillitis with group A streptococcus treated with different penicillin V strategies, divided in groups of Centor Score 3 and 4: a prospective study in primary care - PubMed, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/36368940/
59. Phenoxymethylpenicillin Recruiting Phase 4 Trials for Sore Throat / Tonsillitis Treatment, accessed October 17, 2025, https://go.drugbank.com/drugs/DB00417/clinical_trials?conditions=DBCOND0033906%2CDBCOND0014060&phase=4&purpose=treatment&status=recruiting
60. Study Details | NCT04083417 | Sore Throat in Primary Care - a Comparison of Phenoxymethylpenicillin and No Antibiotic Treatment | ClinicalTrials.gov, accessed October 17, 2025, https://www.clinicaltrials.gov/study/NCT04083417?term=PHENOXYMETHYLPENICILLIN%20POTASSIUM&rank=4
61. Phenoxymethylpenicillin Terminated Phase 3 Trials for Community Acquired Pneumonia (CAP) Treatment | DrugBank Online, accessed October 17, 2025, https://go.drugbank.com/drugs/DB00417/clinical_trials?conditions=DBCOND0037905&phase=3&purpose=treatment&status=terminated
62. Phenoxymethylpenicillin Completed Phase 4 Trials for Erythema Migrans of Lyme Disease / B. Burgdorferi Infection / Early Lyme Disease / Borrelia Infections Treatment - DrugBank, accessed October 17, 2025, https://go.drugbank.com/drugs/DB00417/clinical_trials?conditions=DBCOND0157594%2CDBCOND0161816%2CDBCOND0053286%2CDBCOND0167072&phase=4&purpose=treatment&status=completed
63. (PDF) Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections - ResearchGate, accessed October 17, 2025, https://www.researchgate.net/publication/382445096_Towards_pharmacokinetic_boosting_of_phenoxymethylpenicillin_penicillin-V_using_probenecid_for_the_treatment_of_bacterial_infections
64. A low-volume LC/MS method for highly sensitive monitoring of phenoxymethylpenicillin, benzylpenicillin, and probenecid in human serum - RSC Publishing, accessed October 17, 2025, https://pubs.rsc.org/en/content/articlehtml/2024/ay/d3ay01816d
65. Effects of penicillin V on the faecal microbiota in patients with pharyngotonsillitis—an observational study - PMC, accessed October 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9931529/